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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e318220f792
Review Articles

Early Gastric Neoplasia: Diagnosis and Implications

Alfaro, Eduardo Enrique MD*; Lauwers, Gregory Y. MD

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Author Information

*Department of Pathology, Hospital Mexico, C.C.S.S., La Uruca, San José, Costa Rica

Department of Pathology, Massachusetts General Hospital, Gastrointestinal Pathology Service, Boston, MA

Financial interest: The authors do not have any financial support or interest in the products or companies described in this study.

Funding: No public or private funding was received.

The authors declare no conflicts of interest.

Reprints: Gregory Y. Lauwers, MD, Department of Pathology, Pathology Service, Massachusetts General Hospital, 55 Fruit Street, Warren 2, Boston, MA 02114-2696 (e-mail: glauwers@partners.org).

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Abstract

Early gastric neoplasia, which includes dysplasia and adenocarcinoma invading no more than the submucosa have been the subject of numerous studies in recent years. For example, different dysplastic phenotypes have been identified, in addition to the traditional adenomatous type, foveolar, pyloric, and tubule-neck dysplasia (associated with diffuse type carcinoma) have been recognized. Each subtype of dysplasia shows a different immunohistochemical profile, and may vary in their risk of progression to adenocarcinoma. With regard to early gastric cancer the emergence of better diagnostic techniques allowed the development of endoscopic techniques such as endoscopic mucosal resection and endoscopic submucosal resection that nowadays allow optimal nonsurgical management. The purpose of this review is to discuss the current concepts in gastric dysplasia and early gastric cancer as they relate to diagnosis and management.

Gastric cancer is the fourth most common cancer and the second most frequent cause of death from cancer with 738,000 deaths a year worldwide.1 In the United States 21,130 new cases of stomach cancer were diagnosed in 2009.2 Cancer of the antropyloric region is more common in high-risk regions (Asia, eastern Europe), whereas tumors of the proximal stomach occur more often in low-risk regions (North America, northern Europe).3,4 Despite a decline in incidence over the last decades, and likely because of the aging of the worldwide population, the absolute incidence of gastric cancer has risen.1

Aside from carcinomas of the proximal stomach, which, at least in areas of low incidence, share many risk factors with esophageal adenocarcinomas, the prevalence of gastric cancer is closely related to prevalence of Helicobacter pylori infection. Prospective case-control studies suggest that 35% to 55% of gastric carcinomas may be related to chronic H. pylori infection.5 Similar to gastric cancer, dysplasia shows wide geographic variations in incidence ranging from <4% in western countries to 20% in countries with a high prevalence of H. pylori infection.6 However, some regions with a high incidence of H. pylori (eg, in sub-Sahara Africa) show a low rate of gastric cancer, indicating that other factors are involved in carcinogenesis. Some of these other factors include H. pylori virulence factors such as CagA, VacA, or BabA expressed by certain strains; smoking; dietary factors (high intake of salt-preserved and/or smoked foods); and genetic susceptibility.7–16

Most cases of gastric adenocarcinoma represent the end stage of the so-called Correa multistep gastric carcinogenesis sequence (gastric atrophy, intestinal metaplasia, dysplasia, and cancer).17 Although gastric atrophy and intestinal metaplasia elevate the risk for the development of gastric cancer, gastric epithelial dysplasia (GED) is considered a neoplastic lesion and a direct precursor of gastric cancer.17–26

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GASTRIC EPITHELIAL DYSPLASIA

Gastric dysplasia represents the penultimate stage of the gastric carcinogenesis sequence.27 It is characterized by cellular atypia reflective of abnormal differentiation, and disorganized glandular architecture. Most patients who present with GED are in the sixth to seventh decade of life, and most are male. GED is most often detected on the lesser curvature in the antrum and incisura angularis. In some cases, no characteristic endoscopic abnormalities are noted, but various abnormal endoscopic patterns have been described as well—mucosal irregularity in a background of atrophic mucosa, erosions, ulcers, mucosal scars, diffuse inflammatory changes, plaques, and polyps.28–32

Historically, the greatest challenge with respect to GED has been to establish a classification system reproducible and with clinical significance.

In the classic Japanese group classification, dysplastic lesions correspond to group III (borderline lesions between benign non-neoplastic and malignant lesions, eg, adenomas) and group IV (lesions strongly suspected of being carcinoma).33 In Western countries in the early 1980s, the guidelines for the diagnosis and grading of gastric dysplasia embraced a 3-tiered system of mild, moderate, and severe dysplasia, and dysplasia was defined as “unequivocally neoplastic epithelium that may be associated with or give rise to invasive adenocarcinoma.”34–36 In 1995, Rugge et al37 demonstrated that only moderate and severe dysplasia were significantly associated with a risk of developing carcinoma, and proposed to combine these 2 categories. Consequently, a 2-tiered classification of low-grade and high-grade dysplasia, proved to be more reproducible and to provide clinical relevant risk stratification.29,38–40

It became evident in the late 1990s that there were significant differences between Japan and Western countries in classifying gastric dysplasia and diagnosing carcinoma. Although the complexity of architectural features and nuclear atypia have been considered of paramount importance for the diagnosis of carcinoma in Japan, the breach of the basement membrane and invasion into the lamina propria have been considered the sine qua non characteristics of malignancy in the West.41,42 Consequently, noninvasive intramucosal neoplastic lesions with high-grade cellular and/or architectural atypia are classified as “intramucosal carcinoma” in Japan, whereas similar lesions are diagnosed as “high-grade dysplasia” by most Western pathologists. In an attempt to close the gap between the Japanese and Western views and reporting schemes, 38 pathologists from Asia, North America, Europe, and Australia gathered in 1998 in Vienna and designed the Vienna Classification for Gastric Epithelial Neoplasia (Table 1).40 Independently, in 2000 and 2010, the World Health Organization (WHO) proposed a classification of intraepithelial gastric neoplasia using the terms negative for dysplasia, indefinite for dysplasia, low-grade and high-grade dysplasia, and carcinoma (invasion into the lamina propria or beyond).44 Nevertheless, to date, the terminology of adenoma (raised lesions) and dysplasia (flat lesions) remains widely used in Western literature, and in clinical practice.26

Table 1
Table 1
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Grading of Gastric Dysplasia

The recently published updated WHO classification categorized gastric dysplastic lesions into several categories: indefinite for intraepithelial neoplasia, low-grade intraepithelial neoplasia (low-grade adenoma; low-grade dysplasia), high-grade intraepithelial neoplasia (high-grade adenoma; high-grade dysplasia); noninvasive intramucosal carcinoma; and intramucosal invasive neoplasia (intramucosal invasive carcinoma).43

Indefinite for intraepithelial neoplasia: These lesions may mimic the morphologic appearance of dysplasia, including reparative and regenerative changes that may arise near gastric erosions or ulcerations, on severely inflamed mucosa, or in reactive or chemical gastropathy.26 It is important to recognize these changes to avoid overdiagnosis of dysplastic lesions, or overuse of the term “indefinite for intraepithelial neoplasia.” This term is meant for cases where a diagnosis cannot be established with certainty. It should be seen as a provisional designation, and certainly 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. Morphologic clues to the reactive nature of the changes include the presence of vascular congestion and a gradual rather than abrupt transition between the atypical and adjacent normal cells.35,36 Practically, examination of deeper sections or consultation with a gastrointestinal pathologist is encouraged, as well as an attempt to obtain most suitable biopsies.43

Low-grade intraepithelial neoplasia (low-grade adenoma; low-grade dysplasia): In most cases, the morphologic appearance is reminiscent of colonic adenomas, with minimal architectural disarray and cytological atypia (Fig. 1A, B). The lesions often occur on a background of intestinal metaplasia. The term “adenoma” is usually used for elevated mucosal lesions, and “low-grade dysplasia” for flat lesions.35,36,42,45,46 The criteria for separating type II dysplasia into low and high grades are not well established. The presence of gastric foveolar type epithelium with elongated, hyperchromatic nuclei that show some degrees of pseudostratification is categorized as low-grade type II dysplasia (Fig. 1E). The management for these lesions should be treatment of inflammatory and noninflammatory conditions, followed by endoscopy and biopsies.43

Figure 1
Figure 1
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High-grade Intraepithelial Neoplasia (High-grade Adenoma; High-grade Dysplasia)/Noninvasive Intramucosal Carcinoma: The lesions in this category are characterized by marked cytological atypia or architectural complexity. High-grade dysplastic glands are commonly lined by rounded, pleomorphic nuclei with prominent nucleoli and loss of polarity. Irregularities of the nuclear membrane and clumping of chromatin are characteristic as well. Typical or atypical mitoses may be present in either low-grade or high-grade dysplasia, but are more often and more easily discernible in the latter category (Fig. 1B, C).39,42,46 Although some architectural changes are seen, marked glandular crowding, budding, and intraluminal bridges should raise the question of early gastric cancer (EGC). These lesions should be managed by endoscopic mucosal resection (EMR) or submucosal endoscopic resection.43

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Phenotypic Variants of Gastric Epithelial Dysplasia

The majority of GEDs display an intestinal phenotype similar to colonic adenomas that is sometimes qualified as adenomatous dysplasia or type I dysplasia. This phenotype is characterized by crowded, tubular glands lined by columnar cells with pseudostratified, overlapping, pencillate, and hyperchromatic nucleoli with inconspicuous nucleoli (Fig. 1A, B).26,47

Type II (nonadenomatous) dysplasia was described in 1979 by Cuello, and originally termed hyperplastic dysplasia. This form of dysplasia is characterized by foveolar-type epithelium. Architecturally, type II dysplasia is composed of glands of different size and shape with occasional cyst formation. The lining epithelium ranges from low cuboidal to columnar, with pale-to-clear cytoplasm, round-to-oval nuclei, and prominent nucleoli (Fig. 1C, E, F). Papillary infolding and gland serration can be seen. A small study reported that all cases were positive for MUC5AC and negative for MUC2 and CDX2, whereas 1 case presented focal MUC6 labeling (Figs. 2).48 Although some studies have suggested that this form of dysplasia is almost always low grade,49 more recent series indicate that type II dysplasia not only may be associated with a distinct clinicopathologic characteristics, but is more often high grade when evaluated in a high-risk population.50 Some investigators have also indicated that type II dysplasia is more commonly associated with poorly differentiated adenocarcinoma.47,51,52

Figure 2
Figure 2
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Another recently recognized variant of gastric dysplasia shows a pyloric phenotype. This type of dysplasia frequently presents as polyps and usually arises in the body-fundus mucosa on a background of autoimmune gastritis. This type is characterized by packed pyloric gland-type tubules with a monolayer of cuboidal to low columnar epithelial cells. The cells have a pale-to-eosinophilic cytoplasm that shows a ground glass appearance without an apical mucin cap. The nuclei tend to be round and usually lack prominent nucleoli (Fig. 3A, B). The neoplastic epithelium is distributed throughout the entire mucosa, and not only on the surface as in foveolar-type dysplasia. In contrast to intestinal type adenomas, the nuclei in pyloric type adenomas appeared more bland, rounded, and minimally stratified. Pyloric gland adenomas express MUC6 (pyloric mucin marker) and MUC5AC (foveolar mucin marker), and most lack MUC2 and CDX2.48 A single series indicates that its behavior is more akin to that of intestinal-type adenomas, and commonly shows high-grade dysplasia.48

Figure 3
Figure 3
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Dysplastic Changes in Gastric Polyps

Gastric polyps, which have a prevalence of 3.75% in the United States population, can display dysplastic changes.53

Dysplasia in fundic gland polyps: These are the most common type of gastric polyp in Western countries.53 They develop in a sporadic manner, in association with the use of proton pump inhibitors or in the setting of familial adenomatous polyposis (FAP).9,54 Among the latter, 7% to 51% of patients with FAP develop multiple fundic gland polyps, and surface epithelial cell dysplasia is noted in 25% to 50% of cases (Fig. 3C, D).55–65 Most of the researchers have found that fundic gland polyps associated with FAP with and without dysplasia carries APC mutations; and most sporadic and proton pump inhibitors-related nondysplastic fundic gland polyps carry β-catenin mutations. However, recent studies have shown that sporadic fundic gland polyps with dysplasia exhibit germline mutations in the APC tumor suppressor gene, rather than somatic mutations in the β-catenin gene.66–70 Regardless of whether they are sporadic or FAP-associated, fundic gland polyps with dysplasia very rarely progress to high-grade dysplasia or carcinoma. However, endoscopic surveillance is recommended.

Hyperplastic polyps: These polyps arise most frequently in the antrum in the setting of an inflamed and atrophic gastric mucosa. The incidence of this type of polyps has decreased along with the prevalence of H. pylori.71,72 Between 1% and 20% of hyperplastic polyps show proven foci of dysplasia and p53 gene mutations, chromosomal aberrations, and microsatellite instability. The overall prevalence of dysplasia in hyperplastic polyps is <2% and, it is more often seen in polyps >2 cm.73,74 All large hyperplastic polyps must be completely excised for histologic evaluation, and resection is believed to be curative even if dysplasia or intramucosal carcinoma is present.54

Adenomatous polyps: These lesions are composed of dysplastic epithelium without detectable invasion of the lamina propria.54 Adenomatous polyp is one of the steps in the development of gastric adenocarcinoma, and the larger the lesion, the greater the probability of finding foci of adenocarcinoma (up to 50% when >2 cm in size).54,75,76 These polyps are usually solitary, located in the antrum, <2 cm in diameter, are circumscribed, pedunculated, or sessile.77 A synchronous adenocarcinoma in another area of the stomach has been found in up to 30% of patients with an adenomatous polyp.76,78 Management of these lesions includes complete excision, a search for synchronous adenocarcinoma, and follow-up endoscopic surveillance at 1 year.54,75

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Special Types of Dysplasia

Tubule-neck (or globoid) dysplasia is an exceedingly rare lesion believed to represent a precursor of diffuse-type gastric carcinoma.79 It develops in nonmetaplastic epithelium. Morphologically, tubule-neck dysplasia displays enlarged, cuboidal cells with pale acidophilic cytoplasm and limited mucin production. Evidence of parietal or chief cell differentiation is absent. The nuclei are typically vesicular and enlarged, and contain prominent nucleoli. The nuclear membranes may be thickened.80 These atypical cells classically occupy the gland-neck region and are confined within the basement membrane. The mucosal surface and the deeper glands are commonly spared.26,79 The diagnosis of globoid dysplasia is challenging, and in most cases, the diagnosis can be made with certainly only in the presence of an associated diffuse-type gastric cancer.

The other precursor lesion associated with the development of diffuse-type gastric cancer is signet ring cell carcinoma in situ, which has been described in patients with hereditary diffuse gastric cancer (HDGC). HDGC was first described in 1964 in Maori families from New Zealand, and since has been shown to follow an autosomal dominant mode of genetic transmission, subsequently attributed to mutations of the E-cadherin (CDH-1).81,82 The gastrectomies of affected patients often show signet ring cell carcinoma in situ with a “pagetoid” spread between the gastric foveolar and glandular epithelium within the basement membrane (Fig. 4).83,84

Figure 4
Figure 4
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E-cadherin immunoexpression has been shown to be reduced or absent in early invasive gastric carcinomas, contrasting with the normal membranous E-cadherin expression in adjacent non-neoplastic mucosa. In pagetoid-spread lesions and in situ carcinomas, E-cadherin immunoexpression was also shown to be reduced or absent, and can be helpful for diagnosis.84

In 2010, Fitzgerald et al85 published new guidelines for clinical management of HDGC. Every patient with a positive CDH1 test should be considered for total gastrectomy with a Roux-en-Y reconstruction. If the patient refuses or decides to delay surgery, annual endoscopy should be performed using a white light high-definition endoscope in a 30-minute session including a careful inspection of the mucosa on inflation and deflation, with biopsy of any endoscopically visible lesions and, in addition, 6 randomly sampled biopsies of the antrum, transitional zone, body, fundus, and cardia, for a minimum of 30 biopsies. The gastrectomies should follow a specific protocol that includes mapping and processing the entire specimen for histology observation (usually resulting in 100 to 300 blocks per stomach). In New Zealand patients, the body-antrum transitional zone was the area most commonly affected by clusters of signet ring cell carcinoma in situ.86,87 However, in a series of cases reported by Rogers et al88 (USA), 70% of the total foci were localized in the proximal third of the stomach, as also in a series from the UK, with the highest number of foci observed in the fundus (44.7%) followed by the body (40.2%).89

Notably, in addition to an elevated risk of gastric cancer, approximately 40% of women with CDH1 mutation will develop lobular carcinoma of the breast, and also, there is emerging evidence for an increased risk of colon cancer that displays signet ring cell features.82,85

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Progression and Outcome of Gastric Dysplasia

A diagnosis of gastric dysplasia should alert the gastroenterologist that the patient has an increased risk of progression to gastric cancer.27 However, the rates of progression are variable, and differ between low-grade and high-grade dysplasia.

Low-grade dysplasia: Although assessing regression of low-grade dysplasia is difficult because of sampling issues and interobserver variation in the diagnosis, regression has been reported in 38% to 75% of cases, whereas persistence is seen in 19% to 50% of cases, depending on the study.30,90,91 In contrast, the progression of low-grade dysplasia to adenocarcinoma has been reported in 0% to 23% of cases within a variable time ranging from 1 to 4 years; however, recent studies indicate a lower risk of progression (0% to 9%).92,93

High-grade dysplasia: Has been noted to persist in 14% to 58% of cases, and the progression to cancer, in a median interval of 4 to 48 months, has been reported in 60% to 85% of cases.28–30,32,92,94,95 More recent data report a rate of malignant transformation between 10% to 100%.92,93 However, a diagnosis of carcinoma within 3 months of the diagnosis of dysplasia is more likely to represent failure to recognize a preexisting cancer rather than a true neoplastic progression. Regression, though, also has been reported, and varies from 0% to 16%.27

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EARLY GASTRIC CANCER

Definition

The concept of early gastric carcinoma was first established in Japan in 1962 by the Japanese Endoscopic Society. Early gastric adenocarcinoma was defined as a neoplasm that could be successfully treated by surgery.96 Nowadays, EGC is defined as any invasive adenocarcinoma confined to either the mucosa or submucosa, irrespective of the presence of lymph node metastases.44 These carcinomas are characterized as having a much better prognosis (90% 5-year survival rate) than the advanced stages of gastric carcinoma (60% or lower 5-year survival rate).97–99

Morphologically, the term “intramucosal invasive neoplasia” (intramucosal invasive carcinoma) refers to lesions that show clear invasion of the lamina propria in the form of single cells or small clusters of cells, and have marked architectural atypia in the form of fused glandular pattern, cribriforming, or intraluminal necrosis.26 The management of these lesions depend on the clinical evaluation, and includes surgical or endoscopic treatment.43

The disagreement between Western and Japanese pathologists in distinguishing between dysplasia (especially high grade) and intramucosal adenocarcinoma is well known. However, this problem may not be of great importance, taking into consideration 2 facts: (1) “invasion,” particularly when limited to the lamina propria, is difficult to identify on routine histology; and (2) intramucosal adenocarcinomas have a <10% risk of nodal metastases.97 Thus, neoplastic lesions with invasion of the lamina propria but confined to the mucosa, and cases of high-grade dysplasia, are, therefore, amenable to a conservative approach through endoscopic resection.

EGC represents a relatively stable biological stage, in contrast to advanced stages, which often progress rapidly. One retrospective follow-up study estimated the doubling time of early gastric carcinomas to be several years, but less than a year for advanced ones.100 Another prospective follow-up study of early gastric carcinomas revealed that many of these cases remained stable for a median duration of 3.7 years.101

In Western nations, EGC represents only 15% to 21% of all cancers diagnosed. In Japan, the importance of this diagnosis is shown in the high incidence of early gastric carcinomas, which represent more than 50% of all treated cases.44,97,102,103 These differences can be attributed to the higher prevalence of gastric cancer in Japan, but also to a more liberal use and better technique of upper endoscopy, including chromoendoscopy, and to differences in the diagnostic criteria, which can lead to Western pathologists considering as dysplasias (noninvasive neoplasms) lesions diagnosed as carcinomas by Japanese pathologists.

Most EGCs are small, measuring 2 to 5 cm, and located on the lesser curvature and around the angulus.38,104 Multiple tumors are seen in 3% to 13% of the patients, and are associated with a worse prognosis.97,105

Early gastric carcinomas metastasize to lymph nodes with an incidence of 2% to 3% for intramucosal neoplasms and 20% to 30% for carcinomas with submucosal invasion.106–110 The prognosis of EGC is excellent (5-year survival rate >90%)97,99; however, approximately 2% recur after curative resection, with intervals ranging from 4 months to more than 10 years.111

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Macroscopic Classification of Early Gastric Cancer

The classification of gastric carcinoma published by the Japanese Gastric Cancer Association divides lesions into 6 types (0 to 5) according to macroscopic appearance: Type 0 reflects tumors that invade no further than the submucosa (early gastric carcinomas) and types 1 to 5 correspond mostly to invasive adenocarcinomas. Type 0 (superficial) is subsequently divided into several subtypes (Table 2) (Fig. 5)112 according to a classification that also applies to the radiologic and macroscopic appearance of resected specimens.96

Table 2
Table 2
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Figure 5
Figure 5
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In 2002 in Paris, a workshop convening endoscopists, surgeons, and pathologists confirmed the value of the Japanese classification as a good indicator of the risk for nodal metastasis (low risk in types I or IIa114), and decided to adopt and adapt the classification so as to result in 5 major types (Table 2).112,113 Superficial (type II) EGC accounts for approximately 80% of the cases, with type IIc being the most common subtype.115 The subtype IIb accounts for 58% of tumors measuring <5 mm.116

It is important to keep in mind that approximately 10% of EGC have atypical endoscopic features and may be misdiagnosed as gastritis, erosions, or ulcers.117 Topical contrast agents such as indigo carmine help highlight subtle lesions.118 Newer imaging technologies, such as narrow-band imaging119 and autofluorescence imaging,120 are currently undergoing intense clinical evaluation.117

The histologic type and the depth of invasion influence the macroscopic appearance. Differentiated type 0IIc tends to be reddish with ill-defined margins or mild elevation at the edge. In contrast, undifferentiated tumors are characterized by an abruptly depressed margin, and are associated with secondary ulcers more often than differentiated lesions. Diffuse tumors tend to present as depressed or ulcerated lesions (type 0IIc and type 0III) and have a greater depth of invasion.114,121 Most type 0IIb carcinomas are intramucosal, although a few cases show submucosal invasion. However, once the tumor extends into the submucosa, the frequency of combined macroscopic types (eg, IIc type+IIb type) increases, and even simple type 0IIc lesions tend to show an uneven dull depressed surface.121

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Histologic Patterns of Early Gastric Cancer

The majority of EGCs are well differentiated glandular carcinomas. Tubular and papillary variants represent 52% and 37% of cases, respectively. Signet ring cell carcinoma and poorly differentiated carcinoma represent 26% and 14% of the cases, and are usually depressed or ulcerated (types IIc and III) (Fig. 3E, F).38,97,115

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Clinical Implications of Early Gastric Cancer

In a series of patients diagnosed with early gastric carcinoma and followed without surgery, 63% of the tumors progressed to advanced carcinomas over a span of 6 to 88 months.122 However, when resected, the prognosis of early gastric carcinomas is excellent, with a 5-year survival rate >90% in most series.97,123–126 The size and depth of invasion are the 2 major prognostic indicators; the larger the diameter, the greater the risk of submucosal infiltration.127–129 The risk of invasion should not be overlooked even in very small tumors; early gastric carcinomas of 3 to 5 mm, termed minute gastric carcinomas, invaded the submucosa in 3.3%130,131 to 9%132 of cases.

Analysis of EGC resection specimens show a variable rate of progression to advanced carcinomas. Kodama et al133 classified the growth patterns of early gastric carcinomas into 2 types—superficial (>4 cm in diameter, confined to the mucosa or with very limited invasion to the submucosa) and penetrating (<4 cm in diameter with submucosal invasion).

Ulceration is common in depressed-type early gastric carcinomas (type 0IIc and 0III). In these cases, there is a cycle of ulceration, healing, and reulceration such that these carcinomas remain at an early stage for an extended period, likely explained by tumor cell loss and the deterrent effect of fibrous scarring against invasion.100,134

The risk factors for lymph node metastasis from EGCs are age (<60 y), depressed macroscopic type, ulceration (including histologic ulcers or ulcer scars), large size (>2 to 3 cm), undifferentiated histologic type, lymphatic invasion and deep submucosal invasion (>500 μm), and a gastric mucin phenotype.106–110

The recurrence rate of EGC is approximately 2% after resection, with intervals ranging from 4 months to more than 10 years, with most important risk factors being submucosal invasion, lymph node metastasis, and differentiation.111 The recurrence rate of early gastric carcinoma with lymph node metastasis has been reported at 8%, and in those cases, the most common site of recurrence was lymph nodes.135 This indicates that these patients should be closely monitored, and considered for adjuvant chemotherapy.

The 5-year survival rate for mucosal gastric carcinomas is close to 100%, and for those invading the submucosa, 80% to 90%.97,128,129

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MANAGEMENT OF EARLY GASTRIC NEOPLASMS

Given the limited rate of malignant transformation of low-grade dysplasia and the development of newer endoscopic imaging techniques such as chromoendoscopy, such a diagnosis nowadays indicates the need for annual endoscopic surveillance with rebiopsy, and surgical resection is not necessary.136,137 Similarly, a diagnosis of indefinite for dysplasia should also prompt endoscopic surveillance and biopsy.

In the past, a diagnosis of high-grade dysplasia or intramucosal carcinoma was an indication for surgery; nowadays, high quality endoscopy and intraluminal endoscopic surgery, that is, EMR or ESD, allow for local curative and minimally invasive treatment.

It is interesting to note that western-style endoscopy training emphasizes the detection of gross lesions, and not the subtle changes in color, vascularity, or texture that are the hallmarks of EGC. In contrast, in Japanese endoscopic centers, simple routine measures may play a role in improving the endoscopic yield. Cleaning the endoscope lens with an alcohol-based swab before every procedure to remove residue that can cause subtle degradation of the image quality, and a systematic examination of the entire stomach during endoscope insertion and withdrawal, combined with an adequate air insufflation and endoscopic photography (30 to 40 photos) are common during a typical Japanese esophagogastroduodenoscopy.117

Over the past 20 years, EMR has been actively developed.138–144 This procedure is indicated when the risk of lymph node metastasis is minimal and the tumor can be removed en bloc.106,145–147 The histopathologic basis for the endoscopic resection of lesions was established in a landmark paper that analyzed 5265 patients who underwent gastrectomy with lymph node dissection for EGC.107 The key results were: (1) none of the 1230 well differentiated intramucosal cancers <30 mm diameter in size, regardless of surface ulceration, was associated with nodal metastasis [95% confidence interval (CI), 0-0.3%]; (2) none of the 929 intramucosal cancers without ulceration, regardless of size, was associated with nodal metastasis (95% CI, 0-0.4%); (3) none of the 145 differentiated adenocarcinoma <30 mm in diameter, without lymphatic or venous permeation, and with submucosal invasion of <500 um, was associated with lymph node metastasis (95% CI, 0-2.5%).

Consequently, the generally accepted standard criteria for EMR are elevated EGCs <2 cm in diameter and small (≤1 cm) depressed EGCs without ulceration.112 However, conventional EMR is not reliable for lesions >20 mm in diameter or lesions with ulceration.148,149 Furthermore, EMR in such cases is associated with a high risk of local recurrence (range, 2% to 35%), especially when resections are not accomplished en bloc or the margins are not clear.150

In an effort to solve limitations in the EMR technique, a new technique has been developed by Japanese endoscopists, dissecting directly along the submucosal layer using specialized devices, including a variety of endoscopic knives. This technique is known as endoscopic submucosal dissection (ESD).150–154

The advantage of ESD is to allow the removal in a single block of larger tumors, ulcerated neoplasms, or lesions where submucosal invasion or fibrosis after ulcer healing is suspected.117,148,152,155 The en bloc specimens allow precise histologic assessment of the depth of the invasion and the lateral resection margins, and as such may prevent residual disease and local recurrence.117,149,150,156 The extended criteria for endoscopic resection are shown in Table 3.117,150

Table 3
Table 3
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The principal complications of EMR and ESD are bleeding and perforation. Perforation in EMR is uncommon (<1%), and in ESD happens in approximately 4% of cases.150 In most instances, endoscopic closure without need for surgery is possible, and the patients may even stand up the following day.117 In 2009, Nakamoto et al151 reported a series of 177 patients (202 lesions) treated with either EMR or ESD, and found that the incidence of perforation tended to be higher after ESD than after EMR (2.5% vs. 0%). Isomoto et al153 also reported perforations in 25 patients of a series of 555 patients (4.5%), but all could be managed by conservative medical treatment after endoscopic closure with clipping.

The incidence of bleeding in ESD ranges from 6% as reported by Oda et al157 to as low as 1.8% in Isomoto et al153 series. In the study from Nakamoto et al,151 the incidence of bleeding requiring blood transfusion did not differ between EMR (0%) and ESD (1.6%) cases. In all series, the bleeding was successfully controlled by endoscopic treatment.151,153,157 Bleeding is more common in the treatment of lesions located in the upper third of the stomach, especially because those lesions require a more tangential approach of the endoscopes.157

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After Endoscopic Resections

A recent study of surveillance biopsies taken within 2 weeks post EMR underscored the difficulties in differentiating reactive changes versus persistent adenocarcinoma.158 Notably, increased glandular mitoses, epithelial anisonucleosis, and signet ring cell-like change were seen in 7.6%, 4.5%, and 6.1% of the cases, respectively. Thus, it is favored that the first follow-up gastroscopy should be performed at 3 months. Subsequently, gastroscopy should be repeated yearly to screen for metachronous lesions, and this for an indefinite period of time, depending on the patient's overall health. For patients with EGC that do not fulfill the histopathologic criteria for curative resection (cases with submucosal invasion exceeding 500 μm), but who refuse salvage surgery, close follow-up is needed, including the possibility of endoscopic ultrasound at 3 to 6-month intervals to detect perigastric nodal metastasis, and computed tomographic scans to detect distant metastasis.117

Finally, the eradication of H. pylori improves the prognosis of patients with early neoplasms. In a study of 132 patients with EGC who underwent EMR, no new cases of gastric cancer were observed after resection when H. pylori was eradicated; in contrast, 13.5% of untreated patients had new early-stage intestinal-type gastric cancer.159

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REPORTING ENDOSCOPICALLY RESECTED SPECIMENS

The histopathologic reporting of endoscopically resected specimens should include: grade of differentiation (well or moderately differentiated); the vertical margin, and if submucosal invasion is noted, the depth of invasion in micrometers; the lateral margin; and lymphatic and/or vascular invasion. If the histology criteria are fulfilled, there is a minimal to no risk of nodal metastasis, and the EMR and ESD are considered curative.117,150 If any of these criteria are not met, the patient is at risk of regional nodal metastasis, and should therefore undergo a radical gastrectomy. An exception may be made if only the lateral margin is positive, as repeat ESD or ablative therapy of the involved area, as mapped out by the pathologist, may be attempted. Therefore, the labeling by the endoscopist of the oral/anal orientation of the specimen is of great importance in the event that a lateral margin is found to be positive.117

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Keywords:

gastric dysplasia; gastric preneoplastic lesions; foveolar dysplasia; adenomatous dysplasia

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