9 Premalignant Lesions of the Stomach

1. BACKGROUND

Dysplasia is the precursor lesion for the development of carcinoma throughout the gastrointestinal tract. Certain condi- tions, which may lead to the occurrence of dysplasia, are labeled precursor conditions. The most readily identified such condition is Barrett’s esophagus. All esophageal adenocarcinoma follows the sequence of intestinalized Barrett’s epithelium progressing to dysplasia and subsequently to adenocarcinoma with relatively measurable frequencies. Gastric dysplasia, however, is usually found in the setting of chronic atrophic gastritis. Unlike the Barrett’s lesion, there are no gross endo- scopic features or a demarcated anatomic location. Furthermore, patients with Barrett’s esophagus are at about the same risk for progression to cancer irrespective of ethnicity, environment, and socioeconomic status. However, these are all important factors contributing to gastric cancer risk in patients with atrophic gastritis. Finally, the symptoms of gastroesophageal reflux characterize the population at risk for Barrett’s, but there are no symptoms attributable to the development of chronic atrophic gastritis (CAG). This chapter reviews the premalignant gastric lesions and their management.

2. THE GASTRITIS–CANCER SEQUENCE

Based on epidemiological and pathological information, Pelayo Correa proposed a model of gastric carcinogenesis known as Correa’s cascade (1). He originally described the sequence as starting with chronic gastritis, which evolved to atrophy and intestinal metaplasia (IM). The metaplastic epithe- lium, as in Barrett’s, can become dysplastic and these cells can lead to invasive malignancy. The discovery of the pathogenic role of Helicobacter pylori places it at the site of initiation of

From: Endoscopic Oncology: Gastrointestinal Endoscopy and Cancer Management. Edited by: D. O. Faigel and M. L. Kochman © Humana Press, Totowa, NJ

Premalignant Lesions of the Stomach

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the sequence. In other words, H. pylori infection results in the chronic active gastritis that starts the process.

This model is a very useful way to approach the gastric cancer process. But the progression is not invariable. For example, chronic active gastritis may lead to duodenal ulcer, not gastric cancer. Diet, sanitary conditions, and genetics play a major role in gastric cancer development. Their impact is most likely related to the development of atrophic gastritis as well as further steps along the way. Duodenal ulcer disease arises in patients with H. pylori chronic active gastritis with- out atrophy, and a history of duodenal ulcer reduces the risk of gastric cancer. Not all atrophic gastritis is a result of H.

pylori. The gastric body predominant, type A or autoimmune, gastritis is associated with pernicious anemia and has a risk of gastric carcinoma.

Gastric cancers are subtyped as intestinal or diffuse. The Correa model fits the intestinal type with precursor conditions of atrophic gastritis and IM. H. pylori infection is more fre- quent in patients with the intestinal type than in the general population with an odds ratio (OR) of 2.49 (2). The diffuse type lacks precursor conditions, atrophic gastritis and IM are absent, but the OR for H. pylori infection vs the general popu- lation is 2.58, similar to the intestinal type (2).

The next sections review aspects of gastritis, IM, and dys- plasia as they relate to gastric cancer. But it is important to recall that these are not all inclusive in the paradigm of gastric cancer pathogenesis.

3. GASTRITIS

Probably no term in gastroenterology is so widely misused as gastritis. As an endoscopic finding it may be used to indicate redness of the mucosa, or whiteness, mucosal lesions, erosions or red dots, and the state of the stomach when yellow fluid is present. In this chapter, gastritis refers to the histological state,

9

specifically chronic active or atrophic. The types, their features, location, and associated diseases are summarized in Table 1.

As noted earlier, the types that do not lead to atrophy may be associated with increased gastric acid secretion and duode- nal ulcer. Mild IM may be present in the antrum. Consequently, the finding of IM on a gastric biopsy from the antrum is not clinically significant as regards cancer risk. H. pylori is the cause of the antral chronic active gastritis related to duodenal ulcer and, also, the pangastritis in which metaplasia is absent and acid secretion is normal. These subjects have no disease associations and are asymptomatic.

The two forms of atrophic gastritis are the conditions poten- tially associated with gastric cancer. Multifocal atrophic gas- tritis predominates in patients with intestinal-type gastric cancer. It involves the antrum and body and there are multiple foci of IM. The finding is especially common on the lesser curve near the angularis. H. pylori is an important causative factor but there are likely to be other significant cofactors such as diet and genetics. Gastric acid secretion is reduced and both gastric ulcer and gastric cancer may develop.

Body or corpus-predominant atrophic gastritis, which spares the antrum, is autoimmune in origin and is associated with anti- bodies to parietal cells and intrinsic factor. This results in perni- cious anemia. The IM is marked. There is achlorhydria leading to hypergastrinemia. There is an association with Hashimoto’s thyroiditis, insulin-dependent diabetes, and Addison’s disease.

There is an increased risk of cancer, 1.5–3 times the general population, but this is less than the sixfold risk of multifocal atrophic gastritis (3).

The finding of multifocal atrophic gastritis suggests that the subject may be at risk for pernicious anemia and/or gastric can- cer. Thus, it is a clinically relevant finding. To best diagnose the condition, biopsies should be taken from the antrum, incisura angularis, and body (4). There is great interobserver variability among pathologists for the diagnosis of atrophic gastritis.

Atrophy includes architectural distortion, loss of oxyntic glands, which are replaced by metaplastic pyloric glands (pseudopyloric metaplasia), and fibrosis. Multiple teams of

expert pathologists have been convened to create diagnostic criteria for the histopathological diagnosis. The original Sydney classification was published in 1991, updated in 1994, and there have been additional working groups since then. Thus, an accu- rate diagnosis requires appropriate gastric sampling and an experienced gastrointestinal pathologist.

4. DYSPLASIA

Gastric dysplasia is most often found in indistinguishable sites. In other words, the dysplastic mucosa is endoscopically no different from the surrounding mucosa. Dysplasia, manifest as an adenomatous polyp, is uncommon in the stomach. In a study of 1900 cases of early gastric cancer from Japan, 95%

arose in an epithelial change within atrophic gastritis and only 3% within an adenomatous polyp (5). Most gastric polyps are non-neoplastic, the most common are hyperplastic or fundic gland. Gastric adenomas represent about 8–10% of polyps in North American series (5). These adenomas are more often flat than polypoid or sessile and arise in the setting of multifocal atrophic gastritis. Dysplasia can be found on the surface of non- neoplastic polyps, but this is rare. It is reported in about 1% of hyperplastic or fundic gland polyps. An exception are those patients with familial adenomatous polyposis (FAP). About one-fourth of fundic gland polyps in FAP can be dysplastic (5).

The prevalence of gastric dysplasia in Western countries ranges between 0.5 and 3.75% with higher rates in patients with pernicious anemia or postgastric resection, 4–40% (6).

As elsewhere in the gut, dysplasia is graded as low or high.

The importance of follow-up of patients with dysplasia is high- lighted by the fact that 60% of cancers found after the diagno- sis of dysplasia are early (6). About 15% of cases of low grade progress to high grade, and carcinoma can be diagnosed with an average follow-up of 10–30 mo. Progression from high- grade dysplasia to cancer is nearly universal, 80–85%. The diagnosis of adenocarcinoma follows the discovery of high- grade dysplasia by several weeks up to 39 mo (6). In fact, in a series of studies reviewed by Meining et al., gastric carcinoma was diagnosed in 75% of patients with high-grade dysplasia

Gastritis Classification

Acid Associated

Types Etiology Pathology secretion conditions

Antral H. pylori Chronic active Increased Duodenal

inflammation ulcer

of antrum with intestinal metaplasia

Pangastritis H. pylori Chronic active Normal None

inflammation of antrum and body, no intestinal metaplasia

Multifocal H. pylori Atrophy with Decreased Gastric ulcer

atrophic and environmental intestinal metaplasia in or cancer

gastritis or genetic factors antrum and body

Atrophic Autoimmune Body atrophy and Absent Pernicious

gastritis of intestinal metaplasia, anemia,

body none in antrum gastric cancer

several cofactors for gastric cancer. Most likely eradication, to be effective, needs to occur before the progression to extensive IM and gastric atrophy.

6. RISK FACTORS

The pathogenesis of gastric cancer is multifactorial, and numerous risk factors have been implicated with its develop- ment. Twin studies have demonstrated a relative risk of deve- loping gastric cancer of 9.9 for monozygotic twins and 6.6 for dizygotic twins, suggesting that both environmental and genetic factors are involved in the pathogenesis of gastric cancer (12).

Hereditary factors have been shown to play a role in the devel- opment of gastric cancer as evidenced by clustering of this dis- ease in families (13). In addition, studies have confirmed the effect of the environment on the incidence of gastric cancer by observing distinct variations in the incidence and mortality of gastric cancer among persons of different countries, and socio- economic groups (14). Specifically, first-generation immigrants from high-risk countries have been shown to consistently have incidence rates of gastric cancer similar to that of their home country, whereas subsequent generations have risk levels approximating that of the host country (15,16).

6.1. FAMILY HISTORY

A familial predisposition to gastric cancer has been demon- strated in several studies with approximately a two- to threefold increased relative risk (17–19). In one large cohort study of more than 1000 patients with gastric cancer, Palli et al. found a signif- icant association with a family history of gastric cancer in a sib- ling or a parent (adjusted OR, 2.6 and 1.7, respectively) after controlling for confounding risk factors. Moreover, they reported that gastric cancer risk was higher for subjects having an affected mother than an affected father (OR, 2.3 and 1.3, respectively), and also showed a further increase for subjects reporting both parents (OR, 3) or two or more siblings affected with gastric can- cer (OR, 8.5) (17). Others have confirmed this general increased risk but have failed to show a consistent pattern of risk with ref- erence to the type of first-degree relationship (20).

Familial clustering of gastric cancer defined by the presence of at least four cancer cases in family members has also been demon- strated in about 10% of cases (20,21). Some have suggested that this familial clustering of gastric cancer corresponds, in part, to the familial clustering of H. pylori infection by citing studies showing higher rates of H. pylori infection, hypochlorhydia, and atrophic gastritis in first-degree relatives of gastric cancer patients vs healthy controls (22). Despite these findings, investigators have argued that H. pylori infection alone cannot explain all of the family concordance of gastric cancer (23,24). They maintain that H. pylori infection within families seems to only explain a 36%

increase in family cancer rate, a smaller amount than the 100–300% increase in cancer risk that has been observed among first-degree relatives (23). Some experts argue that the response to H. pylori infection, rather than its mere presence is important in dis- ease outcome. They demonstrate that polymorphisms in proinflam- matory cytokine genes (tumor nectosis factor-α, interleukin-10, and interleukin-1) are associated with an elevated risk for the development of precancerous conditions for gastric cancer in H.

pylori infected patients but not in uninfected ones (24,25).

Table 2

Helicobacter pylori and Gastric Cancer Animal model—Mongolian gerbil demonstrating gastric

carcinogensis in chronically infected animals

Increased odds ratio for gastric cancer in H. pylori infected subjects especially if cagA-positive

Development of precancerous conditions, atrophy, and intestinal metaplasia, after H. pylori infection

Regression of those lesions, to some degree, after H. pylori eradication

within a mean of 8 mo (7). The authors indicated that the explanation for this result is likely a misdiagnosis of high- grade dysplasia rather than invasive carcinoma. In summary, the issue of dysplasia in chronic gastritis has some parallels to dysplasia in the setting of ulcerative colitis. In both cases sam- pling error and pathologists agreement are critical.

5. HELICOBACTER PYLORI

In 1994, the World Health Organization classified H. pylori as a human carcinogen. It is beyond the scope of this chapter to review the relevant evidence to support this finding. The evi- dence is summarized in Table 2. The principle issue to review here is the effect of H. pylori eradication on gastritis and gastric cancer risk. Because there is a long latency between the onset of H. pylori infection and the development of gastric cancer, prospective studies measuring the effect of eradication on develop- ment of cancer require decades of follow-up. Uemura et al. (8) found that there were no cancers in 253 patients treated success- fully for H. pylori after 7.8 yr of follow-up as compared with 36 cancers in 971 patients with persistent infection (8). Wong and associates studied 1630 healthy carriers of H. pylori after a 2-wk course of omeprazole, amoxicillin and clavulanate potas- sium (augmentin), and metronidazole or placebo. There was no difference found between treatment groups; 7 cancers devel- oped in the treated group and 11 in the placebo group. However, in the subgroup without precancerous lesions at baseline endoscopy, treatment seemed to be protective. Six patients with- out gastric atrophy, IM, or dysplasia developed cancer. All six were in the placebo group (9).

Recent studies have used surrogate end points of gastritis resolution as a sign of efficacy of H. pylori eradication. Sung et al. reported the effect of eradication on gastric histology after 1 yr. The degree of inflammation in both corpus and antrum decreased in the treated and the placebo groups, but there was less IM in the treated group. Neither group demon- strated a reduction in gastric atrophy (10). A similar study from Mexico failed to show much change in gastric histology with eradication of H. pylori after 1 yr (11).

A 5-yr follow-up of the patients described by Lauwers (6) has been reported by Lichtenstein et al. (12). Cancer risk was similar, four in the treated group and six in the placebo group.

The baseline histology changed in both directions: eight with IM at baseline developed cancer, in 26 the baseline IM resolved.

Progression of IM, which was found in 53% of patients, was

associated with persistent H. pylori infection, age, and some

environmental factors. In summary, H. pylori infection is one of

FAP and hereditary nonpolyposis colorectal cancer (HNPCC) also seem to confer an increased risk of developing gastric cancer in affected patients. Patients with FAP seem to have a 10-fold increased risk of developing gastric cancer com- pared with the general population (26), and those with HNPCC have an about 11% likelihood of developing gastric cancer (27). As such, endoscopic screening is recommended for these populations (28,29).

6.2. DIET

Several dietary facts have been implicated as risk factors for gastric cancer. The advent of widely available refrigeration, the consequent availability of fresh foods and the decreased con- sumption of preserved foods seem to have contributed to the significant decline in gastric cancer incidence observed in the second half of the last century (30). In line with this trend, many studies have shown that a high intake of highly salted and pre- served foods are associated with increased cancer risk (31–35).

Moreover, high salt intake has been associated with increased rates of atrophic gastritis in humans and animals in the setting of H. pylori infection (36). Preserved meat and nitrite intake have also been linked to increased cancer risk (37), possibly owing to the formation of N-nitroso compounds that are known carcinogens in animal experiments (38,39).

An inverse relationship between high consumption of fresh fruits and vegetables and incidence of gastric cancer has also been demonstrated (40–42). The protective effect of fresh fruits and vegetables seems to be in part owing to increased intake of antioxidant vitamins (41,43). The possible protective micronutrients include ascorbic acid (vitamin C), α-tocopherol (vitamin E), β-carotene, and selenium (

dants are believed to be free radical scavengers that reduce reactive radical-induced DNA damage (45). The evidence is strongest for ascorbic acid, with approx 50% risk reduction for gastric cancer in case–control studies (46). In addition, supple- mentation with ascorbic acid in a randomized controlled chemo-prevention trial in subjects with confirmed histological diagnoses of CAG or IM led to significant regression of these precancerous lesions (47). Alcohol ingestion, whereas previ- ously thought to play a role in gastric cancer development, seems not to be an independent risk factor (48,49). Cigarette smoking, however, has been consistently found to be a risk factor for gastric cancer (48,50) and has specifically been found to contribute to the progression of precancerous lesions to gastric cancer in a high-risk population followed with serial endoscopies (49).

6.3. PERNICIOUS ANEMIA

Pernicious anemia is a disorder characterized by autoanti- bodies to gastric parietal cells and intrinsic factor. The resulting CAG involving the parietal cells in the fundus of the stomach leads to achlorhydria, impaired intrinsic-factor secretion, and subsequent vitamin B

malabsorption. The antral mucosa, which is devoid of atrophy and achlorhydria, secretes large amounts of gastrin from antral G cells owing to the loss of nega- tive feedback of acid (51). Although the disease is typically silent until the final stage, gastric pathology may be present many years before the development of anemia (51). Progression to an advanced stage of the disease, which is characterized by

replacement of the normal parietal and zymogenic cells with those resembling IM and subsequent anemia, may take 20–30 yr (51). The significantly increased risk of progression to gastric mucosal dysplasia and even gastric carcinoma and gastric car- cinoid tumors has been widely reported, particularly in popula- tions with higher risks of gastric cancer and as such pernicious anemia is considered to be a risk factor for gastric cancer (51,52).

6.4. PARTIAL GASTRECTOMY FOR BENIGN DISEASE

Since its first description (53), numerous clinical studies have shown an increased incidence of gastric adenocarcinoma in patients who underwent stomach resection in comparison with the general population (54–56). Postgastrectomy cancers represent about 5% of all gastric cancers (57) and have been observed after Billroth I and II resections, with some reports of a higher incidence after the latter reconstruction (54,56,58).

Animal studies have also shown that gastric resection promotes carcinogenesis (59). The stump carcinoma is often found to be localized at or near the surgical anastomosis, and only rarely does it reside on the intestinal side of the anastomosis (60). The increased incidence of cancer is thought to be owing to reflux of intestinal contents and bile into the gastric remnant (61). In addition, formation of N-nitroso carcinogens from nitrate and nitrite by gastric bacteria, which have overgrown owing to post- operative hypochlorhydia may play a role (54,59).

The development of carcinoma of the gastric remnant seems to be directly related to the postoperative time interval. Studies have consistently shown no differences between the expected and observed number of cancers occurring within 15 yr after gas- tric resection. However, the overwhelming majority of these stud- ies do indicate a two- to fourfold increase in the risk of gastric cancer in patients who survived 15 or more years after gastric surgery (54–56). Moreover, an association between initial surgi- cal indication and subsequent risk of stomach cancer has also been shown, with patients, who underwent surgery for gastric ulcer, having a twofold increased risk for stump cancer (54,56).

7. SCREENING AND SURVEILLANCE

Identification of preneoplastic conditions and early detec- tion of gastric cancer is of great therapeutic and prognostic importance, particularly in parts of the world where gastric cancer prevalence is high. As such, mass screening of asymp- tomatic populations has been carried out in various endemic areas of the world with varying results. Moreover, surveillance programs in high-risk patients with preneoplastic lesions has been advocated by some. The patients targeted for screening are summarized in Table 3.

7.1. MASS POPULATION SCREENING

Mass screening programs of asymptomatic persons have

been implemented in parts of the world with a high prevalence

of gastric cancer with varying success (62–66). In Japan, mass

screening has lead to increased detection of early gastric cancer

(62), with case–control studies suggesting that detection of these

more favorable lesions has resulted in up to a 50% reduction of

gastric cancer mortality in the screened population (63). In a

recent study, Inaba and colleagues reported a risk ratio of 0.72

of dying from gastric cancer in more than 24,000 Japanese patients

who underwent screening endoscopy and were followed for 40 mo (64). Although this data supports the survival benefit of con- ducting routine endoscopic screening in high-risk populations, the cost-effectiveness of such an approach remains unknown.

However, similar mass screening programs are unlikely to be effective in Western countries, in large part owing to the significantly lower incidence of gastric cancer in this popula- tion. As such, the most recent guidelines by the American Society of Gastrointestinal Endoscopy does not support mass screening of this population group (29).

7.2. CHRONIC ATROPHIC GASTRITIS

The progression of CAG to dysplasia and even adenocarci- noma has been reported in the literature leading some to rec- ommend endoscopic surveillance of these lesions (67,68).

Although there is some controversy over the management of these lesions, the majority of experts however agree that rou- tine endoscopic surveillance for progression to dysplasia or even gastric cancer in low-risk countries such as the United States is not cost-effective and not indicated (3,29). They cite studies showing that this progression seems to be relatively slow with a long latency period (67). Moreover, this associa- tion seems to be most pronounced in areas such as regions of South America or eastern Asia were the prevalence of gastric cancer is high. In addition, despite findings for progression of this lesion, studies have demonstrated that many patients with CAG have no progression or actually have regression on serial gastric biopsies, particularly with the eradication of H. pylori (69). A role for surveillance endoscopy has been suggested in patients with CAG and a higher risk of developing gastric car- cinoma on the basis of family history, racial or ethnic origin, or emigration from an area endemic for gastric cancer (3). The frequency or cost-effectiveness of this approach is unclear.

7.3. INTESTINAL METAPLASIA

Gastric IM is considered a premalignant condition, how- ever, controversy exists regarding whether these lesions war- rant endoscopic surveillance for malignant progression. Most investigators agree that surveillance endoscopy is not indicated for IM, in general (70–72). However, some experts have sug- gested that a subtype of IM is more closely associated with gastric cancer and therefore argue that close endoscopic moni- toring of this subtype of IM is necessary (70,73).

Other investigators maintain that IM is common in Western countries with a reported prevalence of up to one-fourth of the general population (74), and that the overall risk of malignant progression is extraordinarily low, particularly in populations with a low gastric cancer prevalence (72). Moreover, they state

that the likelihood that subsequent surveillance of individuals with IM would increase detection of curable gastric cancers in such a low-risk cancer population is extraordinarily low unless dysplasia is also present (72). Regarding subtyping IM, they refer to recent studies conducted in the United States showing no progression to gastric carcinoma in patients followed with serial endoscopy for these lesions (75,76). At the same time, they point out that routine endoscopic surveillance of IM would be problematic because this lesion is endoscopically invisible in the majority of cases and that surveillance would be difficult without the use of expensive techniques such as tissue staining (chromoendoscopy) (72,77).

Given the combination of low sensitivity and likely high cost of serial endoscopic procedures current guidelines state that endoscopic surveillance of IM is not routinely indicated (29).

An endoscopic surveillance program may be considered in patients who come from a population at high risk for gastric cancer or have a positive family history of gastric malignancy, although the exact efficacy, frequency, or appropriate technique (e.g., chromoendoscopy) of a such a program is unclear (72).

7.4. DYSPLASIA

Follow-up studies have clearly established the high risk of malignant progression of gastric dysplasia (78–80). The man- agement of dysplasia depends in large part on the severity of the lesion detected since the chronology of progression from one dysplastic grade to a higher grade or to invasive adeno- carcinoma varies. High-grade dysplasia has been shown to progress to gastric carcinoma in as little as a month, suggest- ing concomitant invasive carcinoma, to about 39 mo with a mean between 4 and 23 mo (78). Low-grade dysplasia, however, has been found in most series to lead to gastric carcinoma on average between 10 and 30 mo but has been reported in as early as 1 mo following initial diagnosis of dysplasia, again suggesting concomitant invasive carcinoma (78). In the past, discrepancies in the diagnosis of gastric dysplasia vs carci- noma between Western and Japanese pathologists have com- plicated interpreting the literature and thus the management of these lesions (78,81).

With this in mind, it is critical that whenever dysplasia is diagnosed, one should get a second opinion from another pathologist, if the diagnosis was made by a pathologist who may not see many such cases (82–84). As soon as a diagnosis of dysplasia is confirmed, many experts suggest that immedi- ate endoscopic reevaluation be undertaken to map the extent of dysplasia and to rule out concomitant gastric carcinoma (82–84). This should be done by taking biopsy specimens near any visible lesions if present, and from the rest of the stomach (e.g., eight samples equidistant from each curvature) (82).

Few experts have suggested that dysplasia of any grade should be resected citing studies showing progression to higher grade of dysplasia or even gastric carcinoma in patients even with low-grade dysplasia on initial biopsy specimens (82). On the other hand, a few have argued that careful endoscopic monitoring is sufficient for all grades of dysplasia with closer intervals for those with more advanced lesions (85). However, most investiga- tors agree that surgical resection, whether total or subtotal, should be performed for cases in which high-grade dysplasia has been

Screening Recommendations Positive family history

FAP/HNPCC history Pernicious anemia

Postgastrectomy patients, after 15–20 yr

Multifocal atrophic gastritis with other associated genetic or environmental factors

FAP, familail adenomatous polyposis; HNPCC, hereditary nonpoly- posis colon cancer.

confirmed because of the intimate association of this lesion with invasive gastric adenocarcinoma (79,83,84,86). As always, the age and general condition of the patient must be taken into account and in some instances a less aggressive approach may be appropriate. More recently, endoscopic mucosal resection has become a less radical alternative to gastrectomy in the manage- ment of severe dysplasia located in focally identifiable lesions (78). If resection is reserved for severe grades of dysplasia, lesions of lesser severity require close endoscopic surveillance (78,84). Follow-up of low-grade dysplasia has been recom- mended every three to 12 mo at least during the first year (84).

The duration of such follow-up is not clear (78).

7.5. POST GASTRECTOMY

Studies have repeatedly demonstrated an increased risk of gastric stump cancer 15–20 yr following partial gastrectomy for benign conditions (54,56,87,88). Although the risk is highest in countries with high gastric cancer rates, studies conducted in Western countries including the United States also demon- strate an elevated risk of gastric remnant carcinoma (89). At the same time, endoscopic screening programs of this patient population have demonstrated a dramatic survival improve- ment when resection is performed for early-stage gastric rem- nant cancer (89,90).

Surveillance programs of patients who have undergone partial gastrectomy for benign disease have recommended screening endoscopy starting 15–20 yr postsurgery in order to detect malig- nancy at an earlier stage and in turn improve prognosis (88,89,91,92). A few have shown that the risk of gastric carci- noma is not significantly higher in the postgastrectomy patient as compared with the general population and have thus recom- mended that screening for neoplastic progression is not neces- sary (93,94). Accounting for this discrepancy is the fact that the majority of the latter studies had a follow-up period less than 20 yr, which is often inadequate given the longer latency of malig- nant progression in this population. Despite the findings of a significantly elevated risk of gastric cancer, the cost-effectiveness of such surveillance has not been well established, leading to guidelines stating that such surveillance is not indicated in low-risk countries (29). Yet, in populations at higher risk, screening endoscopy may be considered 15–20 yr postgastrec- tomy. Since early cancer in the gastric remnant may occur in the absence of a gross lesion, multiple biopsies should be obtained and a significant number of these specimens should come from the anastomotic area in which cancer is most likely to be found (60). A finding of high-grade dysplasia has been shown to be a good marker for the development or the presence of malignancy and surgical resection is recommended.

However, it is important that dysplasia not be confused with reactive gastritis that is common to the postoperative stomach and likely represents regenerative atypia.

7.6. PERNICIOUS ANEMIA

An excess risk of gastric carcinoma and carcinoid tumors have been reported in long-term endoscopic surveillance stud- ies of large cohorts of patients with pernicious anemia (51,52).

As such, endoscopic screening protocols have been suggested for the early detection of gastric neoplasia and malignancy (95).

Many experts recommend that patients with pernicious anemia

should have upper endoscopy with biopsy shortly following initial diagnosis. At least six biopsies should be obtained from the fundus and body spaced equidistant along the lesser and greater curvature. In addition, four specimens should be obtained from the antrum. It is important to keep in mind that biopsies of the thinner mucosa along the lesser curvature or in the transition zones (antral-body and cardiac-body) could be misinterpreted as atrophic and therefore are not ideal in diag- nosing severe fundic gland gastritis. In the majority of patients in whom dysplasia, adenomatous neoplasms, or carcinoids are not found, further endoscopic surveillance is not necessary (29);

except possibly for those patients with a first-degree relative with gastric cancer in which case, repeat endoscopy should be considered every 5 yr (96).

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