19. Smith SR, Weissman NJ, Anderson CM, et al. Behavioral Modification and Lorcaserin for

Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial

of lorcaserin for weight management. N Engl J Med 2010;363(3):245–256.

20. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with

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controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a

randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012;95(2):297–308.

21. Payne JH, DeWind LT. Surgical treatment of obesity. Am J Surg 1969; 118:141–147.

22. Sudan R, Jacobs DO. Biliopancreatic diversion with duodenal switch. Surg Clin North Am

2011;91(6):1281–1293.

23. Arapis K, Chosidow D, Lehmann M, et al. Long-term results of adjustable gastric banding in a

cohort of 186 super-obese patients with a BMI≥ 50 kg/m2. J Visc Surg 2012;149(2):e143–e152.

24. Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg 2013;23(4):427–

436.

25. Sjöström L, Narbro K, Sjöström CD, et al. Swedish Obese Subjects Study. Effects of bariatric surgery

on mortality in Swedish obese subjects. N Engl J Med 2007;357(8):741–752.

26. O’Rourke RW. Management strategies for internal hernia after gastric bypass. J Gastrointest Surg

2011;15(6):1049–1054.

27. Maggard-Gibbons M, Maglione M, Livhits M, et al. Bariatric surgery for weight loss and glycemic

control in nonmorbidly obese adults with diabetes: a systematic review. JAMA 2013;309(21):2250–

2261.

28. Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists,

the Obesity Society, and American Society for Metabolic & Bariatric Surgery medical guidelines for

clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the

bariatric surgery patient. Obesity 2009;17(supp 1):S1–S70.

29. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and metaanalysis. JAMA 2004;292(14):1724–1737.

30. Maggard MA, Shugarman LR, Suttorp M, et al. Meta-analysis: surgical treatment of obesity. Ann

Intern Med 2005;142(7):547–559.

31. O’Brien PE, McPhail T, Chaston TB, et al. Systematic review of medium-term weight loss after

bariatric operations. Obes Surg 2006;16(8):1032–1040.

32. Garb J, Welch G, Zagarins S, et al. Bariatric surgery for the treatment of morbid obesity: a metaanalysis of weight loss outcomes for laparoscopic adjustable gastric banding and laparoscopic

gastric bypass. Obes Surg 2009;19(10):1447–1455.

33. Padwal R, Klarenbach S, Wiebe N, et al. Bariatric surgery: a systematic review of the clinical and

economic evidence. J Gen Intern Med 2011; 26(10):1183–1194.

34. Chang SH, Stoll CR, Song J, et al. The effectiveness and risks of bariatric surgery: an updated

systematic review and meta-analysis, 2003–2012. JAMA Surg 2013;149(3):275–287.

35. Yip S, Plank LD, Murphy R. Gastric bypass and sleeve gastrectomy for type 2 diabetes: a systematic

review and meta-analysis of outcomes. Obes Surg 2013;23:1994–2003.

36. Lynch J, Belgaumkar A. Bariatric surgery is effective and safe in patients over 55: a systematic

review and meta-analysis. Obes Surg 2012;22(9):1507–1516.

37. Trastulli S, Desiderio J, Guarino S, et al. Laparoscopic sleeve gastrectomy compared with other

bariatric surgical procedures: a systematic review of randomized trials. Surg Obes Relat Dis

2013;9(5):816–829.

38. Banka G, Woodard G, Hernandez-Boussard T, et al. Laparoscopic vs. open gastric bypass surgery:

differences in patient demographics, safety, and outcomes. Arch Surg 2012;147(6):550–556.

39. Finks JF, Kole KL, Yenumula PR, et al. Michigan Bariatric Surgery Collaborative, from the Center

for Healthcare Outcomes and Policy. Predicting risk for serious complications with bariatric

surgery: results from the Michigan Bariatric Surgery Collaborative. Ann Surg 2011;254(4):633–640.

40. Carlin AM, Zeni TM, English WJ, et al. Michigan Bariatric Surgery Collaborative. The comparative

effectiveness of sleeve gastrectomy, gastric bypass, and adjustable gastric banding procedures for

the treatment of morbid obesity. Ann Surg 2013;257(5):791–797.

41. Courcoulas AP, Christian NJ, Belle SH, et al. Longitudinal Assessment of Bariatric Surgery (LABS)

Consortium. Weight change and health outcomes at 3 years after bariatric surgery among

individuals with severe obesity. JAMA 2013;310(22):2416–2425.

42. Flum DR, Belle SH, King WC, et al. Longitudinal Assessment of Bariatric Surgery (LABS)

Consortium. Perioperative safety in the longitudinal assessment of bariatric surgery. N Engl J Med

2009;361(5):445–454.

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Chapter 47

Gastric Neoplasms

Hari Nathan and Rebecca M. Minter

Key Points

1 The presence of a gastric adenomatous polyp is a marker of increased risk for the development of

cancer in the remaining gastric mucosa, and therefore these patients should be enrolled in an

appropriate endoscopic surveillance program.

2 Helicobacter pylori infection is the predominant risk factor for gastric carcinogenesis. However,

additional cofactors also play an important role and likely drive the progression from a premalignant

condition to adenocarcinoma in most individuals.

3 The symptoms produced by gastric cancer are not specific and can mimic those associated with a

number of nonneoplastic gastroduodenal diseases, especially benign gastric ulcer.

4 The extent of gastric resection is determined by the need to obtain a resection margin free of

microscopic disease, and examination of a minimum of 15 nodes is suggested for adequate staging.

5 Multimodality treatment should be the standard of care for treating locally advanced resectable

gastric cancer.

6 Low-grade gastric MALT lymphomas are usually effectively treated with eradication of H. pylori

infection alone.

7 Almost all (95%) gastrointestinal stromal tumors (GISTs) express the KIT antigen, and this is an

important molecular target for medical therapy.

Gastric cancer is a relatively common, frequently lethal affliction and remains a serious and unsolved

problem in general surgery. The disease often is not recognized until it is at an advanced stage. Gastric

cancer usually cannot be controlled by surgery alone, and surgical cure rates have remained

disappointingly low. Increasingly, a multidisciplinary approach is being applied to these difficult

neoplasms, with some modest improvements in outcome finally being observed. Technical innovations

and basic scientific investigations continue to be applied to this disease, and cautious optimism for the

future is appropriate.

ADENOCARCINOMA

Epidemiology

Starting in 1930, the incidence of gastric cancer declined dramatically in the United States. By 1990, the

incidence of gastric cancer (10 cases per 100,000 population) was approximately one-fourth the

incidence recorded in 1930.1 By 2010, gastric cancer accounted for 2% of cancer deaths in the United

States, compared with 20% to 30% in the 1930s.1 Nevertheless, more than 22,000 new cases continue to

be diagnosed annually in the United States, with over 10,000 deaths per year attributable to the disease.

Worldwide, its impact is much larger, and gastric cancer remains the third leading cause of cancer death

among men and the fifth leading cause among women, accounting for 10% of cancer deaths overall.2 It

has long been thought that environmental exposures play a role in gastric carcinogenesis, a notion that

is supported by the finding that groups who migrate from regions with high prevalence of gastric cancer

to those with low prevalence experience a decreasing incidence of gastric cancer with time.3,4 It has

been theorized that dietary changes and reductions in smoking have contributed to decrease in gastric

cancer incidence in some parts of the world.2 Food preservation methods using large amounts of salt

and nitrites have been partially supplanted by improved refrigeration, and fresh fruits and vegetables

have become more widely available. The strongest known risk factor for gastric cancer, however, is

infection with Helicobacter pylori, which is associated with a six-fold increased risk of (noncardia) gastric

cancer.5,6 Approximately 75% of gastric cancer cases are attributable to H. pylori infection, making this

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organism the dominant infectious cause of cancer in the world.7

Due at least in part to these environmental factors, there is marked worldwide geographic variability

in the incidence of gastric cancer (Fig. 47-1).8 The highest incidence occurs in Eastern Asia, but Central

and Eastern Europe and South America also have high incidence of gastric cancer. The lowest incidence

of gastric cancer is seen in Africa and North America.2 In the United States, higher gastric cancer

incidence and mortality are seen in black, Asian American/Pacific Islander, American Indian/Alaska

Native, and Hispanic patients as compared with non-Hispanic white patients.1 The anatomic distribution

of gastric cancers also varies, with proximal cancers occurring more commonly in relatively younger,

white, and male patients.9

Premalignant Lesions

The risk for development of gastric cancer is greater in stomachs that harbor polyps. This risk is related

most closely to polyp histologic type, size, and number. Variations in these three factors account for the

wide range in reported risk associated with gastric polyps. In terms of malignant potential, gastric

polyps can be divided into two broad categories—hyperplastic polyps and adenomatous polyps.

Although not premalignant, hyperplastic polyps are discussed here because they are common,

occurring in up to 1% of the general population and accounting for 75% of all gastric polyps. The

hyperplastic polyp contains an overgrowth of histologically normal-appearing gastric epithelium. Atypia

is rare, and hyperplastic gastric polyps have no neoplastic potential. Hyperplastic polyps are generally

asymptomatic. Dyspepsia and vague epigastric discomfort are the most common complaints, although

coexistent gastroduodenal disease is also frequently identified. Complications are unusual, and

gastrointestinal hemorrhage occurs in less than 20% of patients. When hyperplastic polyps are

discovered, endoscopic removal for histologic examination is indicated and is sufficient treatment.

Subsequent surveillance is not necessary, given the lack of neoplastic potential in these polyps.

Figure 47-1. Worldwide geographic variability in gastric cancer incidence. (From Ferlay J, Soerjomataram I, Ervik M, et al.

GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International

Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on August 1, 2015.)

1 Adenomatous polyps also tend to be asymptomatic, but in contrast to hyperplastic polyps,

adenomatous polyps carry a distinct risk for the development of malignancy.10 Mucosal atypia is

frequent, and mitotic figures are more common than in hyperplastic polyps. Dysplasia and carcinoma in

situ have developed in adenomatous polyps observed over time. The risk for the development of

carcinoma has been estimated at 10% to 20% and is greatest for polyps more than 2 cm in diameter.

The presence of multiple adenomatous polyps increases the risk of cancer. The presence of an

adenomatous polyp is also a marker indicating a diffusely increased risk for the development of cancer

in the remainder of the gastric mucosa.

Endoscopic removal is indicated for pedunculated lesions and is sufficient if the polyp is completely

removed and shows no evidence of invasive cancer on histologic examination. Operative excision is

recommended for sessile lesions larger than 2 cm, for polyps with biopsy-proved invasive carcinoma,

and for polyps complicated by pain or bleeding. After removal, repeat endoscopic surveillance is

indicated to rule out recurrence at the site of previous excision, evaluate for new or missed polyps or an

early carcinoma, and confirm eradication of H. pylori, if applicable.

Gastritis

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The incidence of both gastric cancer and atrophic gastritis increases with age. Chronic gastritis is

frequently associated with intestinal metaplasia and mucosal dysplasia, and these histologic features are

often observed in mucosa adjacent to gastric cancer. Gastritis is frequently progressive and severe in the

gastric mucosa of patients with cancer.

Gastric malignancy seems to be increased in patients with chronic gastritis associated with pernicious

anemia, although the risk appears to have been overstated in the past. This disease, characterized by

fundic mucosal atrophy, loss of parietal and chief cells, hypochlorhydria, and hypergastrinemia, is

present in 3% of people older than 60 years. For people in whom pernicious anemia has been active for

more than 5 years, the risk of gastric cancer is twice that of age-matched control subjects. Patients with

pernicious anemia also have an increased risk of gastric carcinoid development. This increased risk

warrants aggressive investigation of new symptoms in patients with long-standing pernicious anemia,

but it is not high enough to justify repeated endoscopic surveillance.

Intestinal metaplasia, the presence of intestinal glands within the gastric mucosa, is also commonly

associated with both gastritis and gastric cancer. The evolution from metaplasia to dysplasia to

carcinoma to invasive cancer has been demonstrated in other organs and in adenocarcinoma arising in

the gastroesophageal junction. However, no direct evidence has been provided for this progression in

gastric cancer.

Helicobacter Pylori

2 As outlined above, infection with H. pylori has been unequivocally associated with chronic

inflammatory conditions in the stomach, and this association has stimulated interest in the role of

chronic infection by this organism in gastric carcinogenesis. Childhood acquisition of H. pylori infection

is frequent in areas of high gastric cancer incidence, and high rates of infection have been identified in

patients with premalignant lesions and invasive cancer. Infection with H. pylori is associated with an

increased risk of adenocarcinoma of both major histologic types (intestinal and diffuse) and of both the

body and the antrum of the stomach.11 In contrast, H. pylori infection is not a risk factor for cancers of

the gastroesophageal junction, which are frequently associated with mucosal abnormalities of Barrett

esophagus and which seem to follow the metaplasia to dysplasia to carcinoma pattern of development.

The mechanism of carcinogenesis related to H. pylori infection is incompletely understood but is

thought to be related to the chronic inflammation caused by the organism.12 However, only ∼1% of

patients chronically infected with H. pylori will develop the gastric cancer phenotype, which consists of

corpus-predominant gastritis, multifocal atrophic gastritis, high gastrin levels, hypo/achlorhydria, and

low pepsinogen I/II ratio. The majority of subjects infected with H. pylori will develop the simple

gastritis phenotype which is not associated with any significant clinical outcome, or the duodenal ulcer

phenotype (10% to 15% of infected subjects) which consists of antral-predominant gastritis and high

gastrin and acid secretion and actually provides protection from developing gastric cancer.13 Of note,

there is variable distribution of these three phenotypes geographically, with particular prevalence of the

gastric cancer phenotype in certain parts of Asia where gastric cancer is common.14 Bacterial virulence

factors, environmental exposures, and host genetic factors also clearly play an important role in the

pathogenesis of gastric carcinogenesis following infection-related gastritis.12,13,15 Eradication of H. pylori

may not prevent the development of gastric cancer once premalignant lesions have already developed.16

Previous Gastric Surgery

A number of uncontrolled reports have suggested that gastric cancer is more likely to develop in people

who have undergone previous partial gastrectomy, with patients who have undergone a gastrojejunal

(Billroth II) anastomosis at apparently higher risk for carcinogenesis than those reconstructed with a

gastroduodenal anastomosis (Billroth I).17,18 The so-called gastric remnant cancer is a true clinical entity,

although the risk for development of this gastric neoplasm appears to have been overestimated. Several

large, prospective studies with long-term follow-up indicate that the relative risk is not increased for up

to 15 years after gastric resection, likely due to surgical removal of mucosa at risk for development of

gastric cancer, followed by modest increases in cancer risk (three times the control value) observed only

after 25 years.19–22

The cellular mechanisms that contribute to the development of neoplasia in the remnant stomach are

unknown. Decreased luminal pH, bacterial overgrowth with increased production of N-nitroso

carcinogens, and reflux of bile acids into the stomach have been postulated to promote cancer

development, but remains unproved. Vagotomy, often performed in conjunction with gastric surgery for

benign disease, does not appear to promote cancer development. A population-based study from Sweden

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of 7,198 vagotomized patients followed for up to 18 years did not report increased risk.20

A recent study explored genetic alterations in gastric remnant cancer and found that the microsatellite

instability high (MSI-H) phenotype was much more common (43%) in gastric remnant cancers than in

sporadic gastric cancers (6%), and that this incidence was much higher in patients who had undergone a

Billroth II anastomosis (67%) as compared to those who had undergone a Billroth I anastomosis (11%).

The MSI-H phenotype in these tumors was associated with inactivation of the DNA mismatch repair

genes hMLH1 and hMSH2. The significance of this relationship is not yet clear.23 Reported 5-year

survival ranges from only 7% to 33% for gastric remnant cancers, but this poor prognosis is most likely

due to the fact that these cancers are usually diagnosed at an advanced stage when treatment options

are limited.

Hereditary Syndromes

Approximately 5% to 10% of gastric cancer may have a familial component, and 3% to 5% are

associated with known inherited cancer syndromes. Hereditary diffuse gastric cancer (HDGC) is an

autosomal dominant syndrome that confers a lifetime risk for the development of gastric cancer by age

80 years of 67% for men and 83% for women.24 The average age at diagnosis is 37 years, and cancers

tend to be of the diffuse type. Germline mutations in CDH1, a tumor suppressor gene that encodes the

cell-to-cell adhesion protein E-cadherin, are found in 25% of patients with HDGC.25 Patients with

documented CDH1 mutations and a family history of gastric cancer may be offered prophylactic

gastrectomy at a young age. Other familial cancer syndromes associated with an increased risk of

gastric cancer include Lynch syndrome, juvenile polyposis syndrome, and Peutz–Jeghers syndrome.

Surveillance upper endoscopy may be considered in patients with these syndromes.

Clinical Features

3 The symptoms produced by gastric cancer are nonspecific and can closely mimic those associated with

a number of nonneoplastic gastroduodenal diseases, especially benign gastric ulcer (Fig. 47-2). In early

gastric cancers, epigastric pain is present in over 70% of patients.26 The pain is often constant,

nonradiating, and unrelieved by food ingestion. In a surprising number of patients, pain can be relieved,

at least temporarily, by antacids or gastric antisecretory drugs. Anorexia, nausea, and weight loss are

present in less than 50% of patients with early gastric cancers but become increasingly common with

disease progression. Dysphagia is present in 20% of patients with proximal gastric lesions. Overt

gastrointestinal hemorrhage is present in only 5%. Perforation is uncommon (1%).

Figure 47-2. Clinical symptom frequency in benign gastric ulcer, early gastric cancer, and advanced gastric cancer. (After Meyer

WC, Damiano RJ, Postlethwait RW, et al. Adenocarcinoma of the stomach: changing patterns over the past four decades. Ann Surg

1987;205:18.)

In most patients with early gastric cancers, physical examination is unremarkable. Stool tests positive

for occult blood in one-third. Abnormal physical findings usually reflect advanced disease (Table 47-1).

Cachexia, abdominal mass, hepatomegaly, and supraclavicular adenopathy usually indicate metastasic

disease.27 There are no simple laboratory tests specific for gastric neoplasms.

Diagnosis and Staging

Fiberoptic endoscopy is the most definitive diagnostic method when gastric neoplasm is suspected. In

the initial stages, gastric cancers can appear polypoid, as flat, plaquelike lesions, or as shallow ulcers.

Advanced lesions are typically ulcerated. The ulcer border can have an irregular, beaded appearance

because of infiltrating cancer cells, and the base is frequently necrotic and shaggy. The ulcer can appear

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to arise from an underlying mass. Although each of these features suggests a malignant ulcer,

differentiation of benign from malignant gastric ulcers can be made definitively only with gastric

biopsy. Multiple biopsies of any gastric ulcer should be performed. The sensitivity of a single biopsy for

diagnosing a gastric cancer is 70%, but performing multiple biopsies can increase the sensitivity to

greater than 98%.28 False-negative results occur in approximately 10% of patients, usually as the result

of sampling error or due to the absence of a mucosal abnormality as can occur with linitis plastica; falsepositive results are rare. Diagnostic accuracy can be further enhanced by the addition of endoscopic

ultrasound (EUS) with fine-needle aspiration biopsy for infiltrative tumors involving the wall of the

stomach without obvious mucosal abnormalities.

DIAGNOSIS

Table 47-1 Common Symptoms and Physical Findings in Gastric Cancer

Figure 47-3. Early cancer survival rate in Japan.

Annual mass screening programs have been instituted in some countries (e.g., Japan, Venezuela,

Chile) with high incidence of gastric cancer. Whether such programs significantly reduce gastric cancer

mortality is unclear. In Japan, compliance with screening has been associated with a 50% decrease in

gastric cancer mortality, but most of this benefit is attributable to confounding factors such as baseline

general health.29 A large cohort study failed to show any effect of screening on mortality.30 Cancers

detected in screened patients tend to be earlier cancers with fewer nodal metastases,31 and patients with

resected gastric cancer diagnosed by screening have better survival than those diagnosed after

development of symptoms (Fig. 47-3). However, a survival difference between screened and unscreened

gastric cancer patients persists even after accounting for stage,31 suggesting that patient selection

confounds the effect of screening on mortality. The Japanese findings that early detection and

identification of early gastric cancer can improve survival has been confirmed by European

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investigations, in which patients with early gastric cancers have been shown to have survival rates

equivalent to those of patients with benign gastric ulcer (Fig. 47-4).26 Mass screening programs have

been found to be cost-effective in high-incidence countries such as Japan and China,32 but they are

unlikely to be cost-effective in lower-incidence countries such as the United States. The costeffectiveness of the Japanese screening program is likely to change given the significant decrease in the

rate of chronic H. pylori infection in Japanese under the age of 30 (25% vs. 60% as compared to their

parents).33

Figure 47-4. Early cancer survival rate in Europe.

Barium-contrast radiographs have, in the past, been the standard method for diagnosing gastric

neoplasm. Single-contrast examinations have a diagnostic accuracy of 80%. This diagnostic yield

increases to approximately 90% when double-contrast (air and barium) techniques are used. Typical

findings include ulceration, the presence of a gastric mass, loss of mucosal detail, and distortion of the

gastric silhouette (Fig. 47-5). Contrast radiography has been largely supplanted by endoscopy because

of the ability to obtain biopsy material by the latter technique.

Figure 47-5. Barium-contrast radiograph demonstrating extensive involvement of the gastric body by infiltrating adenocarcinoma

(linitis plastica). The gastric silhouette is narrowed (arrows), and the stomach is nondistensible.

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