Chapter 38. The Stomach

The stomach lies in the epigastrium and is composed of mucosa, submucosa, a thick muscle layer, and serosa. The mucosa of the stomach is thrown into regular folds, or rugae. The serosa on the lesser and greater curvatures is continuous with the lesser and greater omentum.

The Gastric Mucosa

(Figure 38-1)

The epithelial lining of the mucosa is composed of uniform mucous cells without goblet cells. Simple tubular glands open on the surface at epithelial pits. The glands vary in structure in different parts of the stomach: (1) In the cardiac region near the gastroesophageal junction, the glands are composed mainly of mucous cells; (2) in the body and fundus, the glands contain parietal (oxyntic) cells that secrete acid and chief (zymogen, or peptic) cells that secrete pepsin. The parietal cells also probably secrete intrinsic factor; (3) in the pyloric antrum, the glands contain mainly mucous cells.

Neuroendocrine cells are present in the mucosa of the stomach just as they are throughout the remainder of the intestinal tract. These cells are present throughout the mucosa and produce a variety of biogenic amines and peptide hormones. Neuroendocrine cells in the pyloric antral region (G cells) represent the source of gastrin and may be stained by immunohistologic methods using antigastrin antibodies.

Gastric Mucosal Resistance to Acid

The secretion of acid by the stomach is a continuous process, occurring at a basal rate during fasting periods and increasing markedly in response to a meal.

The gastric mucosa is protected by a variety of mechanisms from the erosive effect of gastric acid:

1. The anatomic integrity of the mucosa: The mucosal cells have a specialized apical surface membrane that resists the diffusion of acid into the cell. Back-diffused hydrogen ions are actively extruded by ionic carrier mechanisms.

2.  Gastric mucus: Mucin and HCO3− secreted by surface epithelial cells create a mucous layer that has a pH gradient which is very acid in the lumen to nearly neutral near the cell surface.

3. Prostaglandins (E series), which are synthesized and secreted by gastric mucosal cells, have a cytoprotective effect on the gastroduodenal mucosa. They act to increase bicarbonate secretion, gastric mucus production, mucosal blood flow, and the rate of mucosal cell regeneration.

4. Mucosal blood flow: Ischemia of the mucosa decreases mucosal resistance.

Functions of the Stomach

The main function of the stomach is to serve as a reservoir for meals, presenting food to the duodenum in small regulated amounts. The acid gastric juice contains the proteolytic enzyme pepsin and initiates digestion. The acidity also has an antibacterial action. Simple molecules such as iron, alcohol, and glucose may be absorbed from the stomach.

The stomach has two sphincters. A physiologic sphincter at the cardioesophageal junction prevents reflux of acid gastric contents into the esophagus. The distal or pyloric sphincter is an anatomic thickening of the muscle that controls the rate of gastric emptying and prevents reflux of bile into the stomach.

Pain & Dyspepsia

Pain is a feature of acute erosive gastropathy and peptic ulcer disease. It is epigastric, burning in nature, and is related to intake of food. Pain of gastric origin is often accompanied by nausea and vomiting. Dyspepsia may include pain but is also manifested by bloating, distention, and eructation.

Loss of Appetite

A loss of desire for food (anorexia) occurs in gastritis and gastric carcinoma. This must be distinguished from a fear of eating because it precipitates pain (as occurs with peptic ulcer) and from early satiety (feeling of fullness), which occurs in conditions where gastric volume is decreased (commonly neoplasms).

Bleeding

Bleeding into the gastric lumen is a common manifestation of gastric disease, occurring in any disease where the mucosal surface becomes eroded. The clinical manifestations depend on the severity and rate of bleeding. When bleeding is severe and rapid, the patient vomits bright red blood (hematemesis). When bleeding is less rapid, the blood is altered by gastric acid and passes through the intestines, forming tarry black stools (melena). With chronic slow bleeding, the patient commonly presents with iron deficiency anemia and the fecal occult blood test is positive.

Gastric Mass

Neoplasms of the stomach may produce a palpable mass in the epigastrium. In most cases, radiologic examination is required to confirm the gastric origin of an epigastric mass.

Gastric Outlet Obstruction (Pyloric Stenosis)

Obstruction at the pylorus leads to dilation of the stomach and active peristalsis, which may be visible. Vomiting is a feature and is often profuse. The loss of large volumes of acidic gastric juice in vomiting leads to hypokalemic alkalosis.

Pyloric stenosis may occur as a congenital anomaly (see below) or may be associated with peptic ulcer disease or gastric neoplasms, mainly carcinoma.

The mucosal structure of the stomach can be assessed by x-rays taken after a meal of radiopaque material such as barium or by gastric endoscopy. Endoscopy also permits photography and biopsy of suspicious areas.

Abdominal ultrasound and computerized tomography permit assessment of the stomach wall and are particularly useful in the detection of mass lesions.

Gastric function tests include the following: (1) tests to determine secretion of acid under a variety of conditions, including resting acid secretion and maximum secretion after histamine or pentagastrin stimulation; (2) Schilling's test for absorption of vitamin B12, which gives information about secretion of intrinsic factor; (3) measurement of the serum gastrin level, which is useful in evaluation of peptic ulcer disease and certain rare neoplasms; and (4) detection of antibodies in serum against parietal cell components and intrinsic factor, which may aid in diagnosis of autoimmune gastritis (pernicious anemia).

Pyloric stenosis is one of the most common congenital disorders of the gastrointestinal tract, occurring in 1:500 live births. It is four times more common in males than in females and tends to affect the first-born. There is a familial tendency, but no clear inheritance pattern has been demonstrated.

Marked hypertrophy of the muscle at the pyloric sphincter results in obstruction to gastric emptying. Symptoms of gastric outlet obstruction typically appear 1–3 weeks after birth. Projectile vomiting is accompanied by visible enlargement of the stomach in the epigastric region. Peristalsis can be observed in the dilated stomach, and in most cases the hypertrophied pylorus can be palpated as a firm ovoid mass.

Treatment consists of surgical splitting of the hypertrophied muscle to the level of the mucosa (myotomy). This procedure is successful in most cases.

Acute Erosive Gastropathy

(Table 38-1)

Acute erosive gastropathy is common. It is characterized endoscopically by diffuse hyperemia of the mucosa with multiple small, superficial erosions and ulcers (Figure 38-2). (Note: an erosion is a denudation of the surface epithelium with the deep part of the mucosa remaining intact; an ulcer involves the full thickness of the mucosa.) Microscopically, there is surface epithelial injury and denudation and variable necrosis of superficial glands. Hemorrhage may be present in the lamina propria (acute hemorrhagic gastritis). Deep ulceration extending into the wall and resulting in perforation occurs very rarely. Inflammatory cells are not present in large numbers. (The previous term for this entity—acute gastritis—is a misnomer.) In the healing phase, the epithelium regenerates rapidly. In some cases, features of regenerative activity dominate (reactive gastropathy).

Etiology & Pathogenesis

The basic cause of acute erosive gastropathy is damage of the gastric epithelium. Many etiologic agents have been implicated (Table 38-1), but in many cases, the mechanism for damage is not known.

Drugs

Drugs are the most common cause of acute erosive gastropathy. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and corticosteroids are the most potent. These probably act by inhibiting prostaglandin synthesis in the mucosa, thus making it more susceptible to acid. Cigarette smoking also inhibits prostaglandin synthesis and tends to aggravate all forms of ulceration, although it is not a primary cause.

Luminally Acting Toxic Chemicals

Ethyl alcohol causes acute gastropathy, most commonly after a bout of heavy drinking. The mucosal abnormality in alcoholic “gastritis” is dominated by hemorrhage into the lamina propria. Reflux of bile is believed to be toxic to the gastric mucosa. However, bile reflux commonly occurs in normal people without producing any change in the gastric mucosa. The severe reflux of bile that occurs after partial gastrectomy with removal of the pylorus has been reported to cause gastropathy. Ingestion of corrosives may damage the gastric mucosa, in some cases so extensively as to cause perforation.

Stress

Stress of many types causes acute erosive gastropathy. Severe burns (Curling's ulcers), myocardial infarction, intracranial lesions (Cushing's ulcers), and the postoperative period are some of the stressful states associated with gastric erosion. Endogenous corticosteroids may be responsible.

Chemotherapy

Chemotherapy, in particular hepatic arterial infusion of cytotoxic drugs, may cause direct mucosal toxicity.

Ischemia

Ischemia of the mucosa may be involved in the pathogenesis of erosive gastropathy associated with shock where there is severe vasoconstriction of the splanchnic circulation. Portal hypertension may also cause venous congestion and an element of vascular compromise leading to gastropathy. Gastric antral vascular ectasia caused by antral mucosal prolapse may also result in gastropathy due to vascular compromise.

Clinical Features

Mild cases are asymptomatic or associated with mild dyspepsia. Epigastric pain as well as nausea and vomiting occur in moderate to severe cases. Acute gastric hemorrhage causing hematemesis and melena is the most significant symptom; this occurs commonly in cases induced by drugs, stress, shock, and hepatic arterial chemotherapy. In rare cases, hemorrhage can be severe enough to threaten life. Treatment is by withdrawal of the etiologic factor, drug suppression of acid secretion, and supportive fluid care when hemorrhage occurs.

Chronic Gastritis

(Table 38-2)

Chronic gastritis is defined histologically as an increase in the number of lymphocytes and plasma cells in the gastric mucosa. The mildest degree of chronic gastritis is chronic superficial gastritis, which involves the subepithelial region around the gastric pits. More severe cases involve the glands in the deeper mucosa; this is commonly associated with gland atrophy (chronic atrophic gastritis) and intestinal metaplasia.

Most cases of chronic gastritis are of one of two types—type A, which is an autoimmune gastritis that primarily involves the body and is associated with pernicious anemia; and type B, which primarily involves the antrum and is associated with Helicobacter pylori infection (Table 38-2). There are a few cases of chronic gastritis of neither type whose etiology remains unknown.

Type a Chronic Gastritis (Autoimmune Type Associated with Pernicious Anemia)

Pernicious anemia (Chapter 24: Blood: I. Structure & Function; Anemias Due to Decreased Erythropoiesis) results from failure of vitamin B12 absorption caused by lack of intrinsic factor due to autoimmune chronic gastritis. The autoimmunity is directed against the parietal cells in the body and fundus of the stomach that secrete both intrinsic factor and acid. Several autoimmune mechanisms exist: (1) a T cell-mediated response against parietal cells, and (2) a humoral response associated with the presence of three different serum autoantibodies that are of diagnostic value: (a) in 90%, antiparietal cell antibody (also called parietal canalicular antibody); (b) in 75%, intrinsic factor blocking antibody (interferes with intrinsic factor complexing to dietary vitamin B12); and (c) in 50%, intrinsic factor binding antibody (binds with the intrinsic factor–vitamin B12 complex, preventing absorption of vitamin B12). The antibodies against intrinsic factor are also present in gastric juice. A small number of patients with pernicious anemia lack these antibodies. Pernicious anemia is associated with autoimmune diseases of the thyroid and adrenals.

The autoimmune reaction manifests as a lymphoplasmacytic infiltrate in the mucosa around parietal cells, which progressively decrease in number (Figure 38-3A). Neutrophils are rarely seen, and H pylori is absent. The fundic and body mucosa decreases in thickness, and the glands become lined predominantly by mucous cells. The mucosa frequently shows intestinal metaplasia, characterized by the appearance of goblet cells and Paneth cells. In the end stage of the disease, the mucosa is atrophic, with absent parietal cells (type A chronic atrophic gastritis). Because the target of the immune response has been completely destroyed, the immune cells decrease in number at this end stage, which is sometimes called simple gastric atrophy. The functional results are as follows: (1) Failure of secretion of acid (achlorhydria) associated with parietal cell loss. This causes an increase in serum gastrin level and frequently leads to hyperplasia of the neuroendocrine cells in the gastric mucosa. In some patients, multiple small carcinoid tumors may occur. (2) Failure of absorption of vitamin B12, due either to defective secretion of intrinsic factor, blocking of intrinsic factor complexing with dietary vitamin B12 (blocking antibody), or to prevention of absorption of the intrinsic factor–vitamin B12 complex (binding antibody). Failure of vitamin B12 absorption causes the hematologic (megaloblastic anemia) and neurologic (subacute combined degeneration of the cord) manifestations of pernicious anemia (Chapter 24: Blood: I. Structure & Function; Anemias Due to Decreased Erythropoiesis). Patients with pernicious anemia have an increased incidence of gastric carcinoma—ie, type A autoimmune chronic gastritis is a premalignant lesion. The epithelial cells show increasing degrees of dysplasia before cancer develops. Regular endoscopic surveillance with biopsy is indicated in all patients with pernicious anemia; recognition of high-grade dysplasia in a biopsy specimen (Figure 38-3B) is an indication for prophylactic gastric resection.

Type B Chronic Gastritis (Chronic Antral Gastritis; Helicobacter Pylori Gastritis)

Type B chronic gastritis has a strong association with H pylori. In 60–70% of patients, H pylori is demonstrable in biopsies by histologic examination or culture. In many patients in whom the organism is not demonstrable, serologic studies show antibodies against H pylori, indicating previous infection.

Type B chronic gastritis maximally involves the antrum, which is the favored site of infection with H pylori. Early cases show lymphoplasmactyic infiltration of the superficial gastric mucosa. Active infection with H pylori is almost always associated with the presence of neutrophils, both in the lamina propria and the antral mucous glands (Figure 38-4). As the lesion progresses, there is extension of the inflammation to involve the deep mucosa as well as the body of the stomach. Deep mucosal involvement is associated with destruction of the antral mucous glands and the appearance of intestinal metaplasia (type B chronic atrophic gastritis). H pylori disappears in glands showing intestinal metaplasia because it cannot survive in the milieu of intestinal epithelium. Reactive lymphoid hyperplasia, characterized by reactive follicles in the mucosa, is common.

Helicobacter pylori is a small, curved vibriolike organism that is present in the surface mucous layer which covers the surface epithelium and the glandular lumina. It can be seen in routine sections but is better demonstrated in sections stained by the genta silver stain. The presence of H pylori correlates best with active inflammation associated with neutrophils. Organisms may be absent in patients with inactive chronic gastritis, particularly when intestinal metaplasia is present.

Helicobacter gastritis is associated with numerous diseases of this region, and the relationships have not been completely clarified. These include (1) chronic duodenal ulcer, which has a nearly 100% association, (2) chronic gastric ulcer (75%), (3) gastric adenocarcinoma (> 80%), and (4) malignant lymphoma arising in the mucosa-associated lymphoid tissue.

Most patients with type B chronic gastritis—even severe atrophic gastritis—are asymptomatic. Mild epigastric discomfort and pain, nausea, and anorexia may occur, particularly in the presence of active inflammation. Endoscopic features may be absent or there may be loss of normal rugal folds. Lymphoid hyperplasia may result in rugal thickening and nodularity. The correlation between the presence of symptoms, endoscopic features, and histologic gastritis is poor; 30% of patients with normal gastric mucosa on endoscopy show chronic gastritis.

Patients with type B chronic gastritis have an increased incidence of gastric cancer. The risk is very low and does not justify regular surveillance in all patients with type B chronic gastritis. However, the incidence of type B chronic gastritis in the population is so high that a large number of gastric carcinomas may actually occur in patients with type B chronic atrophic gastritis, as evidenced by the greater than 80% incidence of H pylori infection in patients with gastric adenocarcinoma.

Menetrier's disease (hypertrophic gastritis; Rugal Hypertrophy)

Menetrier's disease is a rare condition of unknown cause that occurs mainly in males over 40 years of age. It is characterized by greatly thickened gastric rugal folds (Figure 38-5) that are visible both radiologically and endoscopically. Hyperplasia and cystic dilation of mucous glands, together with proliferation of the smooth muscle of the muscularis mucosae, suggest that this may be a hamartomatous lesion. Most patients with Menetrier's disease have reduced or normal acid secretion. Overproduction of gastric mucus leads to increased protein loss in the intestine. In the original description of the disease, protein-losing enteropathy was a constant feature.

Enlarged gastric mucosal folds may also occur in gastric neoplasms, notably malignant lymphoma and gastric carcinoma; in Zollinger-Ellison syndrome, in which hypertrophy of parietal cells is associated with hypersecretion of acid; and in eosinophilic gastroenteritis.

Eosinophilic Gastroenteritis

This is a rare disease believed to be due to immunologic hypersensitivity. The gastric and intestinal mucosa is infiltrated by chronic inflammatory cells and numerous eosinophils. The deeper parts of the intestinal wall may be affected, causing thickening of the intestine. Rarely, epithelioid granulomas and a small-vessel vasculitis may be present.

Peptic ulcers are ulcers occurring in any part of the gastrointestinal tract exposed to the action of acidic gastric juice. They occur principally in the duodenum (duodenal ulcer) and stomach (gastric ulcer) (Table 38-3). Peptic ulcer disease is common all over the world. It has been estimated that 5–10% of individuals in the United States suffer from peptic ulcers during their lifetime. Duodenal ulcer is two to three times more frequent in males, particularly those under the age of 50 years.

Peptic ulcers occur at all ages; the most common age at onset is 20–40 years. A familial tendency exists for duodenal ulcers but not for gastric ulcers. Duodenal ulcers are associated with blood group O, absence of blood group antigens in saliva (“nonsecretors”), and the presence of histocompatibility leukocyte antigen (HLA)-B5 histocompatibility antigen.

Pathogenesis

(Figure 38-6)

Hypersecretion of Acid

Acid is necessary for peptic ulcers to form, and ulcers do not occur in achlorhydric states. The cornerstone of treatment of peptic ulcer is to decrease secretion of acid; histamine H2 receptor antagonists (eg, cimetidine, ranitidine, etc) and proton pump inhibitors (eg, omeprazole) are highly effective.

However, the exact causal role played by the acid is uncertain. Patients with duodenal ulcers have increased acid secretion with heightened responses to normal stimuli, but patients with gastric ulcers frequently have normal or low acid production.

A marked increase in acid secretion occurs in patients with Zollinger-Ellison syndrome, caused by a gastrin-producing neoplasm of the pancreas. The high gastrin levels stimulate continuous maximal acid secretion by parietal cells. These patients have severe intractable peptic ulcers affecting the stomach, duodenum, and jejunum. In Zollinger-Ellison syndrome, high acid output is clearly the primary cause of peptic ulceration.

Decreased Mucosal Resistance to Acid

Decreased resistance of the mucosa to acid is believed to be the primary cause of most gastric ulcers. Prostaglandin E2 levels in gastric juice have been shown to be consistently decreased in patients with peptic ulcer. Prostaglandin e2 (PGE2) levels rise during the healing phase and remain low in patients whose ulcers do not heal. Inhibitors of prostaglandin synthesis such as aspirin and ibuprofen—and cigarette smoking—are known to have an adverse effect on the healing of peptic ulcers. Synthetic PGE2 analogues like misoprostol have accelerated healing in experimental studies.

Helicobacter Pylori Infection

H pylori infection of the pyloric antrum is present in nearly all patients with chronic duodenal ulcer and approximately 75% of patients with chronic gastric ulcer. In the stomach, the organism grows in the surface mucous layer, which may become altered, decreasing mucosal resistance. The mechanism whereby H pylori infection of the stomach causes duodenal ulcers is unknown. There is no direct infection of the duodenum by H pylori.

Pathology

Chronic peptic ulcers are usually solitary, often large (larger than 1 cm, rarely larger than 5 cm), and round-to-oval in shape with a punched-out appearance (Figure 38-7). The margins are either flush with the mucosal surface or slightly raised because of edema. The floor of the ulcer is smooth, and its base is thick and firm because of fibrosis. The mucosa around the ulcer is either normal or—in the stomach—shows changes of chronic gastritis. The mucosal folds around the ulcer appear to radiate outward from it, which is an effect of fibrous contraction of the base of the ulcer.

Chronic peptic ulcer differs from acute erosive gastropathy in its etiologic factors and in the size, number, and distribution of lesions (Table 38-4). Ulcers in acute erosive gastropathy tend to be small (< 1 cm), multiple, and distributed throughout the stomach, whereas chronic ulcers are large, solitary, and usually found on the lesser curvature or pyloric antrum (Figure 38-7).

Microscopically, the base of a chronic peptic ulcer is composed of a surface layer of necrotic, acutely inflamed debris below which is a zone of granulation tissue. Chronic peptic ulcers typically have extensive fibrosis of the base, with extension of fibrosis into the muscle wall. The muscle wall is commonly drawn up into the ulcer base. The epithelium at the edge of the ulcer shows regenerative hyperplasia, which frequently demonstrates marked cytologic atypia, mimicking neoplastic change.

Clinical Features

Peptic ulcer disease is chronic, with remissions and relapses of symptoms, associated with healing and reactivation of the ulcer. Relapses may be precipitated by emotional stress, by drugs such as aspirin, ibuprofen, and steroids, and by cigarette smoking.

Burning or gnawing epigastric pain related to meals is the characteristic symptom of chronic peptic ulcer. Ingestion of food leads to an immediate reduction in pain because the food neutralizes the acid. However, acid secretion is stimulated by the meal, and eating therefore leads to recurrence of pain at a variable time after a meal.

The diagnosis is best established by endoscopy, including biopsy to rule out carcinoma in gastric ulcers.

Complications

(Figure 38-6)

Bleeding

Bleeding is the result of erosion of a blood vessel by the ulcer and occurs in about 30% of patients with peptic ulcer. If slow, it causes occult blood loss in feces, leading to iron deficiency anemia. When bleeding is brisk, as occurs when a large artery like the gastroduodenal artery is eroded, hematemesis or melena occurs. Peptic ulcer disease is the most common cause of hematemesis. Hemorrhage is responsible for 10% of deaths from peptic ulcer disease.

Perforation

Perforation occurs in about 5% of peptic ulcer patients and is most common with anterior duodenal ulcers. The entry of gastric juice into the peritoneal cavity results in chemical peritonitis with sudden onset of abdominal pain and board-like rigidity of the abdominal muscles. Perforation is responsible for over 70% of deaths due to peptic ulcer.

Pyloric Obstruction

The fibrosis associated with an ulcer in the pyloric canal or first part of the duodenum may result in gastric outlet obstruction. Severe vomiting with hypochloremic alkalosis results.

Penetration

The ulcerative process may extend through the full thickness of the gut wall into adjacent organs. The fibrotic base of the ulcer is intact in such slow penetration, and there is no perforation. Penetration into the pancreatic substance occurs with posterior ulcers and may lead to constant back pain.

Treatment

Symptomatic treatment includes dietary change in the form of frequent small meals and avoidance of cigarette smoking, coffee, and alcohol, and the use of antacids. Suppression of acid secretion with drugs such as histamine H2 receptor blockers and proton pump inhibitors is very effective. Surgical procedures to reduce acid secretion (vagotomy, antrectomy) are needed in rare refractory cases. Treatment of H pylori infection with antibiotics decreases the likelihood of relapse after the ulcer has healed.

If a gastric ulcer does not heal with medical treatment, it must be reexamined by endoscopy and biopsied because ulcerative carcinomas of the stomach can mimic both the symptoms and the gross appearance of peptic ulcers. Biopsy of duodenal ulcers that are slow to heal is not essential because carcinomas are extremely rare in the first part of the duodenum.

Benign Neoplasms

Mucosal Polyps

Epithelial polyps are rare in the stomach. Three types occur: hyperplastic polyps (70%), fundic gland polyps (20%), and adenomatous polyps (10%). The risk of carcinoma is moderate in adenomatous polyp, slight in hyperplastic polyp, and nil in fundic gland polyps. Few gastric carcinomas arise in polyps; even when the two are associated, carcinoma commonly occurs not in the polyp but in adjacent mucosa. Gastric polyps appear as small pedunculated lesions, often multiple, that can be removed endoscopically. Large polyps are very rare.

Mesenchymal Neoplasms

Benign mesenchymal neoplasms are uncommon. They include leiomyomas and neurofibroma. Also presenting as a gastric tumor is heterotopic pancreas (also called choristoma but not a true neoplasm; see Chapter 17: Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms). All of these present as intramural or submucosal nodules that rarely cause symptoms.

Malignant Neoplasms

Gastric Adenocarcinoma

Incidence & Etiology

(Table 38-5)

Adenocarcinoma accounts for over 90% of malignant neoplasms of the stomach. The incidence of gastric carcinoma is five to ten times higher in Japan than in the United States. The incidence is also high in Iceland and Chile. In the United States, the incidence has declined since 1950; presently, about 25,000 new cases occur every year. There is an increased prevalence in the USA among Native Americans, Native Hawaiians, and Latino Americans.

Studies in Japanese immigrants to the United States show a decreased incidence from generation to generation, strongly suggesting that some environmental factor causes gastric cancer in Japan. It has been postulated that polycyclic hydrocarbons in smoked fish may be responsible.

The declining incidence of gastric carcinoma in the United States has been attributed to better refrigeration of meat, thereby decreasing the need for preservatives such as nitrites. Nitrites are converted to nitrosamines, which have been shown to cause gastric carcinoma in experimental animals. Antibiotic usage, which reduces Helicobacter pylori infection, may also have contributed to the decline in incidence over time.

Gastric carcinoma is statistically more common in individuals with blood group A. There is no significant familial tendency.

Precancerous Lesions

Gastric carcinoma occurs with increased frequency (1) in patients with chronic atrophic gastritis associated with pernicious anemia (high risk); (2) in those with chronic atrophic gastritis associated with H pylori infection, particularly when there is intestinal metaplasia (uncertain risk); (3) in those with adenomatous and hyperplastic polyps (low risk); and (4) in patients who have had subtotal gastrectomy, when the residual gastric stump is believed to be at increased risk. Chronic peptic ulcers of the stomach were at one time believed to carry an increased risk of carcinoma, but that view is no longer held.

Pathology

Gross Appearance

1. Early gastric cancer (defined as gastric carcinoma restricted to the mucosa and submucosa) is increasingly recognized. In Japan, where the incidence is high, population screening for gastric cancer is carried out, and early gastric cancer accounts for 30% of cases. In the United States, the incidence is much lower, and screening is not attempted; consequently, less than 10% of cases are detected at this early stage. Early gastric cancer appears as a small, flat mucosal thickening that may have a minimal polypoid and ulcerative component (Figure 38-8). It is thought that there may be a long period (months to years) before invasion of the muscle occurs.

2. Late gastric cancer (defined as a gastric carcinoma that has invaded the muscle wall) is the stage at which the tumor is commonly diagnosed in the United States. It may present in various ways: (1) as a fungating mass that protrudes into the lumen; (2) as a malignant ulcer with raised, everted edges (Figure 38-9); (3) as an excavated ulcer resembling a chronic peptic ulcer; or (4) as a diffusely infiltrating lesion that causes thickening and contraction of the stomach wall with relatively little mucosal involvement (linitis plastica, or leather-bottle stomach). Differentiation of benign peptic ulcer and ulcerative carcinoma may be difficult without histologic examination (Figure 38-10). Any gastric ulcer that does not heal as expected should be biopsied to rule out carcinoma.

Microscopic Appearance

Gastric carcinomas are adenocarcinomas of varying differentiation. The most common form is poorly differentiated (diffuse type), with cells distended by intracellular mucin (signet ring cell carcinoma;Figure 38-11). Well-differentiated (intestinal type) adenocarcinoma is less common. A reactive fibrosis is commonly present in relation to the neoplastic cells.

Spread

(Figure 38-12.) Gastric carcinoma infiltrates the submucosa and invades through the muscle wall into the omental fat. Involvement of the serosa leads to spread of tumor cells in the peritoneal fluid (transcoelomic spread). Such metastasis occurs to the ovary (Krukenberg tumor) and rectovesical pouch. Involvement of submucosal lymphatics by tumor results in microscopic satellite nodules, often some distance from the main mass. Microscopic examination of frozen sections of the resection margins is therefore very important at the time of surgical removal of tumor. Lymphatic involvement also leads to metastasis to lymph nodes around the stomach. Later, extension of tumor up the thoracic duct may lead to involvement of the left supraclavicular nodes (Virchow's node). Lymph node metastases are present in about 50% of cases at the time of diagnosis. Hematogenous spread to the liver and lungs also occurs early.

Clinical Features

Gastric carcinoma is asymptomatic in its early stages and can be detected only by screening of high-risk populations. A few patients with early gastric cancer have symptoms resembling chronic peptic ulcer. Biopsy of a nonhealing gastric ulcer is essential because some of these patients prove to have carcinoma.

Late gastric cancer presents with anorexia, anemia (due to blood loss), and weight loss. Early satiety may occur in a patient with a large mass or a contracted (linitis plastica) stomach. Hematemesis and melena may occur. Tumors near the pylorus may cause gastric outlet obstruction.

Diagnosis may be established by endoscopy and biopsy, which provides a histologic diagnosis; and by radiologic examination—particularly computerized tomography—which provides information about the extent of spread and surgical resectability. Note that radiologic diagnosis of carcinoma must always be confirmed by endoscopic biopsy.

Prognosis

The prognosis depends almost entirely on the depth of invasion of the neoplasm. Early gastric cancer restricted to the mucosa and submucosa has a 5-year survival rate of about 85%. Tumors that have invaded the muscle wall (late gastric cancer) but have not involved lymph nodes have only a 30% 5-year survival rate. When there is extension of tumor through the full thickness of the wall and lymph node involvement is present, the 5-year survival rate drops to about 5%.

Histologic features and degree of differentiation are of little prognostic importance.

Malignant Lymphoma

Gastric lymphoma accounts for about 5% of malignant tumors of the stomach. Two common types occur: (1) low-grade malignant lymphoma, arising in mucosa-associated lymphoid tissue (MALT lymphoma); and (2) high-grade aggressive B-cell lymphomas, most commonly B-immunoblastic lymphoma.

Gastric lymphomas present as polypoid masses, ulcers, thickened mucosal folds, and large intramural masses (Figure 38-13). The diagnosis is difficult on clinical grounds. Histologic examination of endoscopic biopsies can provide a diagnosis in both MALT lymphomas and in high-grade lymphoma. In MALT lymphomas, differentiation from reactive lymphoid proliferation can be very difficult; large biopsies to demonstrate immunoglobulin gene rearrangement may be needed. In high-grade lymphoma, the mucosa is infiltrated by large malignant cells. Differentiation from poorly differentiated carcinoma may require special stains. Lymphoma cells are negative for mucin and keratin and positive for common leukocyte antigen (CD45). MALT lymphomas are commonly restricted to the stomach (no systemic involvement) and are cured by surgical resection. High-grade lymphomas respond to chemotherapy, which is the primary treatment method. They have a 5-year survival rate of about 60% when the lymphoma is localized to the stomach at presentation.

Malignant Gastric Stromal Neoplasms

Malignant gastric stromal neoplasms, although they are the most common mesenchymal neoplasm in the stomach, account for only 2% of gastric malignancies. They arise from undifferentiated mesenchymal cells in the gastric wall. They present as large masses that originate in and involve the wall, usually protruding both into the mucosa and outward as an extragastric mass. Mucosal ulceration and cavitation of the central part of the tumor occur commonly. Although it forms a large mass, the tumor has less tendency to infiltrate and metastasize than gastric carcinoma. Surgical resection is therefore more successful than with carcinoma.

Microscopically, gastric stromal neoplasms are composed of spindle cells that show varying cellularity, pleomorphism, and mitotic activity. In very large tumors, hemorrhage and necrosis are common. Most are undifferentiated; some show smooth-muscle differentiation (positive staining for desmin and actin); some show neural differentiation (S100 protein positivity). Most show positivity for the antigen CD34. These tumors can be divided into low-grade neoplasms (< 10 mitotic figures per 10 hpf), with a low metastatic potential; and high-grade neoplasms (> 10 mitoses per 10 hpf, with necrosis), with a high incidence of metastasis.

Patients present with bleeding, blood loss anemia, or a palpable mass. The diagnosis is usually suggested by radiologic appearances. Endoscopic biopsy of the intramural mass is frequently negative for tumor, which is located deep to the submucosa. With surgical resection, over 50% of patients survive for 5 years. Failures may be due either to local recurrence or to distant metastases.

Carcinoid Tumors

Carcinoid tumors of the stomach are discussed along with other intestinal carcinoid tumors in Chapter 41: The Intestines: III. Neoplasms.