Chapter 26: Stomach

1. Any patient admitted to a hospital because of peptic ulcer disease should be considered for lifelong acid suppression.

2. Lifelong acid suppressive medication may be equivalent to surgical vagotomy in preventing recurrent peptic ulcer or ulcer complications.

3. Roux-en-Y gastrojejunostomy should be avoided unless more than half of the stomach has been removed. Otherwise marginal ulceration and/or gastric stasis (Roux syndrome) may become problematic.

4. Gastric resection for peptic ulcer should be avoided in the asthenic or high-risk patient, if possible.

5. Many patients with locally advanced gastric cancer (T2b, T3, T4) are cured by an oncologically sound operation that includes wide margins and adequate lymphadenectomy.

6. Most patients with primary gastric lymphoma can be treated without gastric resection.

7. Gastric carcinoids should usually be removed either endoscopically or surgically. The surgeon should treat gastric carcinoid without hypergastrinemia (type III) as if it were malignant.

The stomach is a remarkable organ with important digestive, nutritional, and endocrine functions. The stomach stores and facilitates the digestion and absorption of ingested food, and it helps regulate appetite. Treatable diseases of the stomach are common, and it is accessible and relatively forgiving. Thus, the stomach is a favorite therapeutic target. To provide intelligent diagnosis and treatment, the physician and surgeon must understand gastric anatomy, physiology, and pathophysiology. This includes a sound understanding of the mechanical, secretory, and endocrine processes through which the stomach accomplishes its important functions; and a familiarity with the common benign and malignant gastric disorders of clinical significance. The surgeon must also understand the indications, complications, and outcomes of procedures utilized to treat diseases of the stomach. The purpose of this chapter is to enhance the reader’s current understanding and familiarity with these concepts and topics. Some important milestones in the history of gastric surgery^1,2,3,4,5,6 are listed in Table 26-1.

Anatomic Relationships and Gross Morphology

The stomach is readily recognizable as the asymmetrical, pear-shaped, most proximal abdominal organ of the digestive tract (Fig. 26-1).⁷ The part of the stomach attached to the esophagus is called the cardia. Just proximal to the cardia at the gastroesophageal (GE) junction is the anatomically indistinct but physiologically demonstrable lower esophageal sphincter. At the distal end, the readily apparent pyloric sphincter connects the stomach to the proximal duodenum. The stomach is relatively fixed at these points, but the large midportion is quite mobile with the shorter lesser curvature on the right and the longer greater curvature on the left.

The superior-most part of the stomach is the distensible fundus, bounded superiorly by the diaphragm and laterally by the spleen. The angle of His is where the fundus meets the left side of the GE junction. Generally, the inferior extent of the fundus is considered to be the horizontal plane of the GE junction, where the body (corpus) of the stomach begins. The body of the stomach contains most of the parietal (oxyntic) cells, some of which are also present in the cardia and fundus. At the angularis, incisura the lesser curvature turns rather abruptly to the right, marking the anatomic beginning of the antrum, which comprises the distal 25% to 30% of the stomach.

The organs that commonly abut the stomach are the liver, colon, spleen, pancreas, and occasionally the kidney (Fig. 26-2). The left lateral segment of the liver usually covers a large part of the anterior stomach. Inferiorly, the stomach is attached to the transverse colon by the gastrocolic omentum. The lesser curvature is tethered to the liver by the hepatogastric ligament, also referred to as the lesser omentum or pars flaccida. Posterior to the stomach is the lesser omental bursa and the pancreas.

Arterial and Venous Blood Supply

The stomach is the most richly vascularized portion of the alimentary tube with ample blood flow and a dense intramural vascular anastomotic network. The large majority of the gastric blood supply is from the celiac axis via four named arteries (Fig. 26-3). The left and right gastric arteries form an anastomotic arcade along the lesser curvature, and the right and left gastroepiploic arteries form an arcade along the greater gastric curvature. The consistently largest artery to the stomach is the left gastric artery, which usually arises directly from the celiac trunk and divides into an ascending and descending branch along the lesser gastric curvature. Approximately 20% of the time, the left gastric artery supplies an aberrant vessel that travels in the gastrohepatic ligament (lesser omentum) to the left side of the liver. Rarely, this is the only arterial blood supply to this part of the liver, and inadvertent ligation may lead to clinically significant hepatic ischemia in this unusual circumstance. The more common smaller aberrant left hepatic artery may be ligated without significant consequences.

The second largest artery to the stomach is the right gastroepiploic artery, which arises consistently from the gastroduodenal artery behind the first portion of the duodenum. The left gastroepiploic artery arises from the splenic artery, and, together with the right gastroepiploic artery, forms the rich gastroepiploic arcade along the greater curvature. The right gastric artery usually arises from the hepatic artery near the pylorus and hepatoduodenal ligament, and runs proximally along the distal stomach. In the fundus along the proximal greater curvature, the short gastric arteries and veins arise from the splenic circulation. There also may be additional vascular branches to the proximal stomach from the phrenic and splenic circulation.

The veins draining the stomach generally parallel the arteries. The left gastric (coronary vein) and right gastric veins usually drain into the portal vein, though occasionally the coronary vein drains into the splenic vein. The right gastroepiploic vein drains into the superior mesenteric vein near the inferior border of the pancreatic neck, and the left gastroepiploic vein drains into the splenic vein.

The richness of the gastric blood supply and the extensiveness of the anastomotic connections have some important clinical implications, such as: a) At least two of the four named gastric arteries may be occluded or ligated with impunity. This is done routinely when the stomach is mobilized and pedicled on the right gastric and right gastroepiploic vessels to reach into the neck as an esophageal replacement (see Chapter 25) or during sleeve gastrectomy for weight loss when the gastroepiploic arcade is interrupted distally and resected (see Chapter 27), b) Following radical subtotal gastrectomy during which the right and left gastric arteries and both gastroepiploic arteries are all ligated, the gastric remnant is adequately supplied by short gastric arteries as long as the splenic artery is patent and intact; c) Angiographic control of gastric bleeding from deep ulcer or tumor often requires embolization of more than one feeding artery; d) Because of the rich venous interconnections in the stomach, a distal splenorenal shunt, which connects the distal end of the divided splenic vein to the side of the left renal vein, can effectively decompress esophagogastric varices in patients with portal hypertension.^8,9

Lymphatic Drainage

Generally speaking, the gastric lymphatics parallel the blood vessels (Fig. 26-4).¹⁰ The cardia and medial half of the corpus commonly drain to nodes along the left gastric and celiac axis. The lesser curvature side of the antrum usually drains to the right gastric and pyloric nodes, while the greater curvature half of the distal stomach drains to the nodes along the right gastroepiploic chain. The proximal greater curvature side of the stomach usually drains into nodes along the left gastroepiploic or splenic hilum. The nodes along both the greater and lesser curvature commonly drain into the celiac nodal basin. There is a rich anastomotic network of lymphatics that drain the stomach, often in a somewhat unpredictable fashion. Thus, a tumor arising in the distal stomach may give rise to positive lymph nodes in the splenic hilum. The rich intramural plexus of lymphatics and veins accounts for the fact that there can be microscopic evidence of malignant cells in the gastric wall at a resection margin that is several centimeters away from palpable malignant tumor. It also helps explain the not infrequent finding of positive lymph nodes which may be many centimeters away from the primary tumor, with closer nodes that remain negative.

Extensive and meticulous lymphadenectomy is considered by many surgeons to be an important part of the operation for gastric cancer. Surgeons and pathologists have numbered the primary and secondary lymph node groups to which the stomach drains (see Fig. 26-4).^11,12

Innervation

The vagus nerves provide the extrinsic parasympathetic innervation to the stomach, and acetylcholine is the most important neurotransmitter.¹³ From the vagal nucleus in the floor of the fourth cerebral ventricle, the vagus traverses the neck in the carotid sheath and enters the mediastinum, where it gives off the recurrent laryngeal nerve and divides into several branches around the esophagus. These branches come together again above the esophageal hiatus and form the left (anterior) and right (posterior) vagal trunks (mnemonic LARP). Near the GE junction the anterior vagus sends a branch (or branches) to the liver in the gastrohepatic ligament, and continues along the lesser curvature as the anterior nerve of Latarjet (Fig. 26-5). Similarly, the posterior vagus sends branches to the celiac plexus and continues along the posterior lesser curvature. The nerves of Latarjet send segmental branches to the body of the stomach before they terminate near the angularis incisura as the “crow’s foot,” sending branches to the antropyloric region. There may be additional branches to the distal stomach and pylorus that travel near the right gastric and/or gastroepiploic arteries. In 50% of patients, there are more than two vagal nerves at the esophageal hiatus. The branch that the posterior vagus sends to the posterior fundus is termed the criminal nerve of Grassi. This branch typically arises above the esophageal hiatus and is easily missed during truncal or highly selective vagotomy (HSV). Vagal fibers originating in the brain synapse with neurons in Auerbach’s myenteric plexus and Meissner’s submucosal plexus. In the stomach the vagus nerves affect secretion (including acid), motor function, and mucosal bloodflow and cytoprotection. They also play a role in appetite control and perhaps even mucosal immunity and inflammation. Most of the axons contained in the vagal trunks are afferent (i.e., carrying stimuli from the viscera to the brain).

The extrinsic sympathetic nerve supply to the stomach originates at spinal levels T5 through T10 and travels in the splanchnic nerves to the celiac ganglion. Postganglionic sympathetic nerves then travel from the celiac ganglion to the stomach along the blood vessels.

Neurons in the myenteric and submucosal plexuses constitute the intrinsic nervous system of the stomach. There may be more intrinsic gastric neurons than extrinsic neurons, but their function is poorly understood.

It is obviously an oversimplification (and incorrect) to think exclusively of the vagus as the cholinergic system and the sympathetic system as the adrenergic system of innervation. Although acetylcholine is an important neurotransmitter mediating vagal function, and epinephrine is important in the sympathetic nerves, both systems (as well as the intrinsic neurons) have various and diverse neurotransmitters, including cholinergic, adrenergic, and peptidergic (e.g., substance P and somatostatin).

Histology

There are four distinct layers of the gastric wall: mucosa, submucosa, muscularis propria, and serosa (Fig. 26-6).⁷ The inner layer of the stomach is the mucosa, which is lined with columnar epithelial cells of various types. Beneath the basement membrane of the epithelial cells is the lamina propria, which contains connective tissue, blood vessels, nerve fibers, and inflammatory cells. Beneath the lamina propria is a thin muscle layer called the muscularis mucosa, the deep boundary of the mucosal layer of the gut. The epithelium, lamina propria, and muscularis mucosa constitute the mucosa (Fig. 26-7).¹⁴ The epithelium of the gastric mucosa is columnar glandular. A scanning electron micrograph shows a smooth mucosal carpet punctuated by the openings of the gastric glands. The gastric glands are lined with different types of epithelial cells, depending upon their location in the stomach (Fig. 26-8, Table 26-2).^15,16 There are also endocrine cells present in the gastric glands. Progenitor cells at the base of the glands differentiate and replenish sloughed cells on a regular basis. Throughout the stomach, the carpet consists primarily of mucus-secreting surface epithelial cells (SECs) that extend down into the gland pits for variable distances. These cells also secrete bicarbonate and play an important role in protecting the stomach from injury due to acid, pepsin, and/or ingested irritants. In fact, all epithelial cells of the stomach (except the endocrine cells) contain carbonic anhydrase and are capable of producing bicarbonate.

In the cardia, the gastric glands are branched and secrete primarily mucus and bicarbonate, but not much acid. In the fundus and body, the glands are more tubular and the pits are deep. Parietal and chief cells are common in these glands (Fig. 26-9). Histamine-secreting enterochromaffin-like (ECL) cells and somatostatin-secreting D cells are also found. Parietal cells secrete acid and intrinsic factor into the gastric lumen, and bicarbonate into the intercellular space. They have a characteristic ultrastructural appearance with secretory canaliculi (deep invaginations of the surface membrane), and cytoplasmic tubulovesicles containing the acid-producing apparatus H⁺/K⁺-ATPase (proton pump) (see Fig. 26-9). There are numerous mitochondria; in fact the parietal cell is the most mitochondria rich cell in the body. When the parietal cell is stimulated, the cytoplasmic tubulovesicles fuse with the membrane of the secretory canaliculus; when acid production ceases, the process is reversed. Arguably, parietal cells produce the only truly essential substance made by the stomach (i.e., intrinsic factor). Parietal cells tend to occupy the midportion of the gastric glands found in the corpus of the stomach.

Chief cells (also called zymogenic cells) secrete pepsinogen I, which is maximally activated at a pH of 2.5. They tend to be clustered toward the base of the gastric glands and have a low columnar shape. Ultrastructurally, chief cells have the characteristics of protein-synthesizing cells: basal granular endoplasmic reticulum, supranuclear Golgi apparatus, and apical zymogen granules (Fig. 26-10). When stimulated, the chief cells produce two immunologically distinct proenzyme forms of pepsinogen: predominantly pepsinogen I and some pepsinogen II, most of which is produced by SECs. These proenzymes are activated in an acidic luminal environment.

In the antrum, the gastric glands are again more branched and shallow, parietal cells are rare, and gastrin-secreting G cells and somatostatin-secreting D cells are present. A variety of hormone-secreting cells are present in various proportions throughout the gastric mucosa (Fig. 26-11).¹⁷ Histologic analysis suggests that in the normal stomach, 13% of the epithelial cells are oxyntic (parietal) cells, 44% are chief (zymogenic) cells, 40% are mucous cells, and 3% are endocrine cells. In general, the antrum produces gastrin but not acid, and the proximal stomach produces acid but not gastrin. The border between the corpus and antrum migrates proximally with age (especially on the lesser curvature side of the stomach).

Deep to the muscularis mucosa is the submucosa, which is rich in branching blood vessels, lymphatics, collagen, various inflammatory cells, and nerve fibers and ganglion cells of Meissner’s autonomic submucosal plexus. The collagen-rich submucosa gives strength to GI anastomoses. The mucosa and submucosa are folded into the grossly visible gastric rugae, which tend to flatten out as the stomach becomes distended.

Below the submucosa is the thick muscularis propria (also referred to as the muscularis externa), which consists of an incomplete inner oblique layer, a complete middle circular layer (continuous with the esophageal circular muscle and the circular muscle of the pylorus), and a complete outer longitudinal layer (continuous with the longitudinal layer of the esophagus and duodenum). Within the muscularis propria is the rich network of autonomic ganglia and nerves that make up Auerbach’s myenteric plexus. Specialized pacemaker cells, the interstitial cells of Cajal (ICC), also are present.

The outer layer of the stomach is the serosa, also known as the visceral peritoneum. This layer provides significant tensile strength to gastric anastomoses. When tumors originating in the mucosa penetrate and breach the serosa, microscopic or gross peritoneal metastases are common, presumably from shedding of tumor cells that would not have occurred if the serosa had not been penetrated. In this way, the serosa may be thought of as an outer envelope of the stomach.

The stomach stores food and facilitates digestion through a variety of secretory and motor functions. Important secretory functions include the production of acid, pepsin, intrinsic factor, mucus, and a variety of GI hormones. Important motor functions include food storage (receptive relaxation and accommodation), grinding and mixing, controlled emptying of ingested food, and periodic interprandial “housekeeping.”

Acid Secretion

Hydrochloric acid in the stomach hastens both the physical and (with pepsin) the biochemical breakdown of ingested food. In an acidic environment, pepsin and acid facilitate proteolysis. Gastric acid also inhibits the proliferation of ingested pathogens, which protects against both infectious gastroenteritis and intestinal bacterial overgrowth. Long-term acid suppression with proton pump inhibitors (PPIs) has been associated with an increased risk of community acquired Clostridium difficile colitis and other gastroenteritis, presumably because of the absence of this protective germicidal barrier.^18,19

Parietal Cell

The parietal cell is stimulated to secrete acid (Fig. 26-12) when one or more of three membrane receptor types is stimulated by acetylcholine (from vagal nerve fibers), gastrin (from D cells), or histamine (from ECL cells).^7,20,21 The enzyme H⁺/K⁺-ATPase is the proton pump. It is stored within the intracellular tubulovesicles and is the final common pathway for gastric acid secretion. When the parietal cell is stimulated, there is a cytoskeletal rearrangement and fusion of the tubulovesicles with the apical membrane of the secretory canaliculus. The heterodimer assembly of the enzyme subunits into the microvilli of the secretory canaliculus results in acid secretion, with extracellular potassium being exchanged for cytosolic hydrogen. Although electro-neutral, this is an energy requiring process because the hydrogen is secreted against a gradient of at least 1 million-fold, which explains why the parietal cell is packed with energy producing mitochondria. During acid production, potassium and chloride are also secreted into the apical secretory canaliculus through separate channels, providing potassium to exchange for H⁺ via the H⁺/K⁺-ATPase, and chloride to accompany the secreted hydrogen. At the basolateral membrane, the combined activity of various cotransporters and ion exchangers accomplishes intracellular pH regulation and electrolyte homeostasis.²⁰

The normal human stomach contains approximately 1 billion parietal cells, and total gastric acid production is proportional to parietal cell mass. The potent acid-suppressing PPI drugs irreversibly interfere with the function of the H⁺/K⁺-ATPase molecule. These agents must be incorporated into the activated enzyme to be effective, and thus work best when taken before or during a meal (when the parietal cell is stimulated). When PPI therapy is stopped, acid secretory capability gradually returns (within days) as new H⁺/K⁺-ATPase is synthesized.

Gastrin, acetylcholine, and histamine stimulate the parietal cell to secrete hydrochloric acid (see Fig. 26-12). Gastrin binds to type B cholecystokinin (CCK) receptors, and acetylcholine binds to M₃ muscarinic receptors. Both stimulate phospholipase C via a G-protein–linked mechanism leading to increased production of inositol trisphosphate from membrane bound phospholipids. Inositol trisphosphate stimulates the release of calcium from intracellular stores, which leads to activation of protein kinases and activation of H⁺/K⁺-ATPase. Histamine binds to the histamine 2 (H₂) receptor, which stimulates adenylatecyclase, also via a G-protein–linked mechanism. Activation of adenylatecyclase results in an increase in intracellular cyclic adenosine monophosphate which activates protein kinases, leading to increased levels of phosphoproteins and activation of the proton pump. Somatostatin from mucosal D cells binds to membrane receptors and inhibits the activation of adenylatecyclase through an inhibitory G protein.

Physiologic Acid Secretion

Food ingestion is the physiologic stimulus for acid secretion (Fig. 26-13). The acid secretory response that occurs after a meal is traditionally described in three phases: cephalic, gastric, and intestinal.^22,23 The cephalic or vagal phase begins with the thought, sight, smell, and/or taste of food. These stimuli activate several cortical and hypothalamic sites (e.g., tractus solitarius, dorsal motor nucleus, and dorsal vagal complex), and signals are transmitted to the stomach by the vagal nerves. Acetylcholine is released, leading to stimulation of ECL cells and parietal cells. Although the acid secreted per unit of time in the cephalic phase is greater than in the other two phases, the cephalic phase is shorter. Thus, the cephalic phase accounts for no more than 30% of total acid secretion in response to a meal. Sham feeding (chewing and spitting) stimulates gastric acid secretion only via the cephalic phase, and results in acid secretion that is about half of that seen in response to IV pentagastrin or histamine.

When food reaches the stomach, the gastric phase of acid secretion begins. This phase lasts until the stomach is empty, and accounts for about 60% of the total acid secretion in response to a meal. The gastric phase of acid secretion has several components. Amino acids and small peptides directly stimulate antral G cells to secrete gastrin, which is carried in the bloodstream to the parietal cells and stimulates acid secretion in an endocrine fashion. In addition, proximal gastric distention stimulates acid secretion via a vagovagal reflex arc, which is abolished by truncal or HSV. Antral distention also stimulates antral gastrin secretion. Acetylcholine stimulates gastrin release and gastrin stimulates histamine release from ECL cells.

The intestinal phase of gastric secretion is poorly understood. It is thought to be mediated by a hormone released from the proximal small bowel mucosa in response to luminal chyme. This phase starts when gastric emptying of ingested food begins, and continues as long as nutrients remain in the proximal small intestine. It accounts for about 10% of meal-induced acid secretion.

Interprandial basal acid secretion is 2 to 5 mEq hydrochloric acid per hour, about 10% of maximal acid output (MAO), and it is greater at night. Basal acid secretion probably contributes to the relatively low bacterial counts found in the stomach. Basal acid secretion is reduced 75% to 90% by vagotomy or H₂ receptor blockade.

The pivotal role that ECL cells play in the regulation of gastric acid secretion is emphasized in Fig. 26-13. A large part of the acid stimulatory effects of both acetylcholine and gastrin are mediated by histamine released from mucosal ECL cells. H2 receptor knockout mice do not secrete acid in response to gastrin.²⁰ This explains why the histamine 2 receptor antagonists (H₂RAs) are such effective inhibitors of acid secretion, even though histamine is only one of three parietal cell stimulants. The mucosal D cell, which releases somatostatin, is also an important regulator of acid secretion. Somatostatin inhibits histamine release from ECL cells and gastrin release from antral G cells. The function of D cells is inhibited by Helicobacter pylori infection, and this leads to an exaggerated acid secretory response (see section Helicobacter pylori Infection).

Pepsinogen Secretion

The most potent physiologic stimulus for pepsinogen secretion from chief cells is food ingestion; acetylcholine is the most important mediator. Somatostatin inhibits pepsinogen secretion. Pepsinogen I is produced by chief cells in acid producing glands, whereas pepsinogen II is produced by SECs in both acid producing and gastrin producing (i.e., antral) glands. Pepsinogen is cleaved to the active pepsin enzyme in an acidic environment and is maximally active at pH 2.5, and inactive at pH >5, although pepsinogen II may be activated over a wider pH range than pepsinogen I. Pepsin catalyzes the hydrolysis of proteins and is denatured at alkaline pH.

Intrinsic Factor

Activated parietal cells secrete intrinsic factor in addition to hydrochloric acid. Presumably the stimulants are similar, but acid secretion and intrinsic factor secretion may not be linked. Intrinsic factor binds to luminal vitamin B₁₂, and the complex is absorbed in the terminal ileum via mucosal receptors. Vitamin B₁₂ deficiency can be life threatening, and patients with total gastrectomy or pernicious anemia (i.e., patients with no parietal cells) require B₁₂ supplementation by a nonenteric route. Some patients develop vitamin B₁₂ deficiency following gastric bypass, presumably because there is insufficient intrinsic factor present in the small proximal gastric pouch and oral B₁₂ intake may be decreased. Under normal conditions, a significant excess of intrinsic factor is secreted, and acid-suppressive medication does not appear to inhibit intrinsic factor production and release.

Gastric Mucosal Barrier

The stomach’s durable resistance to autodigestion by caustic hydrochloric acid and active pepsin is intriguing. Some of the important elements of gastric barrier function and cytoprotection are listed in Table 26-3.^24,25 When these defenses break down, ulceration occurs. A variety of factors are important in maintaining an intact gastric mucosal layer. The mucus and bicarbonate secreted by SECs form an unstirred mucous gel with a favorable pH gradient. Cell membranes and tight junctions prevent hydrogen ions from gaining access to the interstitial space. Hydrogen ions that do break through are buffered by the alkaline tide created by basolateral bicarbonate secretion from stimulated parietal cells. Any sloughed or denuded SECs are rapidly replaced by migration of adjacent cells, a process known as restitution. Mucosal blood flow plays a crucial role in maintaining a healthy mucosa, providing nutrients and oxygen for the cellular functions involved in cytoprotection. “Back-diffused” hydrogen is buffered and rapidly removed by the rich blood supply. When “barrier breakers” such as bile or aspirin lead to increased back-diffusion of hydrogen ions from the lumen into the lamina propria and submucosa, there is a protective increase in mucosal blood flow. If this protective response is blocked, gross ulceration can occur. Important mediators of these protective mechanisms include prostaglandins, nitric oxide, intrinsic nerves, and peptides (e.g., calcitonin gene-related peptide, gastrin-releasing peptide [GRP], gastrin, and heat shock proteins). Sucralfate acts locally to enhance mucosal defenses. Protective reflexes involve afferent sensory neurons, and can be blocked by the application of topical anesthetics to the gastric mucosa, or the experimental destruction of the afferent sensory nerves. In addition to these local defenses, there are important protective factors in saliva, duodenal secretions, and pancreatic or biliary secretions.

Gastric Hormones

Gastrin

Gastrin is produced by antral G cells and is the major hormonal stimulant of acid secretion during the gastric phase.^13,26 A variety of molecular forms exist: big gastrin (34 amino acids; G₃₄), little gastrin (17 amino acids; G₁₇), and mini-gastrin (14 amino acids; G₁₄). The large majority of gastrin released by the human antrum is G₁₇. The biologically active pentapeptide sequence at the C-terminal end of gastrin is identical to that of CCK. Luminal peptides and amino acids are the most potent stimulants of gastrin release, and luminal acid is the most potent inhibitor of gastrin secretion. The latter effect is predominantly mediated in a paracrine fashion by somatostatin released from antral D cells. Gastrin-stimulated acid secretion is significantly blocked by H₂ antagonists, suggesting that the principal mediator of gastrin-stimulated acid production is histamine from mucosal ECL cells (see Fig. 26-13). In fact, chronic hypergastrinemia is associated with hyperplasia of gastric ECL cells and, rarely, gastric carcinoid. Gastrin is trophic to gastric parietal cells and to other GI mucosal cells. Important causes of hypergastrinemia include pernicious anemia, acid-suppressive medication, gastrinoma, retained antrum following distal gastrectomy and Billroth II surgery, and vagotomy.

Somatostatin

Somatostatin is produced by D cells located throughout the gastric mucosa. The predominant form in humans is somatostatin 14, though somatostatin 28 is present as well. The major stimulus for somatostatin release is antral acidification; acetylcholine from vagal nerve fibers inhibits its release. Somatostatin inhibits acid secretion from parietal cells and gastrin release from G cells. It also decreases histamine release from ECL cells. The proximity of the D cells to these target cells suggests that the primary effect of somatostatin is mediated in a paracrine fashion, but an endocrine (i.e., bloodstream) effect also is possible.

Gastrin-Releasing Peptide

GRP is the mammalian equivalent of bombesin, a hormone discovered more than two decades ago in an extract of skin from a frog. In the antrum, GRP stimulates both gastrin and somatostatin release by binding to receptors on the G and D cells. There are nerve terminals ending near the mucosa in the gastric body and antrum, which are rich in GRP immunoreactivity. When GRP is given peripherally, it stimulates acid secretion, but when it is given centrally into the cerebral ventricles of animals, it inhibits acid secretion, apparently via a pathway involving the sympathetic nervous system. GRP is a mediator of gastroprotective increased mucosal blood flow in response to luminal irritants.

Leptin

Leptin is a protein primarily synthesized in adipocytes. It is also made by chief cells in the stomach, the main source of leptin in the GI tract.²⁶ Leptin works at least in part via vagally mediated pathways to decrease food intake in animals. Not surprisingly, leptin, a satiety signal hormone, and ghrelin, a hunger signal hormone, are both primarily synthesized in the stomach, an organ increasingly recognized as central to the mechanisms of appetite control.^26,27

Ghrelin

Ghrelin is a small peptide described in 1999 that is produced primarily in the stomach.²⁸ Ghrelin is a potent secretagogue of pituitary growth hormone (but not adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, or thyroid-stimulating hormone). Ghrelin appears to be an orexigenic regulator of appetite (i.e., when ghrelin is elevated, appetite is stimulated, and when it is suppressed, appetite is suppressed). Resection of the primary source of this hormone (i.e., the stomach) may partly account for the anorexia and weight loss seen in some patients following gastric resection including sleeve gastrectomy (Fig. 26-14).²⁹ The gastric bypass operation, a very effective treatment for morbid obesity, has been shown by some investigators to be associated with suppression of plasma ghrelin levels (and appetite) in humans (Fig. 26-15A).^30,31

Other groups have failed to show a significant decrease in ghrelin levels following gastric bypass but have found such decreases following sleeve gastrectomy, another effective weight loss operation (Fig. 26-15B).³¹ Possibly subtle differences in operative technique, patient selection, and/or experimental conditions account for the findings that multiple studies have reported disparate results on the effect of bariatric surgery on ghrelin levels in obese patients. Obviously appetite control is complex with redundant and overlapping orexigenic and anorexigenic pathways and signals.^26,27

Gastric Motility and Emptying

Gastric motor function has several purposes.^13,32,33,34 Interprandial motor activity clears the stomach of undigested debris, sloughed cells, and mucus. When feeding begins, the stomach relaxes to accommodate the meal. Regulated motor activity then breaks down the food into small particles and controls the output into the duodenum. The stomach accomplishes these functions by coordinated smooth muscle relaxation and contraction of the various gastric segments (proximal, distal, and pyloric). Smooth muscle myoelectric potentials are translated into muscular activity, which is modulated by extrinsic and intrinsic innervation and hormones. The mechanisms by which gastric distention is translated into a neurohormonal satiety signal have only been partially elucidated.^26,27

Intrinsic Gastric Innervation

The extrinsic parasympathetic and sympathetic gastric innervation was discussed previously under Innervation. The intrinsic innervation consists of ganglia and nerves that constitute the enteric nervous system (Fig. 26-16).³⁵ There are a variety of neurotransmitters, which are generally grouped as excitatory (augment muscular activity) and inhibitory (decrease muscular activity). Important excitatory neurotransmitters include acetylcholine, the tachykinins, substance P, and neurokinin A. Important inhibitory neurotransmitters include nitric oxide (NO) and vasoactive intestinal peptide (VIP). Serotonin has been shown to modulate both contraction and relaxation. A variety of other molecules affect motility, including GRP, histamine, neuropeptide Y, norepinephrine, and endogenous opioids.

Specialized cells in the muscularis propria also are important modulators of GI motility. These cells, called interstitial cells of Cajal, are distinguishable histologically from neurons and myocytes, and appear to amplify both cholinergic excitatory and nitrergic inhibitory input to the smooth muscle of the stomach and intestine.³⁶ They are thought to be the cell of origin for gastrointestinal stromal tumors (GISTs) which are the most common mesenchymal neoplasm in the GI tract.

Segmental Gastric Motility

^13,36,37 In general, the proximal stomach serves a short-term food storage function and helps regulate basal intragastric tone, and the distal stomach mixes and grinds the food. The pylorus helps the latter process when closed, facilitating retropulsion of the solid food bolus back into the body of the stomach for additional breakdown. The pylorus opens intermittently to allow metered emptying of liquids and small solid particles into the duodenum.

Most of the motor activity of the proximal stomach consists of slow tonic contractions and relaxations, lasting up to 5 minutes. This activity is the main determinant of basal intragastric pressure, an important determinant of liquid emptying. Rapid phasic contractions may be superimposed on the slower tonic motor activity. When food is ingested, intragastric pressure falls as the proximal stomach relaxes. This proximal relaxation is mediated by two important vagovagal reflexes: receptive relaxation and gastric accommodation. Receptive relaxation refers to the reduction in proximal gastric tone associated with the act of swallowing. This occurs before the food reaches the stomach, and can be reproduced by mechanical stimulation of the pharynx or esophagus. Gastric accommodation refers to the proximal gastric relaxation associated with distention of the stomach. Accommodation is mediated through stretch receptors in the gastric wall and does not require esophageal or pharyngeal stimulation. Because both of these reflexes are mediated by afferent and efferent vagal fibers, they are significantly altered by truncal and highly selective vagotomy. Both these operations result in decreased gastric compliance, shifting the volume/pressure curve to the left. That is, interference with normal receptive relaxation and/or accommodation results in decreased gastric compliance, such that for any given amount of food or liquid ingested, the intragastric pressure is greater. This may increase the rate of liquid emptying, perhaps contributing to dumping symptoms after vagotomy.

NO and VIP are the principal mediators of proximal gastric relaxation. But a variety of other agents increase proximal gastric relaxation and compliance, including dopamine, gastrin, CCK, secretin, GRP, and glucagon. Proximal gastric tone also is decreased by duodenal distention, colonic distention, and ileal perfusion with glucose (ileal brake).

The distal stomach breaks up solid food and is the main determinant of gastric emptying of solids. Slow waves of myoelectric depolarization sweep down the distal stomach at a rate of about three per minute. These waves originate from the proximal gastric pacemaker, high on the greater curvature. The pacing cells may be interstitial cells of Cajal, which have been shown to have a similar function in the small intestine and colon. Most of these myoelectric waves are below the threshold for smooth muscle contraction in the quiescent state, and thus are associated with negligible changes in pressure. Neural and/or hormonal input, which increases the plateau phase of the action potential, can trigger muscle contraction, resulting in a peristaltic wave associated with the electrical slow wave, and of the same frequency (three per minute) (Fig. 26-17). It is possible that implantable gastric pacemakers benefit some patients with gastroparesis by favorably impacting this myoelectric coupling.

During fasting, distal gastric motor activity is controlled by the migrating motor complex (MMC), the “gastrointestinal housekeeper” (Fig. 26-18). The purported function of the MMC is to sweep along any undigested food, debris, sloughed cells, and mucus after the fed phase of digestion is complete. The MMC lasts approximately 100 minutes (longer at night, shorter during daytime) and is divided into four phases. Phase I (about half the length of the entire cycle) is a period of relative motor inactivity. High-amplitude muscular contractions do not occur in phase I of the MMC. Phase II (about 25% of the entire MMC cycle) consists of some irregular, high-amplitude, generally nonpropulsive contractions. Phase III, a period of intense, regular, (about three per minute) propulsive contractions, only lasts about 5 to 10 minutes. Most phase III complexes of the GI MMC begin in the stomach, and the frequency approximates that of the myoelectric gastric slow wave. Phase IV is a transition period.

Neurohormonal control of the MMC is poorly understood, but it appears that different phases are regulated by different mechanisms. For example, vagotomy abolishes phase II of the gastric MMC but has little influence on phase III that persists even in the autotransplanted stomach, totally devoid of extrinsic neural input. This suggests that phase III is regulated by intrinsic nerves and/or hormones. Indeed, the initiation of phase III of the MMC in the distal stomach corresponds temporally to elevation in serum levels of motilin, a hormone produced in the duodenal mucosa. Resection of the duodenum abolishes distal gastric phase III in dogs, and resection of the duodenum in humans (e.g., with pancreaticoduodenectomy, the Whipple procedure) commonly results in early postoperative delayed gastric emptying. There are clearly motilin receptors on antral smooth muscle and nerves. Other modulators of gastric MMC activity include NO, endogenous opioids, intrinsic cholinergic and adrenergic nerves, and duodenal pH.

Feeding abolishes the MMC and leads to the fed motor pattern. The fed motor pattern of gastric activity starts within 10 minutes of food ingestion and persists until all the food has left the stomach. The neurohormonal initiator of this change is unknown, but CCK and the vagus appear to play some role: Sham feeding transiently induces antral motor activity resembling the fed motor pattern, and this is blocked by the CCK receptor antagonist loxiglumide. Gastric motility during the fed pattern resembles phase II of the MMC, with irregular but continuous phasic contractions of the distal stomach. During the fed state, about half of the myoelectric slow waves are associated with strong distal gastric contractions. Some are prograde and some are retrograde, serving to mix and grind the solid components of the meal. The magnitude of gastric contractions and the duration of the pattern are influenced by the consistency and composition of the meal.

The pylorus functions as an effective regulator of gastric emptying and an effective barrier to duodenogastric reflux. Bypass, transection, or resection of the pylorus may lead to uncontrolled gastric emptying of food and the dumping syndrome (see Postgastrectomy Problems). Pyloric dysfunction or disruption may also result in uncontrolled entry of duodenal contents into the stomach. Perfusion of the duodenum with lipids, glucose, amino acids, hypertonic saline, or hydrochloric acid results in closure of the pylorus and decreased transpyloric flow. Ileal perfusion with fat has the same effect. A variety of neurohumoral pathways are involved with these physiologic responses, and there is evidence that different pathways may be involved for different stimuli.

The pylorus is readily apparent grossly as a thick ring of muscle and connective tissue. The density of nerve tissue in the pyloric smooth muscle is several folds higher than in the antrum, with increased numbers of neurons staining positive for substance P, neuropeptide Y, VIP, and galanin. Interstitial cells of Cajal are is more closely associated with pyloric myocytes, and the myoelectric slow wave of the pylorus has the same frequency as that seen in the distal stomach. The motor activity of the pylorus is both tonic and phasic. During phase III of the MMC, the pylorus is open as gastric contents are swept into the duodenum. During the fed phase, the pylorus is closed most of the time. It relaxes intermittently, usually in synchronization with lower-amplitude, minor antral contractions. The higher-amplitude, more major antral contractions are usually met with a closed pylorus, facilitating retropulsion and further grinding of food.

Modulation of pyloric motor activity is complex. There is evidence of both inhibitory and excitatory vagal pathways. Some contractile vagal effects are mediated by opioid pathways, because they are blocked by naloxone. Electrical stimulation of the duodenum causes the pylorus to contract, whereas electrical stimulation of the antrum causes pyloric relaxation. Nitric oxide is an important mediator of pyloric relaxation. Other molecules that may play a physiologic role in controlling pyloric smooth muscle include serotonin, VIP, prostaglandin E₁, and galanin (pyloric relaxation); and histamine, CCK, and secretin (pyloric contraction).

Gastric Emptying

¹³ The control of gastric emptying is complex. In general, liquid emptying is faster than solid emptying. Osmolarity, acidity, caloric content, nutrient composition, and particle size are important modulators of gastric emptying. Stimulation of duodenal osmoreceptors, glucoreceptors, and pH receptors clearly inhibits gastric emptying by a variety of neurohumoral mechanisms. CCK has been consistently shown to inhibit gastric emptying at physiologic doses (Fig. 26-19). Recently, it has been noted that the anorexigenic hormone leptin, secreted by fat and gastric mucosa, inhibits gastric emptying, perhaps through the same pathway as CCK (which also has properties of a satiety hormone). The orexigenic hormone ghrelin has the opposite effect.

Liquid Emptying

The gastric emptying of water or isotonic saline follows first-order kinetics, with a half emptying time around 12 minutes. Thus, if one drinks 200 mL of water, about 100 mL enters the duodenum by 12 minutes, whereas if one drinks 400 mL of water, about 200 mL enters the duodenum by 12 minutes. This emptying pattern of liquids is modified considerably as the caloric density, osmolarity, and nutrient composition of the liquid changes (Fig. 26-20). Up to an osmolarity of about 1 M, liquid emptying occurs at a rate of about 200 kcal per hour. Duodenal osmoreceptors and hormones (e.g., secretin and VIP) are important modulators of liquid gastric emptying. Generally, liquid emptying is delayed in the supine position.

Traditionally, liquid emptying has been attributed to the activity of the proximal stomach, but it is probably more complicated than previously thought. Clearly, receptive relaxation and gastric accommodation play a role in gastric emptying of liquids. Patients with a denervated (e.g., vagotomized), resected, or plicated (e.g., fundoplication) proximal stomach have decreased gastric compliance and may show accelerated gastric emptying of liquids.

Some observations suggest an active role for the distal stomach in liquid emptying. For instance even if the proximal intragastric pressure is lower than duodenal pressure, normal gastric emptying of liquids can occur. Also, diabetic patients may have normal proximal gastric motor function and profoundly delayed gastric emptying of liquids. Indeed, antral contractile activity does correlate with liquid gastric emptying, and this distal gastric activity appears to vary with the nutrient composition and caloric content of the liquid meal. Depending on the circumstances, distal gastric motor activity can promote or inhibit gastric emptying of liquids. Distal gastrectomy and pyloric stenting both obviously interfere with distal gastric motor activity, and both accelerate the initial rapid phase of liquid gastric emptying.

Solid Emptying

Normally, the half-time of solid gastric emptying is less than 2 hours. Unlike liquids, which display an initial rapid phase followed by a slower linear phase of emptying, solids have an initial lag phase during which little emptying of solids occurs. It is during this phase that much of the grinding and mixing occurs. A linear emptying phase follows, during which the smaller particles are metered out to the duodenum. Solid gastric emptying is a function of meal particle size, caloric content, and composition (especially fat). When liquids and solids are ingested together, the liquids empty first. Solids are stored in the fundus and delivered to the distal stomach at constant rates for grinding. Liquids also are sequestered in the fundus, but they appear to be readily delivered to the distal stomach for early emptying. The larger the solid component of the meal, the slower the liquid emptying. Patients bothered by dumping syndrome are advised to limit the amount of liquid consumed with the solid meal, taking advantage of this effect. Three prokinetic agents are commonly used to treat delayed gastric emptying. Typical doses and mechanism of action are shown in Table 26-4.

Signs and Symptoms

The most common symptoms of gastric disease are pain, weight loss, early satiety, and anorexia. Nausea, vomiting, bloating, and anemia also are frequent complaints. Several of these symptoms (pain, bloating, nausea, and early satiety) are often described by physicians as dyspepsia, synonymous with the common nonmedical term indigestion. Common causes of dyspepsia include gastroesophageal reflux disease (GERD) and disorders of the stomach, gallbladder, and pancreas. Although none of the above symptoms alone is specific for gastric disease, when elicited in the context of a careful history and physical examination, they point to a differential diagnosis, which can be refined with certain tests.

Diagnostic Tests

Esophagogastroduodenoscopy

Patients with one or more of the alarm symptoms listed in Table 26-5 should undergo expeditious upper endoscopy. Esophagogastroduodenoscopy (EGD) is a safe and accurate outpatient procedure performed under conscious sedation.³⁸ Smaller flexible scopes with excellent optics and a working channel are easily passed transnasally in the unsedated patient. Following an 8-hour fast, the flexible scope is advanced under direct vision into the esophagus, stomach, and duodenum. The fundus and GE junction are inspected by retroflexing the scope. To rule out cancer with a high degree of accuracy, all patients with gastric ulcer diagnosed on upper GI series or found at EGD should have multiple biopsy specimens of the base and rim of the lesion. Brush cytology also should be considered. Gastritis should be biopsied both for histologic examination and for a tissue urease test to rule out the presence of H. pylori. If Helicobacter infection is detected, it should probably be treated because of the etiologic association with peptic ulcers, mucosa-associated lymphoid tissue (MALT), and gastric cancer. The most serious complications of EGD are perforation (which is rare, but can occur anywhere from the cervical esophagus to the duodenum), aspiration, and respiratory depression from excessive sedation. Although EGD is a more sensitive test than double-contrast upper GI series, these modalities should be considered complementary rather than mutually exclusive.

Radiologic Tests

Plain abdominal X-rays may be helpful in the diagnosis of gastric perforation (pneumoperitoneum) or delayed gastric emptying (large air-fluid level).

Double-contrast upper GI series may be better than EGD at elucidating gastric diverticula, fistula, tortuosity, stricture location, and size of hiatal hernia. Although there are radiologic characteristics of ulcers that suggest the presence or absence of malignancy, gastric ulcers always require adequate biopsy.

Computed Tomographic Scanning and Magnetic Resonance Imaging

Usually, significant gastric disease can be diagnosed without these sophisticated imaging studies. However, one or the other should be part of the routine staging work-up for most patients with a malignant gastric tumor. Magnetic resonance imaging (MRI) may prove clinically useful as a quantitative test for gastric emptying, and may even hold some promise for the analysis of myoelectric derangements in patients with gastroparesis. Virtual gastroscopy using multi detector CT scan or MRI is not yet widely used but these techniques may prove useful for screening and staging of gastric disease.^39,40,41 (Fig. 26-21).

Arteriography may be helpful in the occasional poor-risk patient with exsanguinating gastric hemorrhage, or in the patient with occult gastric bleeding.

Endoscopic Ultrasound

Endoscopic ultrasound (EUS) is useful in the evaluation and management of some gastric lesions.^42,43,44 Local staging of gastric adenocarcinoma with EUS is quite accurate, and this modality can be used to plan therapy. At some centers, patients with transmural and/or node positive adenocarcinoma of the stomach are considered for preoperative (neoadjuvant) chemoradiation therapy. EUS is the best way to clinically stage these patients locoregionally. Suspicious nodes can be sampled with EUS-guided endoscopic needle biopsy. Malignant tumors that are confined to the mucosa on EUS may be amenable to endoscopic mucosal resection (EMR). EUS also can be used to assess tumor response to chemotherapy. Submucosal masses are commonly discovered during routine EGD. Large submucosal masses should be resected because of the risk of malignancy, but observation may be appropriate for some small submucosal masses (e.g., lipoma or small GIST). There are endoscopic characteristics of benign and malignant mesenchymal tumors, and thus, EUS can provide reassurance, but no guarantee, that small lesions under observation are probably benign. Submucosal varices also can be assessed by EUS.

Gastric Secretory Analysis

Analysis of gastric acid output requires gastric intubation, and it is performed infrequently nowadays. This test may be useful in the evaluation of patients with hypergastrinemia, including the Zollinger-Ellison syndrome (ZES), patients with refractory ulcer or GERD, and patients with recurrent ulcer after operation. Historically, gastric analysis was performed most commonly to test for the adequacy of vagotomy in postoperative patients with recurrent or persistent ulcer. Now this can be done by assessing peripheral pancreatic polypeptide levels in response to sham feeding.⁴⁵ A 50% increase in pancreatic polypeptide within 30 minutes of sham feeding suggests vagal integrity.

Normal basal acid output (BAO) is greater than 5 mEq/h. MAO is the average of the two final stimulated 15-minute periods and is usually 10 to 15 mEq/h. Peak acid output is defined as the highest of the four stimulated periods. Patients with a gastrinoma commonly have a high BAO, often above 30 mEq/h, but consistently above 15 mEq/h unless there has been previous vagotomy or gastric resection. In patients with gastrinoma, the ratio of BAO to MAO exceeds 0.6. Normal acid output in the patient prescribed acid-suppressive medication usually means that the patient is noncompliant. To assess acid-secretory capacity in the absence of medication effect, H₂ blockers and PPIs should be withheld before gastric analysis.

Scintigraphy

The standard scintigraphic evaluation of gastric emptying involves the ingestion of a test meal with one or two isotopes, and scanning the patient under a gamma camera. A curve for liquid and solid emptying is plotted, and the half-time calculated. Normal standards exist for each facility. Duodenogastric reflux can be quantitated by the IV administration of hepatobiliary iminodiacetic acid (HIDA scan), which is concentrated and excreted by the liver into the duodenum. Software allows a semiquantitative assessment of how much of the isotope refluxes into the stomach. Positron emission tomography (PET) scan or CT/PET scan may be useful in staging certain patients with gastric malignancy.

Tests for Helicobacter pylori.

A variety of tests can help the clinician to determine whether the patient has active H. pylori infection.⁴⁶ The predictive value (positive and negative) of any of these tests when used as a screening tool depends on the prevalence of H. pylori infection in the screened population. A positive test is quite accurate in predicting H. pylori infection, but a negative test is characteristically unreliable. Thus, in the appropriate clinical setting, treatment for H. pylori should be initiated on the basis of a positive test, but not necessarily withheld if the test is negative. Because of the association between H. pylori infection and gastric lymphoma and carcinoma, many clinicians recommend treating Helicobacter infection when the diagnosis is made.

A positive serologic test is presumptive evidence of active infection if the patient has never been treated for H. pylori. Histologic examination of an antral mucosal biopsy using special stains is the gold standard test. Other sensitive tests include commercially available rapid urease tests, which assay for the presence of urease in mucosal biopsy specimens (strong presumptive evidence of infection). Urease is an omnipresent enzyme in H. pylori strains that colonize the gastric mucosa. The labeled carbon-13 urea breath test has become the standard test to confirm eradication of H. pylori following appropriate treatment.⁴⁷ In this test, the patient ingests urea labeled with nonradioactive ¹³C. The labeled urea is acted upon by the urease present in the H. pylori and converted into ammonia and carbon dioxide. The radiolabeled carbon dioxide is excreted from the lungs and can be detected in the expired air (Fig. 26-22). It also can be detected in a blood sample. The fecal antigen test also is quite sensitive and specific for active H. pylori infection and may prove more practical in confirming a cure.

Antroduodenal Motility Testing and Electrogastrography

Antroduodenal motility testing and electrogastrography (EGG) are performed in specialized centers and may be useful in the evaluation of the patient with anomalous epigastric symptoms. EGG consists of the transcutaneous recording of gastric myoelectric activity. Antroduodenal motility testing is done with a tube placed transnasally or transorally into the distal duodenum. There are pressure-recording sensors extending from the stomach to the distal duodenum. The combination of these two tests together with scintigraphy provides a thorough assessment of gastric motility.

Peptic ulcers are focal defects in the gastric or duodenal mucosa that extend into the submucosa or deeper. They may be acute or chronic and, ultimately, are caused by an imbalance between mucosal defenses and acid/peptic injury (Fig. 26-23).^48,49 Peptic ulcer remains a common outpatient diagnosis, but the number of physician visits, hospital admissions, and elective operations for PUD has decreased steadily and dramatically over the past three decades. Interestingly, the start of these trends all predated the use of H₂ receptor blockers, or proton pump inhibitors, fiber-optic endoscopy, and highly selective vagotomy. However, the incidence of emergency surgery and the death rate associated with peptic ulcers has not decreased nearly so dramatically. These epidemiologic changes probably represent the net effect of several factors, including (beneficially) decreased prevalence of H. pylori infection, better medical therapy, and increased outpatient management; and (detrimentally) the use of NSAIDs and aspirin (with and without ulcer prophylaxis) in an aging population with multiple risk factors.

PUD is one of the most common GI disorders in the United States with a prevalence of about 2%, and a lifetime cumulative prevalence of about 10%, peaking around age 70 years.⁵⁰ The costs of PUD, including lost work time and productivity, are estimated to be above $8 billion per year in the United States. In 1998, approximately 1.5% of all Medicare hospital costs were spent treating PUD, and the crude mortality rate for peptic ulcer was 1.7 per 100,000 individuals. Using the National Inpatient Sample, it can be estimated that the mortality rate in patients hospitalized in 2006 with duodenal ulcer was 3.7% compared to 2.1% for gastric ulcer.⁵¹ Recent studies have shown an increase in the rates of hospitalization and mortality in elderly patients for the peptic ulcer complications of bleeding and perforation. This may be due in part to the increasingly common use of NSAIDs and aspirin in this elderly cohort, many of whom also have H. pylori infection.

Pathophysiology and Etiology

A variety of factors may contribute to the development of PUD. Although it is now recognized that the large majority of duodenal and gastric ulcers are caused by H. pylori infection and/or NSAID use^17,52(Fig. 26-24), the final common pathway to ulcer formation is acid-peptic injury of the gastroduodenal mucosal barrier. Thus, the adage “no acid, no ulcer” remains true. Acid suppression heals both duodenal and gastric ulcers and prevents recurrence. In general H. pylori predisposes to ulceration, both by acid hypersecretion and by compromise of mucosal defense mechanisms. NSAID use causes ulcers predominantly by compromise of mucosal defenses. Duodenal ulcer was traditionally viewed as a disease of increased acid-peptic action on the duodenal mucosa, whereas gastric ulcer was viewed as a disease of weakened mucosal defenses. An increased understanding of peptic ulcer pathophysiology has blurred this overly simplistic distinction. Clearly, weakened mucosal defenses play a role in both duodenal and gastric ulcers and acid hypersecretion may result in a duodenal or gastric ulcer in the setting of normal mucosal defenses.

Elimination of H. pylori infection or NSAID use is important for optimal ulcer healing, and perhaps is even more important in preventing ulcer recurrence and/or complications. A variety of other diseases are known to cause peptic ulcer, including ZES (gastrinoma), antral G-cell hyperfunction and/or hyperplasia, systemic mastocytosis, trauma, burns, and major physiologic stress. Other causative agents include drugs (all NSAIDs, aspirin, and cocaine), smoking, and psychologic stress. In the United States, probably more than 90% of serious peptic ulcer complications can be attributed to H. pylori infection, NSAID use, and/or cigarette smoking.

Helicobacter pylori Infection

With specialized flagella and a rich supply of urease, H. pylori is uniquely equipped for survival in the hostile environment of the stomach.^53,54,55 About 50% of the world’s population is infected with H. pylori, a major cause of chronic gastritis. The same sequence of inflammation to metaplasia to dysplasia to carcinoma, that is well known to occur in the esophagus from reflux-induced inflammation (and in the colon from inflammatory bowel disease), is now increasingly well recognized to occur in the stomach with Helicobacter-induced gastritis. The influence of prolonged acid suppression with PPIs or H₂RAs on these esophagogastric processes is largely unknown. Helicobacter also clearly has an etiologic role in the development of gastric lymphoma.

The organism possesses the enzyme urease, which converts urea into ammonia and bicarbonate, thus creating an environment around the bacteria that buffers the acid secreted by the stomach. The ammonia is damaging to the surface epithelial cells. Mutant strains of H. pylori that do not produce urease are unable to colonize the stomach. The organism lives in the mucus layer atop the gastric SECs, and some attach to these cells (Fig. 26-25).^53,54 Apparently Helicobacter strains that lack flagella are unable to navigate through the unstirred mucus layer to get to the apical membrane of the SEC for attachment, and are nonpathogenic. One of the mechanisms by which Helicobacter causes gastric injury may be through a disturbance in gastric acid secretion. This is due, in part, to the inhibitory effect that H. pylori exerts on antral D cells that secrete somatostatin, a potent inhibitor of antral G-cell gastrin production. H. pylori infection is associated with decreased levels of somatostatin, decreased somatostatin messenger RNA production, and fewer somatostatin-producing D cells. These effects are probably mediated by H. pylori–induced local alkalinization of the antrum (antral acidification is the most potent antagonist to antral gastrin secretion), and H. pylori–mediated increases in other local mediators and cytokines. The result is hypergastrinemia and acid hypersecretion (Fig. 26-26).⁴⁹ This hypergastrinemia presumably leads to the parietal cell hyperplasia seen in many patients with duodenal ulcer. The acid hypersecretion and the antral gastritis are thought to lead to antral epithelial metaplasia in the postpyloric duodenum. This duodenal metaplasia allows H. pylori to colonize the duodenal mucosa and, in these patients, the risk of developing a duodenal ulcer increases 50-fold. When H. pylori colonizes the duodenum, there is a significant decrease in acid-stimulated duodenal bicarbonate release. When H. pylori infection is successfully treated, acid secretory physiology tends to normalize. Other mechanisms whereby H. pylori can induce gastroduodenal mucosal injury include the production of toxins (vacA and cagA), local elaboration of cytokines (particularly interleukin-8) by infected mucosa, recruitment of inflammatory cells and release of inflammatory mediators, recruitment and activation of local immune factors, and increased apoptosis (Fig. 26-27).^54,55 The net effect is a weakening of mucosal defenses.The mechanism by which the helicobacter organism avoids recognition and destruction by the mucosal immune system is a topic of interest and active research.⁵⁶

The evidence supporting the central role of H. pylori in the pathophysiology of PUD is strong. Patients with H. pylori infection and antral gastritis are three and one-half times more likely to develop PUD than patients without H. pylori infection. Up to 90% of patients with duodenal ulcers, and 70% to 90% of patients with gastric ulcers, have H. pylori infection. It is clear from multiple randomized prospective studies that curing H. pylori infection dramatically alters the natural history of PUD, decreasing the recurrent ulcer rate from more than 75% in patients treated with a course of acid-suppressive therapy alone (in whom H. pylori is not eradicated) to less than 20% in patients treated with a course of antibacterial therapy (Fig. 26-28).⁵⁷

Obviously, other factors are involved in the etiology of PUD because many patients colonized with H. pylori do not get peptic ulcer disease, and many patients with peptic ulcer disease do not have H. pylori infection. These observations notwithstanding, it is clear from a variety of well-designed laboratory, clinical, and epidemiologic studies that H. pylori is indubitably an important factor in the development and recurrence of PUD. H. pylori also plays an etiologic role in gastric cancer and lymphoma.⁵⁴

Acid Secretion and Peptic Ulcer

A variety of abnormalities related to mucosal acid exposure have been described in patients with duodenal ulcer (Fig. 26-29).⁵⁸ Although duodenal ulcer patients as a group have a higher mean BAO and mean MAO compared to normal controls, many duodenal ulcer patients have basal and peak acid outputs in the normal range, and there is no correlation between acid secretion and the severity of the ulcer disease. As a group, duodenal ulcer patients produce more acid than normal controls in response to any known acid secretory stimulus. Although they usually have normal fasting serum gastrin levels, DU patients often produce more gastric acid at any given dose of gastrin than controls. Considering that many duodenal ulcer patients do produce excessive gastric acid, it has been argued that a “normal” fasting gastrin level in these patients is inappropriately high, and that there is an impaired feedback mechanism, especially in light of the apparently increased sensitivity of the parietal cell mass to gastrin. Many of these long-standing observations now seem reasonable in light of recently gained understanding of the perturbations in acid and gastrin secretion associated with H. pylori infection. Some patients with duodenal ulcer also have increased rates of gastric emptying that deliver an increased acid load per unit of time to the duodenum. Finally, the buffering capacity of the duodenum in many patients with duodenal ulcer is compromised due to decreased duodenal bicarbonate secretion.

In patients with gastric ulcer, acid secretion is variable. Currently, five types of gastric ulcer are described, although the original Johnson classification contained three types (Fig. 26-30).⁵⁹ The most common, Johnson type I gastric ulcer, is typically located near the angularis incisura on the lesser curvature, close to the border between antral and corpus mucosa. Patients with type I gastric ulcer usually have normal or decreased acid secretion. Type II gastric ulcer is associated with active or quiescent duodenal ulcer disease, and type III gastric ulcer is prepyloric ulcer disease. Both type II and type III gastric ulcers are associated with normal or increased gastric acid secretion. Type IV gastric ulcers occur near the GE junction, and acid secretion is normal or below normal. Type V gastric ulcers are medication induced and may occur anywhere in the stomach. Patients with gastric ulcers may have weak mucosal defenses that permit an abnormal amount of injurious acid back-diffusion into the mucosa. Duodenogastric reflux may play a role in weakening the gastric mucosal defenses, and a variety of components in duodenal juice, including bile, lysolecithin, and pancreatic juice, have been shown to cause injury and inflammation in the gastric mucosa. NSAIDs and aspirin have similar effects. Although chronic gastric ulcer usually is associated with surrounding gastritis, it is unproven that the latter leads to the former.

Nonsteroidal Anti-Inflammatory Drugs in Peptic Ulcer Disease

Chronic use of NSAIDs (including aspirin) increases the risk of peptic ulcer disease about 5-fold and upper GI bleeding about 4-fold.^60,61 Complications of PUD (specifically hemorrhage and perforation) are much more common in patients taking NSAIDs. More than half of patients who present with peptic ulcer hemorrhage or perforation report the recent use of NSAIDs, including aspirin. Many of these patients remain asymptomatic until they develop these life-threatening complications.

The overall risk of significant serious adverse GI events in patients taking NSAIDs is more than three times that of controls (Table 26-6). This risk increases to five times in patients more than age 60 years old. In elderly patients taking NSAIDs, the likelihood that they will require an operation related to a GI complication is 10 times that of the control group, and the risk that they will die from a GI cause is about four and one-half times higher. This problem is put into perspective when one realizes that approximately 20 million patients in the United States take NSAIDs on a regular basis; probably more regularly take aspirin. Persons who take NSAIDs also have a higher hospitalization rate for serious GI events than those who do not.

Factors that clearly put patients at increased risk for NSAID-induced GI complications include age >60, prior GI event, high NSAID dose, concurrent steroid intake, and concurrent anticoagulant intake. ANY patient taking NSAIDs or aspirin who has one or more of these risk factors should receive concomitant acid suppressive medication⁶² (Table 26-7). High dose H2 blockers have been shown to be less effective than PPIs in preventing GI complications in these high risk patients on antiplatelet therapy, but clearly they are better than no acid suppression.

Smoking, Stress, and Other Factors

Epidemiologic studies suggest that smokers are about twice as likely to develop PUD as nonsmokers. Smoking increases gastric acid secretion and duodenogastric reflux. Smoking decreases both gastroduodenal prostaglandin production and pancreaticoduodenal bicarbonate production. These observations may be related, and any or all could explain the observed association between smoking and PUD.

Although difficult to measure, both physiologic and psychologic stress undoubtedly play a role in the development of peptic ulcer in some patients. In 1842, Curling described duodenal ulcer and/or duodenitis in burn patients. Decades later, Cushing described the appearance of acute peptic ulceration in patients with head trauma (Cushing’s ulcer). Even the ancients recognized the undeniable links between PUD and stress. Patients still present with ulcer complications (bleeding, perforation, and obstruction) that are seemingly exacerbated by stressful life events. The use of crack cocaine has been linked to juxtapyloric peptic ulcers with a propensity to perforate. Alcohol is commonly mentioned as a risk factor for PUD, but confirmatory data are lacking.

Clinical Manifestations

More than 90% of patients with PUD complain of abdominal pain. The pain is typically nonradiating, burning in quality, and located in the epigastrium. The mechanism of the pain is unclear. Patients with duodenal ulcer often experience pain 2 to 3 hours after a meal and at night. Two thirds of patients with duodenal ulcers will complain of pain that awakens them from sleep. The pain of gastric ulcer more commonly occurs with eating and is less likely to awaken the patient at night. A history of PUD, use of NSAIDs, over-the-counter antacids, or antisecretory drugs is suggestive of the diagnosis. Other signs and symptoms include nausea, bloating, weight loss, stool positive for occult blood, and anemia. Duodenal ulcer is about twice as common in men compared to women, but the incidence of gastric ulcer is similar in men and women. On average, gastric ulcer patients are older than duodenal ulcer patients, and the incidence is increasing in the elderly, perhaps because of increasing NSAID and aspirin.

Diagnosis

In the young patient with dyspepsia and/or epigastric pain, it may be appropriate to initiate empirical PPI therapy for PUD without confirmatory testing. In such cases, it is prudent to discuss with the patient the small possibility of an alternative diagnosis, including malignancy, even if symptoms improve with the initiation of therapy. All patients more than 45 years old with the above symptoms should have an upper endoscopy, and all patients, regardless of age, should have this study if any alarm symptoms (see Table 26-5) are present. A double-contrast upper GI X-ray study may be useful. Once an ulcer has been confirmed endoscopically or radiologically, obvious possible causes (Helicobacter, NSAIDs, gastrinoma, cancer) should always be considered. All gastric ulcers should be adequately biopsied, and any sites of gastritis should be biopsied to rule out H. pylori, and for histologic evaluation. Additional testing for H. pylori may be indicated. It is not unreasonable to test all peptic ulcer patients for H. pylori (Table 26-8) 63A baseline serum gastrin level is appropriate to rule out gastrinoma.

Complications

The three most common complications of PUD, in decreasing order of frequency, are bleeding, perforation, and obstruction.^51,52,64 Most peptic ulcer–related deaths in the United States are due to bleeding. Bleeding peptic ulcers are by far the most common cause of upper GI bleeding in patients admitted to hospital (Fig. 26-31).⁶⁵ Patients with a bleeding peptic ulcer typically present with melena and/or hematemesis. Nasogastric aspiration is usually confirmatory of the upper GI bleeding. Abdominal pain is quite uncommon. Shock may be present, necessitating aggressive resuscitation and blood transfusion. Early endoscopy is important to diagnose the cause of the bleeding and to assess the need for hemostatic therapy.

Three-fourths of the patients who come to the hospital with bleeding peptic ulcer will stop bleeding if given acid suppression and nothing by mouth. However, one fourth will continue to bleed or will rebleed after an initial quiescent period, and virtually all the mortalities (and all the operations for bleeding) occur in this group. This group can be fairly well delineated based on clinical factors related to the magnitude of the hemorrhage, comorbidities, age, and endoscopic findings. Shock, hematemesis, transfusion requirement exceeding four units in 24 hours, and certain endoscopic stigmata (active bleeding or visible vessel) define this high-risk group. Two widely used risk stratification tools have proven useful in predicting rebleeding and death: the Blatchford and Rockall scores (Table 26-9).⁶⁶ High-risk patients benefit from endoscopic therapy to stop the bleeding. The most common endoscopic hemostatic modalities used are injection with epinephrine, and electrocautery. In a case with exposed vessel, mechanical hemostasis using a clip is useful to control the bleeding.^66A Persistent bleeding or rebleeding after endoscopic therapy is an indication for operation, although repeat endoscopic treatment has been successful in treating rebleeding. Elderly patients and patients with multiple comorbidities do not tolerate repeated episodes of hemodynamically significant hemorrhage, and may benefit from early elective operation after initially successful endoscopic treatment, especially if they have a high-risk ulcer.

Planned surgery under controlled circumstances often yields better outcomes than emergent surgery. Deep bleeding ulcers on the posterior duodenal bulb or lesser gastric curvature are high-risk lesions, because they often erode large arteries not amenable to nonoperative treatment, and early operation should be considered.

Perforated peptic ulcer usually presents as an acute abdomen. The patient can often give the exact time of onset of the excruciating abdominal pain. Initially, a chemical peritonitis develops from the gastric and/or duodenal secretions, but within hours a bacterial peritonitis supervenes. The patient is in obvious distress, and the abdominal examination shows peritoneal signs. Usually, marked involuntary guarding and rebound tenderness is evoked by a gentle examination. Upright chest X-ray shows free air in about 80% of patients (Fig. 26-32). Once the diagnosis has been made, the patient is given analgesia and antibiotics, resuscitated with isotonic fluid, and taken to the operating room. Fluid sequestration into the third space of the inflamed peritoneum can be impressive, so preoperative fluid resuscitation is mandatory. Sometimes, the perforation has sealed spontaneously by the time of presentation, and surgery can be avoided if the patient is doing well. Nonoperative management is appropriate only if there is objective evidence that the leak has sealed (i.e., radiologic contrast study), and in the absence of clinical peritonitis.

Gastric outlet obstruction occurs in no more than 5% of patients with PUD. It is usually due to duodenal or prepyloric ulcer disease, and may be acute (from inflammatory swelling and peristaltic dysfunction) or chronic (from cicatrix). Patients typically present with nonbilious vomiting and may have a profound hypokalemic hypochloremic metabolic alkalosis. Pain or discomfort is common. Weight loss may be prominent, depending on the duration of symptoms. A succussion splash may be audible with stethoscope placed in the epigastrium. Initial treatment is nasogastric suction, IV hydration and electrolyte repletion, and acid suppression. The diagnosis is confirmed by endoscopy. Most patients admitted to the hospital nowadays with obstructing ulcer disease require intervention, either balloon dilation or operation. Cancer must be ruled out because most patients who present with the symptoms of gastric outlet obstruction will have a pancreatic, gastric, or duodenal malignancy.

Medical Treatment of Peptic Ulcer Disease

PPIs are the mainstay of medical therapy for PUD, but high dose H₂RAs and sucralfate are also quite effective. Patients hospitalized for ulcer complications should receive PPI by continuous IV infusion and, when discharged, should be considered for lifelong PPIs unless the definitive cause is eliminated or a definitive operation performed. Peptic ulcer patients should stop smoking and avoid alcohol and NSAIDs (including aspirin). Patients who require NSAIDs or aspirin to treat other medical conditions should always take concomitant PPIs or high dose H₂ receptor blockers. If H. pylori infection is documented, it should be treated with one of several acceptable regimens (Table 26-10).⁶³ Infectious disease consultation may be helpful in the compliant, symptomatic patient with persistent H. pylori infection following treatment, or another regimen could be tried (e.g., quadruple therapy). If initial H. pylori testing is negative and ulcer symptoms persist, an empirical trial of anti-H. pylori therapy is reasonable since false-negative H. pylori tests are common. Generally, acid suppression can be stopped after 3 months if the ulcerogenic stimulus (usually H. pylori, NSAIDs, or aspirin) has been removed. However, long-term maintenance PPI therapy should be considered in all patients admitted to hospital with ulcer complications, all high-risk patients on NSAIDs or aspirin (the elderly or debilitated), and all patients with a history of recurrent ulcer or bleeding. Consideration should also be given to maintenance PPI therapy in refractory smokers with a history of peptic ulcer. Sucralfate acts locally on mucosal defects and is well tolerated, and occasionally is useful as a supplement to acid suppression.

Surgical Treatment of Peptic Ulcer Disease

The indications for surgery in PUD are bleeding, perforation, obstruction, and intractability or nonhealing.^67,68 Gastric cancer must always be considered in patients with gastric ulcer or gastric outlet obstruction.

Today, most patients undergoing operation for PUD have simple oversewing of a bleeding ulcer or simple patch of a perforated ulcer.⁵¹ Simultaneous performance of vagotomy either truncal or highly selective is increasingly uncommon, probably due to surgeon unfamiliarity with the procedure and reliance on postoperative PPIs to decrease acid secretion.

Unfortunately, the data from many excellent randomized clinical trials evaluating elective operation for peptic ulcer over the last several decades may be irrelevant to most patients presenting for ulcer surgery today.⁶⁷ The large majority of these excellent studies were done in the pre-PPI, pre-Helicobacter, pre-NSAID era, and focused on elective operation for intractable disease, an unusual indication for operation nowadays. Thus, today’s surgeon should take great care in applying this literature to inform surgical decision making.

Traditionally, the vast majority of peptic ulcers were treated by a variant of one of the three basic operations: parietal cell vagotomy also called highly selective vagotomy or proximal gastric vagotomy (HSV), vagotomy and drainage (V+D), and vagotomy and distal gastrectomy. Recurrence rates were lowest but morbidity highest with the latter procedure, while the opposite was true for HSV (Table 26-11).^67,68,69

HSV severs the vagal nerve supply to the proximal two thirds of the stomach, where essentially all the parietal cells are located, and preserves the vagal innervation to the antrum and pylorus, and the remaining abdominal viscera (Fig. 26-33). Thus, the operation decreases total gastric acid secretion by about 75%, and GI side effects are rare. Elective HSV has largely been supplanted by long-term PPI treatment, but the operation, which has a learning curve, may still be useful in the patient (elective or emergent) who is noncompliant with, intolerant of, or cannot afford medical treatment. Historically, HSV has not performed particularly well for type II (gastric and duodenal) and III (prepyloric) gastric ulcer, perhaps because of hypergastrinemia caused by gastric outlet obstruction and persistent antral stasis. The Taylor procedure consists of a posterior truncal vagotomy and anterior seromyotomy (but anterior HSV is probably equivalent), and is an attractive and simple alternative to HSV with similar results.

Truncal vagotomy and pyloroplasty, and truncal vagotomy and gastrojejunostomy are the paradigmatic vagotomy and drainage procedures. HSV may be substituted for truncal vagotomy. The advantage of V + D is that it can be performed safely and quickly by the experienced surgeon. The main disadvantages are the side effect profile (10% of patients have significant dumping and/or diarrhea). During truncal vagotomy (Fig. 26-34), care must be taken not to perforate the esophagus, a potentially lethal complication. Intraoperative frozen section confirmation of at least two vagal trunks is prudent; additional vagal trunks are common. Unlike HSV, V + D is widely accepted as a successful definitive operation for complicated PUD. It has been described as a useful part of the operative treatment for bleeding duodenal and gastric ulcer, perforated duodenal and gastric ulcer, and obstructing duodenal and gastric (type II and III) ulcer. When applied to gastric ulcer, the ulcer should be excised or biopsied.

Truncal vagotomy denervates the antropyloric mechanism, and therefore, some sort of procedure is necessary to ablate or bypass the pylorus. Gastrojejunostomy is a good choice in patients with gastric outlet obstruction or a severely diseased proximal duodenum. The anastomosis is done between the proximal jejunum and the most dependent portion of the greater gastric curvature, in either an antecolic or retrocolic fashion (Fig. 26-35). Marginal ulceration is a potential complication. Pyloroplasty is useful in patients who require a pyloroduodenotomy to deal with the ulcer complication (e.g., posterior bleeding duodenal ulcer), in those with limited or focal scarring in the pyloric region, or when gastrojejunostomy is technically difficult. The most commonly performed pyloroplasty is the Heineke-Mikulicz type (Fig. 26-36). Other occasionally useful techniques include the Finney (Fig. 26-37) and the Jaboulay pyloroplasties (Fig. 26-38). These more extensive pyloroplasty techniques may make subsequent distal gastric resection more difficult and/or hazardous.

Although vagotomy and antrectomy (V + A) is associated with a very low ulcer recurrence rate and is applicable to many patients with complicated PUD (e.g., bleeding duodenal and gastric ulcer, obstructing peptic ulcer, nonhealing gastric ulcer, and recurrent ulcer), V + A has a higher operative mortality risk (compared with HSV or V + D), and is irreversible. Following antrectomy, GI continuity may be reestablished with a Billroth I gastroduodenostomy (Fig. 26-39) or a Billroth II loop gastrojejunostomy (Fig. 26-40). Since antrectomy routinely leaves a 60% to 70% gastric remnant, routine reconstruction as a Roux-en-Y gastrojejunostomy should be avoided (Fig. 26-41). Although the Roux-en-Y operation is an excellent procedure for keeping duodenal contents out of the stomach and esophagus, in the presence of a large gastric remnant, this reconstruction will predispose to marginal ulceration and/or gastric stasis.

V + A should be avoided in hemodynamically unstable patients, and in patients with extensive inflammation and/or scarring of the proximal duodenum, because secure anastomosis (Billroth I) or duodenal closure (Billroth II) may be difficult.

Distal gastrectomy without vagotomy (usually about a 50% gastrectomy to include the ulcer) has traditionally been the procedure of choice for type I gastric ulcer. The addition of vagotomy should be considered for type II and III gastric ulcers (because the pathophysiology is more analogous to duodenal ulcer), or if the patient is believed to be at increased risk for recurrent ulcer, or perhaps even if Billroth II reconstruction is contemplated (to decrease the chance of marginal ulcer). Subtotal gastrectomy (75% distal gastrectomy) without vagotomy is rarely used to treat PUD today, although it was the most popular ulcer operation at the middle of the last century.

Pylorus preserving gastrectomy (PPG) was first reported as a surgical option for gastric ulcer which could minimize both dumping and duodenogastric reflux. Though not widely adopted for this indication, in some centers PPG is considered a good minimally invasive surgical option for early gastric cancer.^69A,69B

Choice of Operation for Peptic Ulcer

The choice of operation for the individual patient with PUD depends on a variety of factors, including the type of ulcer (duodenal, gastric, recurrent, or marginal), the indication for operation, and the condition of the patient, among others. Other important considerations are intra-abdominal factors (duodenal scarring/inflammation, adhesions, or difficult exposure), the ulcer diathesis status of the patient, the surgeon’s experience and personal preference, whether H. pylori infection is present, the need for NSAID therapy, previous treatment, and the likelihood of future compliance with treatment. Table 26-12 shows the surgical options for managing various aspects of PUD. In general, resective procedures have a lower ulcer recurrence rate, but a higher operative morbidity and mortality rate (see Table 26-11) compared to nonresective ulcer operations. Because ulcer recurrence often is related to H. pylori and/or NSAIDs, it is usually managed adequately without reoperation. Thus, gastric resection to minimize recurrence in duodenal ulcer disease is often not justified today; resection for gastric ulcer remains the standard because of the risk of cancer. Clearly, the modern trend in peptic ulcer operation could be described as “less is more.”^70,71 Vagotomy as a component of emergency ulcer operation is increasingly uncommon.

Bleeding Peptic Ulcer

Bleeding is the most common cause of ulcer-related death, but most patients admitted to hospital with bleeding gastric or duodenal ulcer today will not require an operation. In many hospitals, operation for ulcer perforation is much more common than operation for bleeding ulcer. The success of endoscopic treatment and medical therapy in treating and preventing bleeding PUD has resulted in the selection of a small subgroup of high-risk patients for today’s surgeon. It is likely that patients currently coming to operation for bleeding PUD are at higher risk for a poor outcome than ever before. The surgical options for treating bleeding PUD include suture ligation of the bleeder; suture ligation and definitive nonresective ulcer operation (HSV or V + D); and gastric resection (usually, including vagotomy and ulcer excision). Gastric ulcer requires biopsy if not resected.

The management of bleeding peptic ulcer is summarized in the algorithm provided in Fig. 26-42. All patients admitted to hospital with bleeding peptic ulcer should be adequately resuscitated and started on continuous IV PPI.72 Seventy-five percent of patients will stop bleeding with these measures alone, but 25% will continue to bleed or will rebleed in hospital. It is important to identify this high-risk group early with clinical and endoscopic parameters because, essentially, all the deaths from bleeding ulcer occur in this group. Surgical consultation is mandatory, and endoscopic hemostatic therapy (cautery, epinephrine injection, clipping) is indicated and usually successful in these high-risk patients.^73,74 Indications for operation include massive hemorrhage unresponsive to endoscopic control, and transfusion requirement of more than four to six units of blood, despite attempts at endoscopic control. Lack of availability of a therapeutic endoscopist, recurrent hemorrhage after one or more attempts at endoscopic control, lack of availability of blood for transfusion, repeat hospitalization for bleeding ulcer, and concurrent indications for surgery such as perforation or obstruction, are also indications for surgery. Patients with massive bleeding from high-risk lesions (e.g., posterior duodenal ulcer with erosion of gastroduodenalartery, or lesser curvature gastric ulcer with erosion of left gastric artery or branch) should be considered for early operation. Early operation should also be considered in patients more than 60 years of age, those presenting in shock, those requiring more than four units of blood in 24 hours or eight units of blood in 48 hours, those with rebleeding, and those with ulcers >2 cm in diameter. The mortality rate for surgery for bleeding peptic ulcer is around 20%. Angiography and embolization may be useful in some patients.

Operation for Bleeding Peptic Ulcer

(Fig. 26-43)

The two operations most commonly used for bleeding duodenal ulcer are oversewing of the ulcer usually without vagotomy,⁷⁰ or V + A. Oversewing alone results in a higher rebleeding rate but a lower operative mortality rate. When the mortality for reoperation for rebleeding is considered, the overall mortality is probably comparable for the two approaches. Patients who are in shock or medically unstable should not have gastric resection.

An initial pyloromyotomy incision allows access to the bleeding posterior duodenal ulcer, and an expeditious Kocher maneuver allows the surgeon to control the hemorrhage with the left hand if necessary. Heavy suture material on a stout needle is used to place figure-of-eight sutures or a U-stitch to secure the bleeding vessel at the base of the posterior duodenal ulcer. Multiple sutures are usually necessary. Once the surgeon is unequivocally convinced that hemostasis is secure, a pyloroplasty can be performed. If the patient is stable, vagotomy may be considered if the surgeon is experienced and the vagotomy straightforward. If the patient is not a high operative risk and V + A is selected, smaller duodenal ulcers are resected with the specimen; larger bleeding duodenal ulcers must often be left behind in the duodenal stump. In this situation, suture hemostasis must be attained and a secure duodenal closure accomplished. The anterior wall of the open duodenum can be sutured to either the proximal or distal lip of the posterior ulcer once the bleeding vessel has been sutured. The duodenal closure can be buttressed with omentum and the duodenum should be decompressed, either with a lateral duodenostomy or retrograde tube via the proximal jejunum or nasogastric tube secured with tip well into afferent limb. Right upper quadrant closed suction peritoneal drainage is important. Use of a feeding jejunostomy is also considered. A Billroth II anastomosis reestablishes gastrointestinal continuity.

The initial management of bleeding gastric ulcers and the indications for operation are similar to those for bleeding duodenal ulcer. These lesions tend to occur in older and/or medically complicated patients, and this fact may increase the operative risk. However, experience shows that planned surgery in a resuscitated patient results in a better operative survival rate than emergent operation in a patient who has rebled and is in shock. Distal gastric resection to include the bleeding ulcer is the procedure of choice for bleeding gastric ulcer. Second best is V + D with oversewing and biopsy of the ulcer to rule out cancer. Oversewing of the bleeder followed by long-term acid suppression is a reasonable alternative in high-risk or unstable patients.

Perforated Peptic Ulcer (Fig. 26-44)

Perforation is the second most common complication of peptic ulcer but nowadays a more common indication for operation than bleeding. As with bleeding ulcer, NSAID and/or aspirin use have been inextricably linked with perforated PUD, especially in the elderly population.⁶¹ Surgery is almost always indicated for ulcer perforation, although occasionally nonsurgical treatment can be used in the stable patient without peritonitis in whom radiologic studies document a sealed perforation. Patients with acute perforation and GI blood loss (either chronic or acute) should be suspected of having a second ulcer or a GI cancer.

The options for surgical treatment of perforated duodenal ulcer are simple patch closure, patch closure and HSV, or patch closure and V + D. Simple patch closure, currently the most commonly performed operation for perforated peptic ulcer, should be done in patients with hemodynamic instability and/or exudative peritonitis signifying a perforation >24 hours old. In stable patients without longstanding perforation, the addition of HSV may be considered. However, in the United States and Western Europe, there is clearly a trend away from definitive operation for perforated duodenal ulcer, probably because of the ready availability of PPI, and surgeon unfamiliarity with definitive operation in this setting.^51,70

In the stable patient without multiple operative risk factors, perforated gastric ulcers are best treated by distal gastric resection. Vagotomy is usually added for type II and III gastric ulcers. Patch closure with biopsy; or local excision and closure; or biopsy, closure, truncal vagotomy, and drainage are alternative operations in the unstable or high-risk patient, or in the patient with a perforation in an inopportune location. All perforated gastric ulcers, even those in the prepyloric position, should be biopsied if they are not removed at surgery.

Obstructing Peptic Ulcer

Acute ulcers associated with obstruction due to edema and/or motor dysfunction may respond to intensive antisecretory therapy and nasogastric suction. But most patients with significant obstruction from chronic ulceration will require some sort of more substantial intervention. Endoscopic balloon dilation can often transiently improve obstructive symptoms, but many of these patients ultimately fail and come to operation.⁷⁵

The standard operation for obstructing PUD is vagotomy and antrectomy. Alternatively vagotomy and gastrojejunostomy should be considered if a difficult duodenal stump is anticipated with resection. HSV and gastrojejunostomy may be comparable to V+A for obstructing ulcer disease,⁷⁶ and sometimes has appeal because it can be done laparoscopically, and because it does not complicate future resection, if needed. However, potentially curable gastric or duodenal cancers can be missed with this approach.

Intractable or Nonhealing Peptic Ulcer

Intractability should be an unusual indication for peptic ulcer operation nowadays. The patient referred for surgical evaluation because of intractable PUD should raise red flags for the surgeon: Maybe the patient has a missed cancer; maybe the patient is noncompliant (not taking prescribed PPI, still taking NSAIDs, still smoking); maybe the patient has Helicobacter despite the presence of a negative test or previous treatment. Because acid secretion can be totally blocked and H. pylori eradicated with modern medication, the question remains: “Why does the patient have a persistent ulcer diathesis?” The surgeon should review the differential diagnosis of nonhealing ulcer before any consideration of operative treatment (Table 26-13).

Surgical treatment should be considered in patients with nonhealing or intractable PUD who have multiple recurrences, large ulcers (>2 cm), complications (obstruction, perforation, or hemorrhage), or suspected malignancy. Definitive operation, particularly gastric resection, should be considered most cautiously in the thin or marginally nourished individual.

It is important that the surgeon not fall into the trap of performing a large, irreversible operation on these patients, based on the unproven theory that if all other methods have failed to heal the ulcer, a large operation is required. Although there is a large quantity of very good data in the surgical literature suggesting that the large majority of patients do well after the larger elective ulcer operations, these data may not be particularly relevant to the modern patient.⁶⁷ Candidates for ulcer operation today are different than those of 30 to 50 years ago. One might argue that current medical care has healed the minor ulcers, and that patients presenting with true intractability or nonhealing will be more difficult to treat and are likely to have chronic problems after a major ulcer operation.

If surgery is necessary, a lesser operation may be preferable. It is prudent to avoid truncal vagotomy and/or distal gastrectomy as the initial elective operation for intractable peptic ulcer in the thin or asthenic patient. Alternatives for intractable duodenal ulcer include HSV with or without gastrojejunostomy (reversible drainage operation). In patients with nonhealing gastric ulcer, wedge resection with HSV should be considered in thin or frail patients. Otherwise, distal gastrectomy (to include the ulcer) is recommended. It is unnecessary to add a vagotomy in patients with type I or type IV (juxta-esophageal) gastric ulcers because they are usually associated with acid hyposecretion. Type IV gastric ulcers may be difficult to resect as part of a distal gastrectomy, and a variety of surgical techniques have been described to treat these more proximal lesions (Fig. 26-45).

Zollinger-Ellison Syndrome

ZES is caused by the uncontrolled secretion of abnormal amounts of gastrin by a duodenal or pancreatic neuroendocrine tumor (i.e., gastrinoma).^77,78,79 Most cases (80%) are sporadic, but 20% are inherited. The inherited or familial form of gastrinoma is associated with multiple endocrine neoplasia type I (MEN I), which consists of parathyroid, pituitary, and pancreatic (or duodenal) tumors. Gastrinoma is the most common pancreatic tumor in patients with MEN I. Patients with MEN I usually have multiple gastrinoma tumors, and surgical cure is less common; sporadic gastrinomas are more often solitary and are more often amenable to surgical cure. Currently, about 50% to 60% of gastrinomas are malignant, with lymph node, liver, or other distant metastases at operation. Five-year survival in patients presenting with metastatic disease is approximately 40%. The larger the primary gastrinoma, the higher the likelihood of metastatic disease. More than 90% of patients with sporadically, completely resected gastrinoma will be cured.

The most common symptoms of ZES are epigastric pain, GERD, and diarrhea. More than 90% of patients with gastrinoma have peptic ulcer. Most ulcers are in the typical location (proximal duodenum), but atypical ulcer location (distal duodenum, jejunum, or multiple ulcers) should prompt an evaluation for gastrinoma. Gastrinoma also should be considered in the differential diagnosis of recurrent or refractory peptic ulcer, secretory diarrhea, gastric rugal hypertrophy, esophagitis with stricture, bleeding or perforated ulcer, familial ulcer, peptic ulcer with hypercalcemia, and gastric carcinoid. The majority of patients with ZES have been symptomatic for several years before definitive diagnosis and, in general, patients with ZES and MEN1 are diagnosed in their 20s and 30s, while those with sporadic ZES more typically are diagnosed in their 40s and 50s.

ZES is an important part of the differential diagnosis of hypergastrinemia (Fig. 26-46). All patients with gastrinoma have an elevated gastrin level, and hypergastrinemia in the presence of elevated BAO strongly suggests gastrinoma. Patients with gastrinoma usually have a BAO >15 mEq/h or >5 mEq/h if they have had a previous procedure for peptic ulcer. Acid secretory medications should be held for several days before gastrin measurement, because acid suppression may falsely elevate gastrin levels. Causes of hypergastrinemia can be divided into those associated with hyperacidity and those associated with hypoacidity (see Fig. 26-46). The diagnosis of ZES is confirmed by the secretin stimulation test. An IV bolus of secretin (2 U/kg) is given and gastrin levels are checked before and after injection. An increase in serum gastrin of 200 pg/mL or greater suggests the presence of gastrinoma. Patients with gastrinoma should have serum calcium and parathyroid hormone levels determined to rule out MEN1 and, if present, parathyroidectomy should be considered before resection of gastrinoma.

About 80% of primary tumors are found in the gastrinoma triangle (Fig. 26-47), and many tumors are small (<1 cm), making preoperative localization difficult. Transabdominal ultrasound is quite specific, but not very sensitive. CT will detect most lesions >2 cm in size and MRI is comparable. EUS is more sensitive than these other noninvasive imaging tests, but it still misses many of the smaller lesions, and may confuse normal lymph nodes for gastrinomas. Currently, the preoperative imaging study of choice for gastrinoma is somatostatin receptor scintigraphy (the octreotide scan). When the pretest probability of gastrinoma is high, the sensitivity and specificity of this modality approach 100%. Gastrinoma cells contain type II somatostatin receptors that bind the indium-labeled somatostatin analogue (octreotide) with high affinity, making imaging with a gamma camera possible (Fig. 26-48). Currently, angiographic localization studies are infrequently performed for gastrinoma. Both diagnostic angiography and transhepatic selective venous sampling of the portal system have been supplanted by selective arterial secretin infusion, which helps to localize the tumor as inside or outside the gastrinoma triangle.

In this test, an arterial catheter is selectively placed in a named vessel supplying the pancreas (e.g., gastroduodenal or splenic), and a venous catheter is placed in a hepatic vein. Secretin is injected into the visceral artery and gastrin is sampled in the hepatic vein. A significant elevation in hepatic venous gastrin indicates that the tumor is supplied by the injected artery. This test should be performed if pancreaticoduodenectomy is contemplated. Probably the most important means of locating gastrinomas is intraoperative exploration.

All patients with sporadic (nonfamilial) gastrinoma should be considered for surgical resection and possible cure.The lesions should be located in 90% of patients, and the large majority is cured by extirpation of the gastrinoma(s). A thorough intraoperative exploration of the gastrinoma triangle and pancreas is essential, but other sites (i.e., liver, stomach, small bowel, mesentery, and pelvis) should be evaluated as part of a thorough intra-abdominal evaluation to find the primary tumor, which is usually solitary and often in the duodenal wall. The duodenum and pancreas should be extensively mobilized and intraoperative ultrasound should be used. Intraoperative EGD with transillumination may be considered. If the tumor can not be located, generous longitudinal duodenotomy with inspection and palpation of the duodenal wall is performed. Lymph nodes from the portal, peripancreatic, and celiac drainage basins should be sampled. Ablation or resection of hepatic metastases should be considered.

The management of gastrinoma in patients with MEN I is controversial because the patients are often not cured by operation, and the tumors tend to be small and multiple. If the tumor can be imaged preoperatively, operation by an experienced gastrinoma surgeon is reasonable.

Acid hypersecretion in patients with gastrinoma can always be managed with high-dose PPIs. Highly selective vagotomy may make management easier in some patients and should be considered in those with surgically untreatable or unresectable gastrinoma. Gastrectomy for ZES is no longer indicated.

Pathogenesis and Prevention

Gastritis is mucosal inflammation. The gross endoscopic diagnosis of gastritis correlates poorly with histologic findings, and is thus relatively useless as a diagnosis without confirmatory biopsy. Additionally, there is poor correlation between symptoms and histologic gastritis. The most common cause of gastritis is H. pylori. Other causes of gastritis include alcohol, NSAIDs, Crohn’s disease, tuberculosis, and bile reflux (primary or secondary). These agents cause injury by a variety of different mechanisms. In general, the infectious and inflammatory causes result in immune cell infiltration and cytokine production which damage mucosal cells. The chemical agents (alcohol, aspirin, and bile)generally work to disrupt the mucosal barrier, allowing mucosal damage by back diffusion of luminal hydrogen ions.

Stress gastritis is a peculiar entity that has all but disappeared from the clinical (if not endoscopic) lexicon, largely due to better critical care and acid suppression or cytoprotective agents (e.g., sucralfate) in the intensive care unit (ICU). Stress gastritis and stress ulcer are probably due to inadequate gastric mucosal blood flow during periods of intense physiologic stress. Adequate mucosal blood flow is important to maintain the mucosal barrier, and to buffer any back-diffused hydrogen ions. When blood flow is inadequate, these processes fail and mucosal breakdown occurs. Modern intensive care, with emphasis on adequate tissue perfusion and oxygenation, has undoubtedly decreased the severity of gastric mucosal injury seen in the ICU today. Although it is still common to see small mucosal erosions when performing upper endoscopy in the ICU, it is rare for these lesions to coalesce into the larger bleeding erosions that plagued the ICU patient 30 to 50 years ago. The rationale for routine acid suppression in the ICU, supported by excellent data from clinical trials and the laboratory, is that less mucosal injury will be caused in the potentially weakened gastric mucosa if there is less luminal acid.^80,81 There are some studies suggesting that routine acid suppression leads to overgrowth of gastric bacteria, which increases the incidence and/or severity of aspiration pneumonia in the ICU. Nevertheless, acid suppression, particularly in the severely ill patient, remains an important part of clinical pathways in most ICUs.^82,83,84 In the extraordinarily rare patient requiring operation today for hemorrhagic stress gastritis, the surgical options include V + D with oversewing of the major bleeding lesions, or near total gastrectomy. Angiographic embolization and endoscopic hemostatic treatment should be considered as well.

The three most common primary malignant gastric neoplasms are adenocarcinoma (95%), lymphoma (4%), and malignant GIST (1%) (Table 26-14). Other rare primary malignancies include carcinoid, angiosarcoma, carcinosarcoma, and squamous cell carcinoma. Occasionally the stomach is the site of hematogenous metastasis from other sites (e.g., melanoma or breast). More commonly, malignant tumors from adjacent organs invade the stomach by direct extension (e.g., colon or pancreas) or by peritoneal seeding (e.g., ovary).

Adenocarcinoma

Epidemiology

Globally, gastric cancer is the fourth most common cancer type and the second leading cause of cancer death. Over the past several decades, there has been a dramatic decrease in the gastric cancer incidence and death rate in most Western industrialized countries (Fig. 26-49). This decrease has been largely in the so-called intestinal form rather than in the diffuse form of gastric cancer. In Asia and Eastern Europe, gastric cancer remains a leading cause of cancer death. In 2012 in the United States, there were approximately 21,320 new cases of stomach cancer (13,020 in men and 8300 in women), and 10,540 deaths from this disease (6190 men and 4350 women.⁸³ The estimated 5-year survival rate is 27%, up from about 15% in 1975.

In general, gastric cancer is a disease of the elderly, and it is twice as common in blacks as in whites. In younger patients, tumors are more often of the diffuse variety and tend to be large, aggressive, and more poorly differentiated, sometimes infiltrating the entire stomach (linitis plastic). Gastric cancer has a higher incidence in groups of lower socioeconomic status.

Etiology

Gastric cancer is more common in patients with pernicious anemia, blood group A, or a family history of gastric cancer. When patients migrate from a high-incidence region to a low-incidence region, the risk of gastric cancer decreases in the subsequent generations born in the new region. This strongly suggests an environmental influence on the development of gastric cancer. Environmental factors appear to be more related etiologically to the intestinal form of gastric cancer than the more aggressive diffuse form. The commonly accepted risk factors for gastric cancer are listed in Table 26-15.

Diet and Drugs

Typically, a starchy diet high in pickled, salted, or smoked food is found in many regions of high gastric cancer risk. Dietary nitrates have been impugned as a possible cause of gastric cancer. Gastric bacteria (more common in the achlorhydric stomach of patients with atrophic gastritis, a risk factor for gastric cancer) convert nitrate into nitrite, a proven carcinogen. A diet high in fresh fruits and vegetables and rich in vitamin C and E has been shown to decrease the population’s risk of gastric cancer. The reduced consumption of nitrate-rich preserved foods seen with the growth of refrigeration has been suggested as a cause of the dramatic decrease in gastric cancer seen in North America and Western Europe over the last century. Tobacco use probably increases the risk of stomach cancer, and alcohol use probably has no effect. Regular aspirin use may be protective.

Helicobacter pylori

 The risk of gastric cancer in patients with chronic H. pylori infection is increased about threefold. Compared to uninfected patients, patients with a history of gastric ulcer are more likely to develop gastric cancer (incidence ratio 1.8, 95% confidence interval 1.6–2.0), and patients with a history of duodenal ulcer are at decreased risk for gastric cancer (incidence ratio 0.6, 95% confidence interval 0.4–0.7).^54,84 As diagrammed in Fig. 26-50, this may be due to the fact that some patients develop antral-predominant disease (predisposing to duodenal ulcer and somehow protecting against gastric cancer), while other patients develop corpus-predominant gastritis, resulting in hypochlorhydria and somehow predisposing to gastric ulcer and gastric cancer.⁸⁵ The theoretical sequence for development of gastric adenocarcinoma is diagrammed in Fig. 26-51.^54,85 Recently, it has been demonstrated that bone marrow-derived stem cells play a key role in the pathogenesis of gastric adenocarcinoma in patients with chronic H. pylori infection.⁵⁴ However, it must be recognized that gastric adenocarcinoma is a multifactorial disease. Not all patients with gastric cancer have H. pylori, and there are some geographic areas with a high prevalence of chronic H. pylori infection and a low prevalence of gastric cancer (the “African enigma”). Finally, H. pylori-infected patients seem to be at decreased risk for the development of adenocarcinoma of the distal esophagus and cardia region.⁸⁶ Perhaps the corporeal gastritis decreases acid secretion, creating a less damaging refluxate and thus reducing the risk for Barrett’s esophagus, the precursor lesion for these tumors.

Epstein-Barr Virus

About 10% of gastric adenocarcinomas carry the EBV virus. Recently it has been suggested that EBV infection is a rather late step in gastric carcinogenesis, since EBV transcripts are present in cancer cells but not in the metaplastic cells of precursor epithelium.⁸⁷

Genetic Factors

A variety of genetic abnormalities have been described in gastric cancer (Table 26-16). Most gastric cancers are aneuploid. The most common genetic abnormalities in sporadic gastric cancer affect the p53 and COX-2 genes. Over two thirds of gastric cancers have deletion or suppression of the important tumor-suppressor gene p53. Additionally, approximately the same proportion have overexpression of COX-2. In the colon, tumors with upregulation of this gene have suppressed apoptosis, more angiogenesis, and higher metastatic potential. Gastric tumors that overexpress COX-2 are more aggressive tumors. Recently, a germline mutation in the CDH1 gene encoding E-cadherin was shown to be associated with hereditary diffuse gastric cancer. Prophylactic total gastrectomy should be considered in patients with these mutations.⁸⁸

Recently the role of microRNA abnormalities in gastric cancer have received attention. These are small short sequence molecules (18 to 25 nucleotides) which inhibit the translation or promote the degradation of messenger RNA with complementary sequences. MicroRNAs are important regulators of gene expression, and abnormalities in microRNA have been identified in gastric cancer which effect the cell cycle, apoptosis, and cellular invasiveness and/or metastatic potential.⁸⁹ It is likely microRNA will have increasing diagnostic, therapeutic, and prognostic significance in gastric cancer as well as other tumors.

Premalignant Conditions of the Stomach

Figure 26-52 shows the prevalence of some premalignant conditions associated with the development of early gastric cancer in a series of 1900 cases from Tokyo. By far the most common precancerous lesion is atrophic gastritis. There is a growing appreciation of the important influence of the chronic inflammatory milieu on the genome of mucosal cells. Chronic inflammation leads to both genetic and epigenetic changes in mucosal cells which in the stomach leads to the development of gastritis associated cancer.⁹⁰

Polyps

Benign gastric polyps are classified as neoplastic (adenoma and fundic gland polyps) or nonneoplastic (hyperplastic polyp, inflammatory polyp, hamartomatous polyp).^90A In general, inflammatory and hamartomatous polyps have little or no malignant potential. Fundic gland polyps, commonly seen in patients on long term proton pump inhibitor therapy, are not premalignant but in patients with familial adenomatous polyposis, dysplasia in these lesions is not uncommon. Hyperplastic polyps usually occur in the setting of chronic inflammation. Large hyperplastic polyps (>2cm) may harbor dysplasia or carcinoma in situ, and gastric cancer may develop remote from the hyperplastic polyp in an area of associated chronic inflammation. Gastric adenomas are premalignant, similar to colon adenomas. Patients with familial adenomatous polyposis (FAP) have a high prevalence of gastric adenomatous polyps (about 50%), and are 10 times more likely to develop adenocarcinoma of the stomach than the general population.⁹¹ Screening EGD is indicated in these families. Patients with hereditary nonpolyposis colorectal cancer may also be at risk for gastric cancer.⁹²

Gastric polyps greater than 1cm should be removed to confirm the diagnosis and to eliminate any risk of malignant degeneration. Patients with gastric adenomatous polyps and FAP should have periodic upper endoscopy, which may also be considered in selected patients with hyperplastic polyps and chronic gastric inflammation.

Atrophic Gastritis

Chronic atrophic gastritis (Fig. 26-53) is by far the most common precursor for gastric cancer, particularly the intestinal subtype (see Fig. 26-52). The prevalence of atrophic gastritis is higher in older age groups, but it is also common in younger people in areas with a high incidence of gastric cancer. In many patients, it is likely that H. pylori is involved in the pathogenesis of atrophic gastritis. Correa described three distinct patterns of chronic atrophic gastritis: autoimmune (involves the acid-secreting proximal stomach), hypersecretory (involving the distal stomach), and environmental (involving multiple random areas at the junction of the oxyntic and antral mucosa).⁸⁴

Intestinal Metaplasia

Gastric carcinoma often occurs in an area of intestinal metaplasia. Furthermore, an individual’s risk of gastric cancer is proportional to the extent of intestinal metaplasia of the gastric mucosa. These observations strongly suggest that intestinal metaplasia is a precursor lesion to gastric cancer. There are different pathologic subtypes of intestinal metaplasia in the stomach, based upon the histologic and biochemical characteristics of the changed mucosal glands. In the complete type of intestinal metaplasia, the glands are completely lined with goblet cells and intestinal absorptive cells (Fig. 26-54). These cells are indistinguishable histologically and biochemically from their small bowel counterparts, and are not seen in the normal stomach. There is evidence that eradication of H. pylori infection leads to significant regression of intestinal metaplasia and improvement in atrophic gastritis. Therefore, treatment of H. pylori infection is a reasonable recommendation for patients with these pathologic diagnoses and H. pylori infection.

Benign Gastric Ulcer

Although once considered a premalignant condition, it is likely that the older literature was confounded by mistakenly labeling inadequately biopsied ulcers and healing ulcers as “benign,” when, in fact, they were malignant to begin with. It is now generally recognized that all gastric ulcers are cancer until proven otherwise with adequate biopsy and follow-up. Even today, carcinomas are occasionally found when adequately biopsied “benign” ulcers are resected for nonhealing. It is more than likely that the factors previously discussed are more significant etiologically in the development of gastric cancer than the history of a benign gastric ulcer.

Gastric Remnant Cancer

It has long been recognized that stomach cancer can develop in the gastric remnant, usually years following distal gastrectomy for PUD. The risk is controversial, but the phenomenon is real. Most tumors develop >10 years following the initial operation, and they usually arise in an area of chronic gastritis, metaplasia, and dysplasia. This is often near the stoma, but many of these tumors are quite large at presentation, and are equally divided between intestinal and diffuse subtypes. Most cases have been reported following Billroth II gastroenterostomy, but there also have been cases following Billroth I gastroduodenostomy. Whether simple loop gastrojejunostomy increases a patient’s risk of gastric cancer, and whether a Roux-en-Y anastomosis following gastric resection lowers their risk of gastric cancer is unknown. Stage for stage, the prognosis for gastric stump cancer is similar to proximal gastric cancer.⁹³

Other Premalignant States

A mutated E-cadherin gene is associated with hereditary diffuse gastric cancer. Prophylactic total gastrectomy should be considered.⁸⁸ Obviously, a myriad of genetic and environmental factors will affect members of the same family, and up to 10% of gastric cancer cases appear to be familial without a clear-cut genetic diagnosis. First-degree relatives of patients with gastric cancer have a two- to threefold increased risk of developing the disease. Patients with hereditary nonpolyposis colorectal cancer have a 10% risk of developing gastric cancer, predominantly the intestinal subtype. The mucous cell hyperplasia of Ménétrier’s disease is generally considered to carry a 5% to 10% risk of adenocarcinoma. Periodic surveillance EGD is prudent in all the above conditions. The glandular hyperplasia associated with gastrinoma is not premalignant, but ECL hyperplasia and/or carcinoid tumors can occur.

Pathology

Dysplasia

It is generally accepted that gastric dysplasia is the universal precursor to gastric adenocarcinoma. Patients with severe dysplasia should be considered for gastric resection if the abnormality is widespread or multifocal, or EMR if the severe dysplasia is localized. Patients with mild dysplasia should be followed with endoscopic biopsy surveillance, and Helicobacter eradication.

Early Gastric Cancer

Early gastric cancer is defined as adenocarcinoma limited to the mucosa and submucosa of the stomach, regardless of lymph node status. The entity is common in the Orient, where gastric cancer is a common cause of cancer death, and where aggressive surveillance programs have therefore been established. Approximately 10% of patients with early gastric cancer will have lymph node metastases. There are several types and subtypes of early gastric cancer (Table 26-17 and Fig. 26-55). Approximately 70% of early gastric cancers are well differentiated, and 30% are poorly differentiated. The overall cure rate with adequate gastric resection and lymphadenectomy is 95%. In some Japanese centers, 50% of the gastric cancers treated are early gastric cancer. In the United States, less than 20% of resected gastric adenocarcinomas are early gastric cancer. Small intramucosal lesions can be treated with EMR.⁹⁴

Gross Morphology and Histologic Subtypes

There are four gross forms of gastric cancer: polypoid, fungating, ulcerative, and scirrhous. In the first two, the bulk of the tumor mass is intraluminal. Polypoid tumors are not ulcerated; fungating tumors are elevated intraluminally, but also ulcerated. In the latter two gross subtypes, the bulk of the tumor mass is in the wall of the stomach. Ulcerative tumors are self-descriptive; scirrhous tumors infiltrate the entire thickness of the stomach and cover a very large surface area. Scirrhous tumors (linitis plastica) have a particularly poor prognosis, and commonly involve the entire stomach. Although these latter lesions may be technically resectable with total gastrectomy, it is common for both the esophageal and duodenal margins of resection to show microscopic evidence of tumor infiltration, and death from recurrent disease within 6 months is common. Palliative chemotherapy may prolong median survival94A.

The location of the primary tumor in the stomach is important in planning the operation. Several decades ago, the large majority of gastric cancers were in the distal stomach. Recently, there has been a proximal migration of tumors, so that currently, the distribution is closer to 40% distal, 30% middle, and 30% proximal.

Histology

The most important prognostic indicators in gastric cancer are both histologic: lymph node involvement and depth of tumor invasion. Tumor grade (degree of differentiation: well, moderately, or poorly) is also important prognostically.

There are several histologic classifications of gastric cancer. The World Health Organization recognizes several histologic types (Table 26-18). The Japanese classification is similar but more detailed. The commonly used Lauren classification separates gastric cancers into intestinal type (53%), diffuse type (33%), and unclassified (14%). The intestinal type is associated with chronic atrophic gastritis, severe intestinal metaplasia, and dysplasia, and tends to be less aggressive than the diffuse type. The diffuse type of gastric cancer is more likely to be poorly differentiated and is associated with younger patients and proximal tumors. The Ming classification also is useful and easy to remember, with only two types—expanding (67%) and infiltrative (33%).

Recently, the significance of human epidermal growth factor receptor-2 (HER2) was reported in patients with gastric cancer. In breast cancer, overexpression of HER2 has been reported in 15% to 25% and is well recognized as one of the unfavorable prognostic factors. However, the development of molecular targeted agents such as trastuzumab has improved the survival of HER2 positive patients. Likewise, recently in gastric cancer, HER2 overexpression has been reported in 13% to 30% of patients. According to the result of large clinical trial, Immunohistochemistry (IHC) staining of HER2 has become the important examination for recurrent or metastatic gastric cancer to decide the treatment strategy.^94B

Pathologic Staging

Ultimately, prognosis is related to pathologic stage. The most widespread system for staging of gastric cancer is the tumor-node-metastasis (TNM) staging system based on depth of tumor invasion, extent of lymph node metastases, and presence of distant metastases. This system was developed by the American Joint Committee on Cancer and the International Union Against Cancer, and has under gone several modifications since it was originally conceived (Table 26-19).

Clinical Manifestations

Most patients who are diagnosed with gastric cancer in the United States have advanced stage III or IV disease at the time of diagnosis. The most common symptoms are weight loss and decreased food intake due to anorexia and early satiety. Abdominal pain (usually not severe and often ignored) also is common. Other symptoms include nausea, vomiting, and bloating. Acute GI bleeding is somewhat unusual (5%), but chronic occult blood loss is common and manifests as iron deficiency anemia and heme-positive stool. Dysphagia is common if the tumor involves the cardia of the stomach. Paraneoplastic syndromes such as Trousseau’s syndrome (thrombophlebitis), acanthosis nigricans (hyperpigmentation of the axilla and groin), or peripheral neuropathy are rarely present.

Physical examination typically is normal. Other than signs of weight loss, specific physical findings usually indicate incurability. A focused examination in a patient in whom gastric cancer is a likely part of the differential diagnosis should include an examination of the neck, chest, abdomen, rectum, and pelvis. Cervical, supraclavicular (on the left referred to as Virchow’s node), and axillary lymph nodes may be enlarged, and today can be sampled in the office with fine-needle aspiration cytology. There may be a metastatic pleural effusion, or aspiration pneumonitis in a patient with vomiting and/or obstruction. An abdominal mass could indicate a large (usually T4 incurable) primary tumor, liver metastases, or carcinomatosis (including Krukenberg’s tumor of the ovary). A palpable umbilical nodule (Sister Joseph’s nodule) is pathognomonic of advanced disease, or there may be evidence on exam of malignant ascites. Rectal exam may reveal heme-positive stool and hard nodularity extraluminally and anteriorly, indicating so-called drop metastases, or rectal shelf of Blumer in the pouch of Douglas.

Diagnostic Evaluation

Distinguishing between peptic ulcer and gastric cancer on clinical grounds alone is usually impossible. Patients over the age of 45 years old who have new-onset dyspepsia, as well as all patients with dyspepsia and alarm symptoms (weight loss, recurrent vomiting, dysphagia, evidence of GI bleeding, or anemia) or with a family history of gastric cancer should have prompt upper endoscopy and biopsy if a mucosal lesion is noted. Essentially, all patients in whom gastric cancer is part of the differential diagnosis should have endoscopy and biopsy. If suspicion for cancer is high and the biopsy is negative, the patient should be re-endoscoped and more aggressively biopsied. In some patients with gastric tumors, upper GI series can be helpful in planning treatment. Although a good double-contrast barium upper GI examination is sensitive for gastric tumors (up to 75% sensitive), in most centers, endoscopy has become the gold standard for the diagnosis of gastric malignancy.

In addition, recent advances in endoscopy have contributed to the earlier diagnosis of gastric cancer. Magnifying endoscopy with narrow-band imaging (NBI) has undergone technological improvements and can observe the microvascular architecture of the mucosa and microsurface pattern of the lesion. Magnifying endoscopy with NBI has been reported to be accurate and reliable in the diagnosis of early gastric cancer.^94C Furthermore, endocytoscopy, a technique allowing microscopic visualization of the mucosal surface, has been developed and has the potential for pathological diagnosis.^94D Another diagnostic innovation is virtual endoscopy which is an imaging examination of the gastrointestinal tract reconstructed by multidetector-row computed tomography. The image of virtual endoscopy is now quite similar to that of upper endoscopy. In the near future, this novel technology may play a role in the screening of the stomach.

Preoperative staging of gastric cancer is best accomplished with abdominal/pelvic CT scanning with IV and oral contrast. MRI is probably comparable. The best way to stage the tumor locally is via EUS, which gives fairly accurate (80%) information about the depth of tumor penetration into the gastric wall, and can usually show enlarged (>5 mm) perigastric and celiac lymph nodes. In some centers, if the tumor is transmural (T3) or involves lymph nodes (enlarged nodes can usually be needled under endoscopic ultrasound guidance), preoperative (neoadjuvant) chemotherapy is given. However, there are limitations to tumor staging with EUS. It largely is operator dependent and may underestimate lymph node involvement because normal-sized nodes (<5 mm) can harbor metastases. EUS is most accurate in distinguishing early gastric cancer (T1) from more advanced tumors.

Positron Emission Tomography Scanning

Whole-body PET scanning uses the principle that tumor cells preferentially accumulate positron-emitting 18F-fluorodeoxy glucose. This modality is most useful in the evaluation of distant metastasis in gastric cancer but can also be useful in locoregional staging. PET scan is accurate when combined with spiral CT (PET-CT)⁹⁵ and should be considered before major surgery in patients with particularly high-risk tumors or multiple medical comorbidities.

Staging Laparoscopy and Peritoneal Cytology

To some extent, the usefulness of these modalities depends on the individual patient’s situation as well as the treatment philosophy of the cancer team. The fundamental question is “will it make a difference to this patient’s management?” Patients with gastric cancer who undergo R0 resection (i.e., no gross residual disease) and are found to have positive peritoneal cytology (no gross carcinomatosis) have a much worse prognosis than the cytology negative group (median survival 14.8 months vs. 98.5 months).⁹⁶ It is controversial how much this information adds prognostically to that of pathologic staging (TNM). Whether this poor prognosis can be improved postresection with aggressive adjuvant treatment (systemic, or local intraperitoneal hyperthermic chemotherapy) is unknown. Unfortunately, it is also unclear how much these patients benefit from gastric resection. Currently peritoneal cytology information is unlikely to change the treatment of patients with gastric cancer, and most patients without detectable distant metastases will have (and should have) gastric resection regardless of the peritoneal cytology results. A quick laparoscopic examination can occasionally reveal small peritoneal implants or liver metastases that were not detected on preoperative imaging studies and, in some patients (e.g., high risk for surgery or impressive carcinomatosis), this will change the operative plan and avoid a major but futile surgical procedure. Laparoscopy may be most useful in patients with proximal tumors or with adenopathy on spiral CT scan.⁹⁷ An extensive laparoscopic staging procedure, although quite accurate, has not been widely adopted.

Treatment

Surgical resection is the only curative treatment for gastric cancer^98,99 and most patients with clinically resectable locoregional disease should have gastric resection. Obvious exceptions include patients who cannot tolerate an abdominal operation, and patients with overwhelming metastatic disease.

The goal of curative surgical treatment is resection of all tumor (i.e., R0 resection). Thus, all margins (proximal, distal, and radial) should be negative and an adequate lymphadenectomy performed. Generally, the surgeon strives for a grossly negative margin of at least 5 cm. Some gastric tumors, particularly the diffuse variety, are quite infiltrative and tumor cells can extend well beyond the tumor mass; thus, gross margins beyond 5 cm may be desirable. Frozen section confirmation of negative margins is important when performing operation for cure, but it is less important in patients with nodal metastases beyond the N1 nodal basin. It should be strongly emphasized that many patients with positive lymph nodes are cured by adequate surgery. It should also be stressed that often lymph nodes that appear to be grossly involved with tumor turn out to be benign or reactive on pathologic examination. More than 15 resected lymph nodes are required for adequate staging.¹⁰⁰ Therapeutic nihilism should be avoided and, in the low-risk patient, an aggressive attempt to resect all tumor should be made. The primary tumor may be resected en bloc with adjacent involved organs (e.g., distal pancreas, transverse colon, or spleen) during the course of curative gastrectomy. Palliative gastrectomy may be indicated in some patients with obviously incurable disease, but most patients presenting with stage IV gastric cancer can be managed without major operation.^99,101

Extent of Gastrectomy

The standard operation for gastric cancer is radical subtotal gastrectomy. Unless required for R0 resection, total gastrectomy confers no additional survival benefit and may have adverse nutritional or quality-of-life consequences, and higher peri-operative morbidity and mortality.^98,99 Subtotal gastric resection typically entails ligation of the left and right gastric and gastroepiploic arteries at the origin, as well as the en bloc removal of the distal 75% of the stomach, including the pylorus and 2 cm of duodenum, the greater and lesser omentum, and all associated lymphatic tissue (Fig. 26-56). Reconstruction is usually by Billroth II gastrojejunostomy, but if a small gastric remnant is left, a Roux-en-Y reconstruction is considered. In East Asia especially in Japan, Billroth-I gastroduodenostomy was usually performed after distal gastrectomy. Billroth-I gastroduodenostomy consists of one anastomosis (which is usually straightforward and keeps the duodenum in the food stream). In the United States, traditional surgical teaching eschews gastroduodenostomy following gastric cancer resection because of the possibility of anastomotic recurrence and obstruction. The operative mortality is around 2% to 5%. Radical subtotal gastrectomy is generally deemed to be an adequate cancer operation in most Western countries, provided that tumor-free margins are obtained, >15 lymph nodes are removed, and all gross tumor is resected. In the absence of involvement by direct extension, the spleen and pancreatic tail are not removed.

Total gastrectomy with Roux-en-Y esophagojejunostomy may be required for R0 resection (Fig. 26-57), and may be the best operation for patients with proximal gastric adenocarcinoma. The construction of a jejunal pouch can be beneficial nutritionally, particularly for those patients with a good prognosis.¹⁰² Proximal subtotal gastric resection, a technically feasible alternative to total gastrectomy for some proximal gastric tumors, requires an esophagogastrostomy to a vagotomized distal gastric remnant, and the functional outcome is poor. Pyloroplasty in this setting virtually guarantees bile esophagitis, and if the pylorus is left intact, gastric emptying may be problematic. An isoperistaltic jejunal interosition (Henley loop) between the esophagus and antrum could be considered an alternative reconstruction, but, all things considered, total gastrectomy usually results in superior functional, if not oncologic, results for most patients with proximal gastric cancer.

Extent of Lymphadenectomy

According to the 3^rd edition of Japanese classification of gastric carcinoma, lymph node stations are numbered by anatomical definition. Lymph node stations from 1 to 12, and 14V are classified as regional lymph nodes and metastasis of any other lymph node is classified as distant metastasis (M1) (see Fig. 26-4). According to the type of gastrectomy, the definition of extent of lymphadectomy is different. D1 lymphadenectomy in distal gastrectomy requires the dissection of the stations 1, 3, 4sb, 4d, 5, 6, 7. Furthermore, additional resection of stations 8a, 9, 11p and 12a is needed for D2 lymphadenectomy. D1 lymphadenectomy in total gastrectomy requires dissection of stations 1 through 7 and in D2, from 8a to 12a too. The operation described above (radical subtotal gastrectomy in the Extent of Gastrectomy section), which is by far the most commonly performed procedure in the United States for gastric cancer, is called a D1 resection because it removes the tumor and the perigastric D1 nodes. The standard operation for gastric cancer in Asia and specialized U.S. centers is the D2 gastrectomy, which involves a more extensive lymphadenectomy (removal of the D1 and D2 nodes). In addition to the tissue removed in a D1 resection, the standard D2 gastrectomy removes the peritoneal layer over the anterior mesocolon and selectively over the pancreas, along with nodes along the hepatic and splenic arteries, and the crural nodes. Splenectomy and distal pancreatectomy are not routinely performed, because this clearly has been shown to increase the morbidity of the operation. The purported survival advantage of D2 gastrectomy in gastric cancer is shown in Table 26-20, which shows the 5-year survival rates for gastric cancer stratified by pathologic stage for the United States and Japan. Unfortunately, the randomized prospective trials that have been performed have not confirmed this survival advantage, but the morbidity and mortality in the D2 group was higher (Table 26-21).^103,104,104A This was mostly attributable to the splenectomy and distal pancreatectomy, which are no longer routinely done as part of the D2 gastrectomy in the United States. However, since D2 lymphadenectomy in total gastrectomy requires the dissection of station 10 which is splenic hilar lymph node as described above, splenectomy is recommended to fulfill the criteria of D2. In Japan, pancreas-preserving splenectomy is generally performed to avoid the severe postoperative complications such as pancreas fistula in patients with advanced upper gastric cancer who underwent total gastrectomy. Some experts have argued that the D2 operation is simply a better staging procedure, and that the apparent improved survival with this more extensive dissection is simply an epiphenomenon of improved pathologic staging. This stage shift suggests that many patients in the U.S. series treated with D1 gastrectomy really had metastatic nodes at the D2 level that went unresected and undetected. Therefore, in the U.S. series, there were patients classified as stage I, who, if they had undergone a D2 gastrectomy, would be classified as stage II; and there were patients classified as stage II, who, if they had undergone a D2 gastrectomy, would be classified as stage III. The stage I survival in the United States would then actually be closer to the (more accurately staged) stage II survival in Japan, because this group includes some patients who really are stage II, but the nodes were not found in the D1 resection. All experts would agree that to avoid understaging of gastric cancer, a minimum of 15 nodes should be resected with the gastrectomy specimen. Despite the lack of strong data from RCTs supporting a survival advantage of D2 gastrectomy for gastric cancer, this has become standard practice in Asia and has been adopted by an increasing number of large Western centers. Reasons for this are safety of operation in experienced hands as well as data from observational studies and subgroup analysis of RCTs suggesting a survival benefit.104B

Chemotherapy and Radiation for Gastric Cancer

In general, the actuarial 5-year survival for resected gastric adenocarcinoma stages I, II, and III is about 75%, 50%, and 25%, respectively. Because most surgical patients have stage II disease or greater, it is common to refer gastric cancer patients postoperatively to a medical and/or radiation oncologist. Unfortunately, the existing data suggest that the incremental survival benefit attendant to adjuvant treatment is marginal, particularly in those patients who have had an adequate resection.^98,99 In one prospective randomized study, adjuvant treatment with chemotherapy (5-fluorouracil and leucovorin) and radiation (4500 cGy) has demonstrated a survival benefit in resected patients with stage II and III adenocarcinoma of the stomach.¹⁰⁵ Unfortunately, only 10% of patients entered in the study actually had D2 gastrectomy, and most (54%) had less than an adequate D1 gastrectomy. Because adequacy of lymphadenectomy has clearly been shown to impact survival, particularly in patients with stage III gastric cancer,^99,100 it has been suggested that the benefits of adjuvant chemoradiation shown in this study would be vitiated by an adequate operation. Recent clinical trials suggest the potential importance of adjuvant chemotherapy after D2 lymphadenectomy in patients with advanced gastric cancer. These trials compared surgery alone and surgery plus adjuvant chemotherapy including oral fluoropyrimidines for curatively resected advanced gastric cancer. After D2 lymphadenectomy, the benefit of adjuvant chemotherapy has also been established and further improvement in prognosis is expected.^105A,105B A recently published study from the Japan Clinical Oncology Group showed a 69% overall 5-year survival rate in patients with clinically curable T2b, T3, and T4 gastric cancer, treated with D2 gastrectomy alone (no chemotherapy).¹⁰⁶ There was no incremental benefit from para-aortic lymph node dissection. There is no indication for the routine use of radiation alone in (D3) the adjuvant setting, but in certain patients, it can be effective palliation for bleeding or pain. Although the prognosis of metastatic or recurrent gastric cancer is poor, systemic chemotherapy provides a significant survival benefit over the best supportive care.^106A Agents that have shown activity against gastric cancer include 5-fluorouracil (5-FU), cisplatin, doxorubicin, methotrexate, taxanes, and camptothecin. Until recently, 5-FU based chemotherapy especially in combination with platinums played a key role in the treatment for the unresectable gastric cancer as well as several types of cancer, such as colon and lung. In the 1990s, the introduction of novel anticancer agents such as camptothecin, taxanes, third-generation platinums, and new oral fluoropyrimidines, improved the prognosis of unresectable gastric cancer. Recently, although the risk of the toxicities is increased, triple combination chemotherapy is associated with better prognosis than double agent therapy. In the United States, triple chemotherapy consists of 5-FU, cisplatin and docetaxel and is now recognized as a standard first-line regimen. In Europe, triple therapy is more often epirubicin, cisplatin, and 5-FU. Sometimes 5-FU may be replaced by capecitabine which is an oral fluoropyrimidine, and cisplatin can be replaced by oxaliplatin which does not require hydration, respectively. Neoadjuvant treatment of gastric adenocarcinoma is being evaluated, particularly in patients with clinical T3 or N1 disease. It is likely that targeted molecular agents will have an increasing role in treating gastric cancer. Recently, Trastuzumab, a humanized molecular antibody reactive against the extracellular domain of HER2, increased the effectiveness of cytotoxic chemotherapy in patients with advanced gastric cancer.94B Other large trials are ongoing. Determination of HER2 gene amplification status may have prognostic significance.106B

Endoscopic Resection

 It has been demonstrated initially at numerous East Asian centers that some patients with early gastric cancer can be adequately treated by an endoscopic mucosal resection (EMR).^106C EMR is a minimally invasive procedure that provides curative resection and has dramatically changed the treatment of early gastric cancer. EMR is indicated for patients in whom the probability of lymph node metastasis is low. According to the Japanese treatment guidelines for gastric cancer, EMR is a standard treatment for differentiated mucosal gastric cancer measuring less than 2 cm and without signs of ulceration, which has almost no risk of lymph node metastasis. En bloc resection is required to evaluate the surgical margin for confirmation of curative resection. Furthermore, the development of endoscopic submucosal dissection (ESD) allows en bloc resection of larger tumors. Therefore, the indications for endoscopic treatment of patients with gastric cancer may be broadened. New indications for minimally invasive treatment will require evaluation before implementation. Small tumors (<3 cm) confined to the mucosa have an extremely low chance of lymph node metastasis (3%), which approaches the operative mortality rate for gastrectomy. If the resected specimen demonstrates no ulceration, no penetration of the muscularis mucosae, no lymphatic invasion, and size <3 cm, then the risk of lymph node metastases is less than 1%. Thus, some patients with early gastric cancer might be better treated with the endoscopic technique. Currently, this should be limited to patients with tumors <2 cm in size that are node negative and confined to the mucosa on EUS, in the absence of other gastriclesions. The addition of laparoscopic lymph node sampling may be considered in selected patients.

Prognosis

The 5-year survival for gastric adenocarcinoma has increased from 15% to 22% in the United States over the past 25 years. Survival is dependent on pathologic stage (TNM stage) and degree of tumor differentiation. Other important prognostic factors are sex, age, primary gastric tumor site, tumor size, and tumor depth.

Palliative gastrectomy may be indicated in some patients with obviously incurable disease, but most patients presenting with stage IV gastric cancer can be managed without major operation.^99,101

Screening for Gastric Cancer

In Japan, it clearly has been shown that patients participating in gastric cancer screening programs have a significantly decreased risk of dying from gastric cancer. Thus, screening is effective in a high-risk population. Screening the general population in the United States (a low-risk country) does not make sense, but patients clearly at risk for gastric cancer probably should have periodic endoscopy and biopsy. This includes patients with familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, gastric adenomas, Ménétrier’s disease, intestinal metaplasia or dysplasia, and remote gastrectomy or gastrojejunostomy.

Gastric Lymphoma

Gastric lymphomas generally account for about 4% of gastric malignancies. Over half of patients with non-Hodgkin’s lymphoma have involvement of the GI tract. The stomach is the most common site of primary GI lymphoma, and over 95% are non-Hodgkin’s type. Most are B-cell type, thought to arise in mucosa associated lymphoid tissue (MALT), although most high-grade gastric lymphomas are without any characteristics of the low-grade MALT neoplasm.¹⁰⁷ About half of gastric lymphomas are histologically low grade, and about half are high grade. Interestingly, the normal stomach is relatively devoid of lymphoid tissue. However, in the setting of chronic gastritis, the stomach acquires MALT, which can undergo malignant degeneration. Again, H. pylori is thought to be the culprit. In populations with a high incidence of gastric lymphoma, there is a high incidence of H. pylori infection; patients with gastric lymphoma also usually have H. pylori infection.107A

Low-grade MALT lymphoma, essentially a monoclonal proliferation of B cells, presumably arises from a background of chronic gastritis associated with H. pylori. These relatively innocuous tumors then undergo degeneration to high-grade lymphoma, which is the usual variety seen by the surgeon. Remarkably, when the H. pylori is eradicated and the gastritis improves, the low-grade MALT lymphoma often disappears. Thus, low-grade MALT lymphoma is not a surgical lesion. Careful follow-up is necessary particularly in those lesions with a t(11:18) translocation, thought to be a risk factor for a more aggressive MALT lesion. If low-grade lymphoma persists after H. pylori eradication, radiation should be considered for disease clinically confined to the stomach (stage I), while chemotherapy with or without radiation is used for more advanced lesions (Fig. 26-58).

Patients with high-grade gastric lymphoma require aggressive oncologic treatment for cure and present with many of the same symptoms as gastric cancer patients. However, systemic symptoms such as fever, weight loss, and night sweats occur in about 50% of patients with gastric lymphoma. The tumors may bleed and/or obstruct. Lymphadenopathy and/or organomegaly suggest systemic disease. Diagnosis is by endoscopy and biopsy. Much of the tumor may be submucosal, and an assiduous attempt at biopsy is necessary. Primary lymphoma is usually nodular with enlarged gastric folds. A diffusely infiltrative process akin to linitis plastica is more suggestive of secondary gastric involvement by lymphoma. A diligent search for extragastric disease is necessary before the diagnosis of localized primary gastric lymphoma is made. This includes EUS; CT scanning of the chest, abdomen, and pelvis; and bone marrow biopsy. Most patients with high-grade gastric lymphoma are currently treated with chemotherapy and radiation, without surgical resection. Treatment-related perforation or bleeding is unusual but recognized. For disease limited to the stomach and regional nodes, radical subtotal D2 gastrectomy may be performed, especially for bulky tumors with bleeding and/or obstruction. Palliative gastrectomy for tumor complications also has a role. Certainly, a multidisciplinary team should be involved with the treatment plan for patients with primary gastric lymphoma.

Gastrointestinal Stromal Tumor

GISTs arise from interstitial cells of Cajal (ICC) and are distinct from leiomyoma and leiomyosarcoma, which arise from smooth muscle.^108,109 Prognosis in patients with GIST tumors depends mostly on tumor size and mitotic count, and metastasis, when it occurs, is typically by the hematogenous route. Any lesion >1 cm can behave in a malignant fashion and may recur. Thus, all GISTs are best resected along with a margin of normal tissue. Almost all GISTs (and almost no smooth muscle tumors) express c-KIT (CD117) or the related PDGF receptor A, as well as CD34; almost all smooth muscle tumors (and almost no GISTs) express actin and desmin. These markers can often be detected on specimens obtained by fine-needle aspiration¹¹⁰ and are useful in differentiating between GIST and smooth muscle tumor histopathologically. Lesions that are definitively leiomyoma by current histopathologic criteria are adequately treated by enucleation. Lesions that are definitively GIST or leiomyosarcoma are best treated by resection with negative margins. Most equivocal lesions should be resected provided that the patient is a reasonable operative risk.

Two-thirds of all GISTs occur in the stomach. Epithelial cell stromal GIST is the most common cell type arising in the stomach, and cellular spindle type is the next most common. The glomus tumor type is seen only in the stomach.

GISTs are submucosal tumors that are slow growing. Smaller lesions are usually found incidentally, although they occasionally may ulcerate and cause impressive bleeding. Larger lesions generally produce symptoms of weight loss, abdominal pain, fullness, early satiety, and bleeding. An abdominal mass may be palpable. Metastasis is by the hematogenous route, often to liver and/or lung, although positive lymph nodes are occasionally seen in resected specimens.

Diagnosis is by endoscopy and biopsy, although the interpretation of the latter may be problematic. EUS may be helpful, but symptomatic tumors and tumors >1 cm in size should be removed. Metastatic work-up entails CT of the chest, abdomen, and pelvis (chest X-ray may suffice in lieu of CT of the chest). Most gastric GISTs occur in the body of the stomach, but they also can occur in the fundus or antrum. They are almost always solitary. Wedge resection with clear margins is adequate surgical treatment. True invasion of adjacent structures by the primary tumor is evidence of malignancy. If safe, en bloc resection of involved surrounding organs is appropriate to remove all tumor when the primary is large and invasive. Five-year survival following resection for GIST is about 50%. Most patients with low-grade lesions are cured (80% 5-year survival), but most patients with high-grade lesions are not (30% 5-year survival).

According to the tumor size and mitotic count,^110A the risk of aggressive behavior was classified into four groups. Very low risk was defined as <2 cm and <5/50 HPF (high-power field) and low risk was defined as 2 to 5cm and <5/50 cm. Intermediate risk was defined as <5 cm and 6 to 10/50 HPF or 5 to 10cm and >5/50 HPF. And high risk was defined as >5 cm and >5/50HPF, >10cm with any mitotic rate or >10/50/ HPF with any size. It was known that the risk of recurrence differs by the primary site of the tumor. Recently, new classification based on tumor location, size, and mitotic rate has been used to evaluate the risk of recurrence and metastasis.^110B

GISTs are usually positive for the protooncogene, c-kit, a characteristic shared with the ICC. Imatinib (Gleevec), a chemotherapeutic agent that blocks the activity of the tyrosine kinase product of c-kit, yields excellent results in many patients with metastatic or unresectable GIST. Up to 50% of treated patients develop resistance to imatinib by 2 years, and several newer agents show promise for patients with refractory disease. The efficacy of imatinib as adjuvant therapy for high risk patients has been demonstrated in large clinical trials.110C,110D According to the NCCN guidelines for soft tissue sarcoma (version 2, 2012), the administration of imatinib was recommended in high risk groups as an adjuvant therapy.110E An algorithm for the treatment of patients with GIST is shown in Fig. 26-59.

Gastric Carcinoid Tumors

Compared to midgut and hindgut locations, carcinoid tumors of the stomach are rather unusual.^111,112,113 Gastric carcinoids comprise about 1% of all carcinoid tumors and less than 2% of gastric neoplasms. They arise from gastric enterochromaffin-like (ECL) cells and some have malignant potential. The apparent incidence of gastric carcinoids is increasing, perhaps related to the more common use of upper endoscopy and/or the increasing use of acid suppressive medication. The latter may cause hypergastrinemia, and gastrin has a recognized trophic effect on gastric ECL cells. Gastric carcinoid is equivalent to neuroendocrine tumor (NET) or well-differentiated neuroendocrine tumor/carcinoma according to WHO classification.

Gastric carcinoids are classified into one of three different types. Type I is the most common type of gastric carcinoid, accounting for about 75% of patients. Type I carcinoids occur in patients with chronic hypergastrinemia secondary to pernicious anemia or chronic atrophic gastritis. These lesions occur more frequently in women, are often multiple and small, and have low malignant potential (<5% metastasize). The role of long-term acid suppression with resultant hypergastrinemia in the pathogenesis of type I gastric carcinoids is unclear.

Type II gastric carcinoids are associated with MEN1 and ZES. These lesions also tend to be small and multiple, but have a somewhat higher malignant potential than type I lesions (10% metastasize). Type II gastric carcinoids are more strongly associated with MEN1; they are quite uncommon in patients with sporadic ZES without MEN1. Gastric acid hypersecretion, hypergastrinemia, and gastric carcinoid imply gastrinoma until proven otherwise.

Type III gastric carcinoids are sporadic tumors. They are most often solitary (usually >2 cm) and occur more commonly in men. They are not associated with hypergastrinemia and biopsy shows a heterogeneous cell population. Most patients have nodal or distant metastases at the time of diagnosis, and some present with symptoms of carcinoid syndrome.

Gastric carcinoids are usually diagnosed with endoscopy and biopsy. Some tumors are submucosal and may be quite small. They are often confused with heterotopic pancreas or small leiomyomas. Biopsy may be difficult because of the submucosal location, and EUS can be helpful in defining the size and depth of the lesion. Plasma chromogranin A levels are elevated in patients with gastric carcinoid. CT scan and octreotide scan are useful for staging.

Gastric carcinoids should be resected. Small lesions confined to the mucosa (typically type I or type II lesions) may be treated endoscopically with EMR if there are only a few lesions (<5) and if margins are histologically negative. Careful follow-up is necessary. Larger lesions should be removed by D1 or D2 gastrectomy. Survival is excellent for node-negative patients (>90% 5-year survival); node-positive patients have a 50% 5-year survival. Gastrinoma should be resected if located in patients with type II carcinoid. The 5-year survival for patients with type I gastric carcinoid is close to 100%; for patients with type III lesions, the 5-year survival is less than 50%. Somatostatin analogue treatment is useful in controlling the symptoms of carcinoid syndrome but apparently does not prolong survival in patients with metastatic gastric carcinoid. Surgical debulking may have a role in selected patients with metastatic disease. Because somatostatin has an antiproliferative effect on gastric ECL cells, there may be a possible primary treatment role for octreotide in poor-risk surgical patients with gastric carcinoid.

Leiomyoma

The typical leiomyoma is submucosal and firm. If ulcerated, it has an umbilicated appearance and may bleed. Histologically, these lesions appear to be of smooth muscle origin. Lesions <2 cm are usually asymptomatic and benign. Larger lesions have greater malignant potential and a greater likelihood to cause symptoms such as bleeding, obstruction, or pain. Asymptomatic lesions <2 cm may be carefully observed or enucleated if fine-needle aspiration and immune markers confirm smooth muscle tumor; larger lesions and symptomatic lesions should be removed by wedge resection (often possible laparoscopically). When lesions thought to be leiomyoma are observed rather than resected, the patient should be made aware of their presence and the small possibility for malignancy.

Lipoma

Lipomas are benign submucosal fatty tumors that are usually asymptomatic, found incidentally on upper GI series or EGD. Endoscopically, they have a characteristic appearance; there also is a characteristic appearance on EUS. Excision is unnecessary unless the patient is symptomatic.

Gastric Motility Disorders

Gastric motility disorders include delayed gastric emptying (gastroparesis), rapid gastric emptying, and motor and sensory abnormalities (e.g., functional dyspepsia). Surgically relevant secondary disorders of gastric motility (e.g., dumping, gastric stasis, and Roux syndrome) are discussed under Postgastrectomy Problems. Gastroparesis is the most surgically relevant primary disorder of gastric motility.^114,115

Most patients with primary gastroparesis present with nausea, vomiting, bloating, early satiety, and/or abdominal pain. Eighty percent of these patients are women; some are diabetic. Postprandial vomiting significantly complicates the management of blood glucose in the latter group, predisposing to hypoglycemia following preprandial insulin. In patients with gastroparesis, it is important to rule out mechanical gastric outlet obstruction, and small-bowel obstruction. An upper GI series may suggest slow gastric emptying and relative atony, or it may be normal. EGD may show bezoars or retained food but is frequently normal. Gastric emptying scintigraphy shows delayed solid emptying, and often delayed liquid emptying. Gastroparesis can be a manifestation of a variety of problems (Table 26-22). Medical treatment includes promotility agents, antiemetics, and, perhaps, botulinum injection into the pylorus.

If the diabetic gastroparetic patient is not a candidate for pancreas transplant, both gastrostomy (for decompression) and jejunostomy tubes (for feeding and prevention of hypoglycemia) can be effective. Other surgical options include implantation of a gastric pacemaker, and gastric resection.^115A Generally, gastric resection should be done only after other therapeutic options have been exhausted.

Massive Upper Gastrointestinal Bleeding

Although there have been arbitrary definitions of “massive” upper GI bleeding put forth, perhaps the most practical definition in the current era would be acute bleeding proximal to the ligament of Treitz, which requires blood transfusion. In multiple series, the stomach and proximal duodenum is by far the most common source of pathology associated with this diagnosis.^65,116 The most common causes of acute GI bleeding in emergency room or hospitalized patients are peptic ulcer, gastritis, Mallory-Weiss syndrome, and esophagogastric varices. Less common causes include benign or malignant neoplasm, angiodysplasia, Dieulafoy’s lesion, portal gastropathy, Ménétrier’s disease, and watermelon stomach. Arterioenteric fistula should always be considered in the patient who has an aortic graft or who has undergone repair of a visceral artery aneurysm.

The most important issues in the early hospital management of patients with acute upper GI bleeding are resuscitation and risk stratification. Large-bore IV access and Foley catheterization is accomplished, and nasogastric intubation is considered. Risk stratification is essentially accomplished by answering the following questions:

1. What is the magnitude and acuity of the hemorrhage? Hypotension, tachycardia, oliguria, low hematocrit, pallor, altered mentation, and/or hematemesis suggest a large blood loss that has occurred over a short period of time. This is a high-risk situation.

2. Does the patient have significant chronic disease, particularly lung, liver, kidney, and/or heart disease, which compromises physiologic reserve? If yes, this is a high-risk situation.

3. Is the patient anticoagulated, or immunosuppressed? If yes, this is a high-risk situation.

4. On endoscopy, is the patient bleeding from varices, or is there active bleeding, or is there a visible vessel, or is there a deep ulcer overlying a large vessel (e.g., posterior duodenal ulcer overlying the gastroduodenal artery)? Could the patient be bleeding from an Arterio enteric fistula? If yes, this is a high-risk situation.

If judged to be low risk, most patients will stop bleeding with supportive treatment and IV PPI. Selected patients may be discharged from the emergency room and managed on an outpatient basis.

If the patient is judged to be high risk based on one or more of the questions previously listed, then the following should be done immediately:

1. Type and cross-match for transfusion of blood products.

2. Admit to ICU or monitored bed in specialized unit.

3. Consult surgeon.

4. Consult gastroenterologist.

5. Start continuous infusion of PPI.

6. Perform upper endoscopy within 12 hours, after resuscitation and correction of coagulopathy. Endoscopic hemostasis should be considered in most high-risk patients with acute upper GI bleeding.

Although the surgeon should be involved early in the hospital course of all high-risk patients with acute upper GI bleeding, most of these patients will be adequately managed without operation. Mucosal lesions can usually be controlled with endoscopic hemotherapy and medical management. Occasionally, arteriography can be helpful.¹¹⁷ Operation for bleeding ulcer is discussed previously (see Operation for Bleeding Peptic Ulcer and Fig. 26-43).

Isolated Gastric Varices

Isolated gastric varices are those that occur in the absence of esophageal varices and are classified as type I (fundic) or type II (distal to fundus including proximal duodenum).¹¹⁸ The presence of isolated gastric varices is usually associated with portal hyper-tension or splenic vein thrombosis. Although there is a significant bleeding risk from isolated gastric varices on long-term follow-up, there is no indication for the routine application of prophylactic measures.

Patients with acute upper GI bleeding from isolated gastric varices should be considered high risk. Although data are limited, octreotide and/or vasopressin infusion may decease bleeding, if tolerated. Balloon tamponade with a Sengstaken-Blakemore tube may provide temporary control of exsanguinating hemorrhage from type isolated gastric varices, but if this is used, endotracheal intubation for airway protection is prudent. Endoscopic treatment with sclerotherapy or varix ligation is less successful than in esophageal varices, but should be considered. Interventional radiology should be consulted and balloon occluded retrograde transvenous obliteration considered. A transjugular intrahepatic portosystemic shunt may be useful if there is nonsegmental portal hypertension. If the patient has splenic vein thrombosis and left-sided (sinistral) or segmental portal hypertension, splenectomy is quite effective in controlling bleeding from isolated gastric varices. The operative mortality is 5%. Liver transplantation should always be considered in the cirrhotic patient.

Hypertrophic Gastropathy (Ménétrier’s Disease)

There are two clinical syndromes characterized by epithelial hyperplasia and giant gastric folds: ZES and Ménétrier’s disease. The latter is characteristically associated with protein-losing gastropathy and hypochlorhydria. There are large rugal folds in the proximal stomach, and the antrum is usually spared. Mucosal biopsy shows diffuse hyperplasia of the surface mucus-secreting cells and usually decreased parietal cells (Fig. 26-60). It has recently been suggested that Ménétrier’s disease is caused by local overexpression of transforming growth factor alpha in the gastric mucosa, which stimulates the epidermal growth factor receptor, a receptor tyrosine kinase, on gastric SECs. This results in the selective expansion of surface mucous cells in the gastric body and fundus. A few patients with this unusual disease have been successfully treated with the epidermal growth factor receptor blocking monoclonal antibody cetuximab.¹¹⁹

Most patients with Ménétrier’s disease are middle-aged men who present with epigastric pain, weight loss, diarrhea, and hypoproteinemia. There may be an increased risk of gastric cancer. Sometimes, the disease regresses spontaneously. Gastric resection may be indicated for bleeding, severe hypoproteinemia, or cancer.

Watermelon Stomach (Gastric Antral Vascular Ectasia)

The parallel red stripes atop the mucosal folds of the distal stomach give this rare entity its sobriquet. Histologically, gastric antral vascular ectasia (GAVE) is characterized by dilated mucosal blood vessels that often contain thrombi, in the lamina propria. Mucosal fibromuscular hyperplasia and hyalinization often are present (Fig. 26-61). The histologic appearance can resemble portal hypertensive gastropathy, but the latter usually affects the proximal stomach, whereas watermelon stomach predominantly affects the distal stomach. Beta blockers and nitrates, useful in the treatment of portal hypertensive gastropathy, are ineffective in patients with gastric antral vascular ectasia. Patients with GAVE are usually elderly women with chronic GI blood loss requiring transfusion. Most have an associated autoimmune connective tissue disorder, and at least 25% have chronic liver disease. Nonsurgical treatment options include estrogen and progesterone, and endoscopic treatment with the neodymium yttrium-aluminum garnet (Nd:YAG) laser or argon plasma coagulator.¹²⁰ Antrectomy may be required to control blood loss, and this operation is quite effective but carries increased morbidity in this elderly patient group. Patients with portal hyper-tension and antral vascular ectasia should be considered for transjugular intrahepatic portosystemic shunt (TIPSS).

Dieulafoy’s Lesion

Dieulafoy’s lesion is a congenital arteriovenous malformation characterized by an unusually large tortuous submucosal artery. If this artery is eroded, impressive pulsatile bleeding may occur. To the endoscopist or surgeon, this appears as a stream of arterial blood emanating from what appears grossly to be a normal gastric mucosa. The lesion typically occurs in middle-aged or elderly men and may be more common in patients with liver disease.¹²¹ Patients typically present with upper GI bleeding, which may be intermittent, and endoscopy can miss the lesion if it is not actively bleeding. Treatment options include endoscopic hemostatic therapy, angiographic embolization, or operation. At surgery, the lesion may be oversewn or resected.

Bezoars/Diverticula

Bezoars are concretions of indigestible matter that accumulate in the stomach. Trichobezoars, composed of hair, occur most commonly in young women who swallow their hair (Fig. 26-62). Phytobezoars are composed of vegetable matter and, in the United States, are usually seen in association with gastroparesis or gastric outlet obstruction. They also are associated with persimmon ingestion. Most commonly, bezoars produce obstructive symptoms, but they may cause ulceration and bleeding. Diagnosis is suggested by upper GI series and confirmed by endoscopy. Treatment options include enzyme therapy (papain, cellulase, or acetylcysteine), endoscopic disruption and removal, or surgical removal.

Gastric diverticula are usually solitary and may be congenital or acquired. Congenital diverticula are true diverticula and contain a full coat of muscularis propria, whereas acquired diverticula (perhaps caused by pulsion) usually have a negligible outer muscle layer. Most gastric diverticula occur in the posterior cardia or fundus (Fig. 26-63) and are usually asymptomatic. However, they can become inflamed and may produce pain or bleeding. Perforation is rare. Asymptomatic diverticula do not require treatment, but symptomatic lesions should be removed. This can often be done laparoscopically.

Foreign Bodies

Ingested foreign bodies are usually asymptomatic. Removal of sharp or large objects should be considered. This can usually be done endoscopically, with an overtube technique. Recognized dangers include aspiration of the foreign body during removal, and rupture of drug-containing bags in “body packers.” Both complications can be fatal. Surgical removal is recommended in body packers, and in patients with large jagged objects. Corrosive objects (e.g., watch batteries) should be removed promptly.

Mallory-Weiss Syndrome

The Mallory-Weiss lesion is a longitudinal tear in the mucosa of the GE junction.¹²² It is presumably caused by forceful vomiting and/or retching, and is commonly seen in alcoholics. It presents with upper GI bleeding, often with hematemesis. Endoscopy confirms the diagnosis and may be useful in controlling the bleeding, but 90% of patients stop bleeding spontaneously. Other options to control the bleeding include balloon tamponade, angiographic embolization, or selective infusion of vasopressin, systemic vasopressin, and operation. Surgical treatment consists of oversewing the bleeding lesion through a long gastrostomy.

Volvulus

Gastric volvulus is a twist of the stomach that usually occurs in association with a large hiatal hernia. It also can occur in patients with an unusually mobile stomach without hiatal hernia. Typically, the stomach twists along its long axis (organoaxial volvulus), and the greater curvature flips up (Fig. 26-64C). If the stomach twists around the transverse axis, it is called mesenteroaxial rotation (Fig. 26-64A and Fig. 26-64B). Often, volvulus is a chronic condition that can be surprisingly asymptomatic. In these instances, expectant nonoperative management is typically advised, especially in the elderly. The risk of strangulation and infarction has been overestimated in asymptomatic patients. Symptomatic patients should be considered for operation, especially if the symptoms are severe and/or progressive. Patients may present with symptoms of pain and pressure related to the intermittently distending and poorly emptying twisted stomach. Pressure on the lung may produce dyspnea, pressure on the pericardium may produce palpitations, and pressure on the esophagus may produce dysphagia. Symptoms are often relieved with vomiting or passage of a nasogastric tube. Gastric infarction is a surgical emergency, and the patient can be moribund. Gastric necrosis may be extensive or focal. With or without gastropexy, elective operation for gastric volvulus usually involves reduction of the stomach and repair of hiatal hernia. Gastropexy alone may be considered for high-risk patients since it can nearly always be performed laparoscopically and may be surprisingly effective in relieving mechanical symptoms.

A gastrostomy is performed either for alimentation or for gastric drainage/decompression. Gastrostomy may be done percutaneously, laparoscopically, or via open technique.^123,124 Currently, percutaneous endoscopic gastrostomy is the most common method used. The open techniques include the Stamm method (Fig. 26-65), the Witzel method (Fig. 26-66), and the Janeway method (Fig. 26-67). The last method is meant to create a permanent stoma that can be intubated as needed, but does not drain spontaneously. The Janeway gastrostomy is more complicated than the other open techniques, and is rarely necessary. By far the most common surgical technique is the Stamm gastrostomy, which can be performed open or laparoscopically.

Complications of gastrostomy include infection, dislodgment, leakage with peritonitis, and aspiration pneumonia. Although gastrostomy tubes usually do prevent tense gastric dilatation, they may not adequately drain the stomach, especially when the patient is bedridden.

Dumping Syndrome

Dumping is a phenomenon caused by the destruction or bypass of the pyloric sphincter.^125,126,127 However, other factors undoubtedly play a role because dumping can occur after operations thatpreserve the pylorus, such as parietal cell vagotomy. The appropriate stimulus can provoke dumping symptoms, even in some patients who have not undergone surgery. Clinically significant dumping occurs in 5% to 10% of patients after pyloroplasty, pyloromyotomy, or distal gastrectomy, and consists of a constellation of postprandial symptoms ranging in severity from annoying to disabling. The symptoms are thought to be the result of the abrupt delivery of a hyperosmolar load into the small bowel due to ablation of the pylorus or decreased gastric compliance.Typically, 15 to 30 minutes after a meal, the patient becomesdiaphoretic, weak, light-headed, and tachycardic. These symptoms may be ameliorated by recumbence or saline infusion. Crampy abdominal pain is not uncommon and diarrhea often follows. This is referred to as early dumping, and should be distinguished from postprandial (reactive) hypoglycemia, also called late dumping, which usually occurs later (2–3 hours following a meal), and is relieved by the administration of sugar. A variety of hormonal aberrations have been observed in early dumping, including increased VIP, CCK, neurotensin, peripheral hormone peptide YY, renin-angiotensin-aldosterone, and decreased atrial natriuretic peptide. Late dumping is associated with hypoglycemia and hyperinsulinemia.

The medical therapy for the dumping syndrome consists of dietary management and somatostatin analogue (octreotide). Often, symptoms improve if the patient avoids liquids during meals. Hyperosmolar liquids (e.g., milk shakes) may be particularly troublesome. There is some evidence that adding dietary fiber compounds at mealtime may improve the syndrome. If dietary manipulation fails, the patient is started on octreotide, 100 μg subcutaneously twice daily. This can be increased up to 500 μg twice daily if necessary. The long-acting depot octreotide preparation is useful. Octreotide not only ameliorates the abnormal hormonal pattern seen in patients with dumping symptoms, but also promotes restoration of a fasting motility pattern in the small intestine (i.e., restoration of the MMC). The α-glucosidase inhibitor acarbose may be particularly helpful in ameliorating the symptoms of late dumping.

Only a very small percentage of patients with dumping symptoms ultimately require surgery. Most patients improve with time (months and even years), dietary management, and medication. Therefore, the surgeon should not rush to reoperate on the patient with dumping symptoms. Multidisciplinary nonsurgical management must be optimized first. Before reoperation, a period of inhospital observation is useful to define the severity of the patient’s symptoms, and patient compliance with prescribed dietary and medical therapy.

The results of remedial operation for dumping are variable and unpredictable. There are a variety of surgical approaches, none of which work consistently well. Additionally, there is not a great deal of experience reported in the literature with any of these methods. Long-term follow-up is rare. Patients with disabling refractory dumping after gastrojejunostomy can be considered for simple takedown of this anastomosis provided that the pyloric channel is open endoscopically. The reversed intestinal segment is rarely used today—and rightly so. This operation interposes a 10-cm reversed segment of intestine between the stomach and the proximal small bowel. This slows gastric emptying, but often leads to obstruction, requiring reoperation. Isoperistaltic interposition (Henley loop) has not been successful in ameliorating severe dumping over the long term. The Roux-en-Y gastrojejunostomy is associated with delayed gastric emptying, probably on the basis of disordered motility in the Roux limb. Taking advantage of this disordered physiology, surgeons have used this operation successfully in the management of the dumping syndrome. Although this is probably the procedure of choice in the small group of patients requiring operation for severe dumping following gastric resection, gastric stasis may result, particularly if a large gastric remnant is left. In the presence of significant gastric acid secretion, marginal ulceration is common after both jejunal interposition and Roux-en-Y procedures; thus concomitant vagotomy and hemigastrectomy should be considered. The theoretical possibility of treating postpyloroplasty dumping with a Roux-en-Y to the proximal duodenum (the duodenal switch, a potentially reversible operation) has not yet been reported (Fig. 26-68). Because pyloric ablation seems to be the dominant factor in the etiology of dumping, it is not surprising that conversion of Billroth II to Billroth I anastomosis has not been successful in the treatment of dumping.

Diarrhea

Diarrhea following gastric surgery may be the result of truncal vagotomy, dumping, or malabsorption. Truncal vagotomy is associated with clinically significant diarrhea in 5% to 10% of patients. It occurs soon after surgery and usually is not associated with other symptoms, a fact that helps to distinguish it from dumping. The diarrhea may be a daily occurrence, or there may be significant periods of relatively normal bowel function. The symptoms tend to improve over the months and years after the index operation. The cause of postvagotomy diarrhea is unclear. Possible mechanisms include intestinal dysmotility and accelerated transit, bile acid malabsorption, rapid gastric emptying, and bacterial overgrowth. The latter problem is facilitated by decreased gastric acid secretion and (even small) blind loops. Although bacterial overgrowth can be confirmed with the hydrogen breath test, a simpler test is an empirical trial of oral antibiotics. Some patients with postvagotomy diarrhea respond to cholestyramine, while in others codeine or loperamide may be useful. Octreotide should also be tried. Another theoretical cause of diarrhea following gastric surgery is fat malabsorption due to acid inactivation of pancreatic enzymes or poorly coordinated mixing of food and digestive juices. This can be confirmed with a qualitative test for fecal fat and treated with acid suppression. Postvagotomy diarrhea usually does not respond to treatment with pancreatic enzymes. In the rare patient who is debilitated by postvagotomy diarrhea unresponsive to medical management, operation might be considered but outcomes can be problematic. The operation of choice is probably a 10-cm reversed jejunal interposition placed in continuity 100 cm distal to the ligament of Treitz. Another option is the onlay antiperistaltic distal ileal graft. Both operations can cause obstructive symptoms and/or bacterial overgrowth.^127B

Gastric Stasis

Gastric stasis following surgery on the stomach may be due to a problem with gastric motor function or caused by an obstruction.^128,129 The gastric motility abnormality could have been preexisting and unrecognized by the operating surgeon. Alternatively, it may be secondary to deliberate or unintentional vagotomy, or resection of the dominant gastric pacemaker. An obstruction may be mechanical (e.g., anastomotic stricture, efferent limb kink from adhesions or constricting mesocolon, or a proximal small-bowel obstruction) or functional (e.g., retrograde peristalsis in a Roux limb). Gastric stasis presents with vomiting (often of undigested food), bloating, epigastric pain, and weight loss.

The evaluation of a patient with suspected postoperative gastric stasis includes EGD, upper GI and small bowel series, gastric emptying scan, and gastric motor testing. Endoscopy shows gastritis and retained food or bezoar. The anastomosis and efferent limb should be evaluated for stricture or narrowing. A dilated efferent limb suggests chronic stasis, either from a motor abnormality (e.g., Roux syndrome) or mechanical small bowel obstruction (e.g., chronic adhesion). If the problem is thought to be primarily a disorder of intrinsic motor function, newer techniques such as EGG and GI manometry should be considered, but chronic distal mechanical obstruction may result in disordered motility in the proximal organ confounding interpretation.

Once mechanical obstruction has been ruled out, medical treatment is successful in most cases of motor dysfunction following previous gastric surgery. This consists of dietary modification and promotility agents. Intermittent oral antibiotic therapy may be helpful in treating bacterial overgrowth, with its attendant symptoms of bloating, flatulence, and diarrhea.

Gastroparesis following V + D may be treated with subtotal gastrectomy but simple loop gastrojejunoctomy (GJ) should be tried if previous drainage was pyloroplasty. Billroth II anastomosis with Braun enteroenterostomy may be preferable to Roux-en-Y reconstruction after subtotal gastrectomy for gastric stasis but bile reflux can still occur. Regeneration of gastric stasis is often associated with persistent emptying problems that may subsequently require near-total or total gastrectomy, a nutritionally unattractive option. Delayed gastric emptying following ulcer surgery (V + D or V + A) may represent an anastomotic stricture (often due to recurrent ulcer), or proximal small bowel obstruction. The latter should be dealt with at reoperation. Recurrent ulcer usually responds to medical therapy with PPI and abstinence from NSAIDs, aspirin, and smoking. Endoscopic dilation is occasionally helpful. Gastroparesis following subtotal gastric resection is best treated with near-total (95%) or total gastric resection and Roux-en-Y reconstruction. If total gastrectomy is performed, a jejunal reservoir should be fashioned. Gastric pacing is promising, but it has not achieved widespread clinical usefulness in the treatment of postoperative gastric atony.

Bile Reflux Gastritis and Esophagitis

Most patients who have undergone ablation or resection of the pylorus have bile in the stomach on endoscopic examination, along with some degree of gross or microscopic gastric inflammation. Therefore, attributing postoperative symptoms to bile reflux is problematic because most asymptomatic patients have bile reflux as well. However, it is generally accepted that a small subset of patients have bile reflux gastritis, and present with nausea, bilious vomiting, and epigastric pain, and quantitative evidence of excess enterogastric reflux. Curiously, symptoms often develop months or years after the index operation. The differential diagnosis includes afferent or efferent loop obstruction, gastric stasis, and small-bowel obstruction. Plain abdominal X-rays, upper endoscopy, upper GI series, abdominal CT scan, and gastric emptying scans are helpful in evaluating these possibilities.

Dysfunction of the cardia is one of the causes of bile reflux esophagitis in patients after gastrectomy, Proximal subtotal gastrectomy with esophagoantral anastomosis should be avoided, and if limited resection of the GE junction is performed, the pylorus should be left intact.

Bile reflux may be quantified with gastric analysis or esophageal impedance testing or with scintigraphy (bile reflux scan). Typically, enterogastric reflux is greatest after Billroth II gastrectomy or gastrojejunostomy, and least after vagotomy and pyloroplasty, with Billroth I gastrectomy giving intermediate values. Patients who are well into the abnormal range of bile reflux may be considered for remedial surgery if symptoms are severe. Remedial surgery will eliminate the bile from the vomitus and may improve the patient’s pain, but it is quite unusual to render these patients completely asymptomatic, especially if they are narcotic dependent.

Bile reflux gastritis after distal gastric resection may be treated by one of the following options: Roux-en-Y gastro jejunostomy; interposition of a 40-cm isoperistaltic jejunal loop between the gastric remnant and the duodenum (Henley loop); Billroth II gastro jejunostomy with Braun enteroenterostomy; total gastrectomy with Roux esophagojejunostomy. To avoid bile reflux into the stomach or the esophagus the Roux limb should be at least 45 cm long (preferably 60 cm). The Braun enteroenterostomy should be placed a similar distance from the stomach. Excessively long limbs may be associated with obstruction or malabsorption. All operations can result in marginal ulceration on the jejunal side of the gastrojejunostomy, and thus are combined with a generous distal gastrectomy. If this has already been done at a previous operation, the Roux or Braun operations may be attractively simple. Whether truncal vagotomy is necessary is controversial in the current era of excellent acid-suppressing medications. The benefits of decreased acid secretion following vagotomy may be outweighed by problems with vagotomy-associated dysmotility in the gastric remnant. The Roux operation may be associated with an increased risk of emptying problems compared to the other two options, but controlled data are lacking. Patients with debilitating bile reflux after gastrojejunostomy can be considered for simple takedown of this anastomosis provided that the pyloric channel is open.

Primary bile reflux gastritis (i.e., no previous operation) is rare, and may be treated with the duodenal switch operation, essentially an end-to-end Roux-en-Y to the proximal duodenum (see Fig. 26-68). The Achilles’ heel of this operation is, not surprisingly, marginal ulceration. Thus, it should be combined with highly selective vagotomy, and/or long term acid suppressive medication.

Roux Syndrome

A subset of patients who have had distal gastrectomy and Roux-en-Y gastrojejunostomy will have great difficulty with gastric emptying in the absence of mechanical obstruction. These patients present with vomiting, epigastric pain, and weight loss. This clinical scenario has been labeled the Roux syndrome. Endoscopy may show retained food or bezoars, dilation of the gastric remnant, and/or dilation of the Roux limb. Anastomotic inflammation and stricture from marginal ulceration is a confounding finding. An upper GI series confirms these findings and may show delayed gastric emptying. This is better quantified by a gastric emptying scan, which always shows delayed solid emptying, and may show delayed liquid emptying as well.

GI motility testing shows abnormal motility in the Roux limb, with propulsive activity toward, rather than away from, the stomach.¹³⁰ Gastric motility also may be abnormal. Presumably, the disordered motility in the Roux limb occurs in all patients with this operation. Why only a subset develops the Roux syndrome is unclear. Perhaps those patients with disordered gastric motility are at most risk. The disorder seems to be more common in patients with a generous gastric remnant. Truncal vagotomy also has been implicated.

Medical treatment consists of promotility agents. Surgical treatment consists of paring down the gastric remnant. Care should be taken to preserve adequate blood supply to the new gastric pouch. If the left gastric artery is intact, a vertically oriented lesser curvature based pouch (similar to gastric bypass) with excision of the fundus can be considered. If gastric motility is severely disordered, 95% gastrectomy or total gastrectomy should be done. The Roux limb should be resected if it is dilated and flaccid, unless doing so puts the patient at risk for short bowel problems.

Gallstones

Gallstone formation following gastric surgery generally is thought to be secondary to vagal denervation of the gallbladder with attendant gallbladder dysmotility and stasis. Although prophylactic cholecystectomy is not justified with most gastric surgery, it should be considered if the gallbladder appears abnormal, especially if subsequent cholecystectomy is likely to be difficult. If preoperative evaluation reveals sludge or gallstones, or if intraoperative evaluation reveals stones, incidental cholecystectomy should be considered if it appears straightforward and the gastric operation has gone well.

Weight Loss

Weight loss is common in patients who have had a vagotomy and/or gastric resection. The degree of weight loss tends to parallel the magnitude of the operation. It may be insignificant in the large person, or devastating in the asthenic female. The surgeon should always consider the possible nutritional consequences before performing a gastric resection for benign disease in a thin patient. The causes of weight loss after gastric surgery generally fall into one of two categories: altered dietary intake or malabsorption. If a stool stain for fecal fat is negative, it is likely that decreased caloric intake is the cause. This is the most common cause of weight loss after gastric surgery, and may be due to small stomach syndrome, postoperative gastroparesis, anorexia due to loss of ghrelin, or self-imposed dietary modification because of dumping and/or diarrhea. Consultation with an experienced dietitian may prove invaluable.

Anemia

Iron absorption takes place primarily in the proximal GI tract, and is facilitated by an acidic environment. Intrinsic factor, essential for the enteric absorption of vitamin B₁₂, is made by the parietal cells of the stomach. Vitamin B₁₂ bioavailability also is facilitated by an acidic environment.

With this as background, it is easy to understand why patients who have had a gastric operation are at risk for anemia. Anemia is the most common metabolic side effect in patients who have had a gastric bypass for morbid obesity. It also occurs in up to one third of patients who have had a vagotomy and/or gastric resection. Iron deficiency is the most common cause, but vitamin B₁₂ or folate deficiency also occurs, even in patients who have not had total gastrectomy. Of course, patients who have had a total gastrectomy will all develop B₁₂ deficiency without parenteral vitamin B₁₂. Gastric bypass patients should be given oral iron supplements, and monitored for iron, B₁₂, and folate deficiency. Patients who have had a vagotomy and/or gastrectomy should be similarly monitored with periodic determination of hematocrit, red blood cell indices, iron and transferrin levels, B₁₂, and folate levels. Marginal nutrient status should be corrected with oral and/or parenteral supplementation.

Bone Disease

Gastric surgery sometimes disturbs calcium and vitamin D metabolism. Calcium absorption occurs primarily in the duodenum, which is bypassed with gastrojejunostomy. Fat malabsorption may occur because of blind loop syndrome and bacterial overgrowth, or because of inefficient mixing of food and digestive enzymes. This can significantly affect the absorption of vitamin D, a fat-soluble vitamin. Both abnormalities of calcium and vitamin D metabolism can contribute to metabolic bone disease in patients following gastric surgery. The problems usually manifest as pain and/or fractures years after the index operation. Musculoskeletal symptoms should prompt a study of bone density. Dietary supplementation of calcium and vitamin D may be useful in preventing these complications. Routine skeletal monitoring of patients at high-risk (e.g., elderly males and females and postmenopausal females) may prove useful in identifying skeletal deterioration that may be stopped with appropriate treatment.

The most common laparoscopic gastric operations performed today are for GERD and obesity (see Chapter 27, The Surgical Management of Obesity). However, all of the gastric operations described here can be performed with minimally invasive techniques.¹³¹ Some are technically difficult (e.g., partial or total gastric resection) or are of debatable merit. The operations described in this chapter that lend themselves most readily to minimally invasive techniques are highly selective vagotomy, vagotomy and gastrojejunostomy, and gastrostomy. Laparoscopic wedge resection often is possible for GI stromal tumors, lipomas, or gastric diverticula. Combined endoscopic and laparoscopic techniques occasionally are useful. Robotic gastric operations have been described, but have not yet been widely adopted.¹³² Recently laparoscopic resection has been applied increasingly to patients with gastric cancer¹³³ with promising early results. Advances of laparoscopic instruments particularly energy sources have rendered extended lymph node dissection, including suprapancreatic lymph node dissection feasible. The ratio of D2 lymph node dissection has been increased gradually due to these advances and surgeon’s experiences. Laparoscopy surgery has been widely performed in reconstruction in which the intestine is pulled out of the body through a small laparotomy wound.133A Recently, based on the improvement in anastomosis devices, pure laparoscopic surgery has also been used in which a series of procedures (lymphadenectomy, resection, and reconstruction) is completely performed intra-abdominally. Finally, diagnostic laparoscopy may prevent a futile laparotomy in some patients with gastric cancer.

While transgastric appendectomy and transgastric pancreatic necrosectomy appears safe and effective in selected patients in experienced centers, ^134,135 the role of transgastric natural orifice endoscopic surgery has yet to be defined.