Pathogenesis.

You may recall that the enteric neuronal plexus develops from neural crest cells that migrate into the bowel wall during embryogenesis. Hirschsprung disease, also known as congenital aganglionic megacolon, results when the normal migration of neural crest cells from cecum to rectum is arrested prematurely or when the ganglion cells undergo premature death. This produces a distal intestinal segment that lacks both the Meissner submucosal and the Auerbach myenteric plexus (“aganglionosis”). Coordinated peristaltic contractions are absent and functional obstruction occurs, resulting in dilation proximal to the affected segment.

The mechanisms underlying defective neural crest cell migration in Hirschsprung disease are unknown, but a genetic component is present in nearly all cases and 4% of patients’ siblings are affected.² However, simple Mendelian inheritance is not involved in most cases. Heterozygous loss-of-function mutations in the receptor tyrosine kinase RET account for the majority of familial cases and approximately 15% of sporadic cases.³ Mutations also occur in at least seven other genes encoding proteins involved in enteric neurodevelopment, including the RET ligand glial-derived neurotrophic factor, endothelin, and the endothelin receptor, but, in aggregate, these account for fewer than 30% of patients, suggesting that other defects are yet to be discovered. Because penetrance is incomplete, modifying genes or environmental factors must also be important. In addition, it is clear that sex-linked factors exist, since males are affected preferentially while disease tends to be more extensive in females.

Morphology. Diagnosis of Hirschsprung disease requires documenting the absence of ganglion cells within the affected segment. Because migration of neural crest cells in the Meissner and Auerbach plexi are linked, it is possible to establish the diagnosis preoperatively by examining suction biopsy specimens. In addition to their characteristic morphology in hematoxylin and eosin (H&E)-stained sections, ganglion cells can be identified using immunohistochemical stains for acetylcholinesterase.

The rectum is always affected, but the length of the additional involved segments varies widely. Most cases are limited to the rectum and sigmoid colon, but severe cases can involve the entire colon. The aganglionic region may have a grossly normal or contracted appearance, while the normally innervated proximal colon may undergo progressive dilation (Fig. 17-3). With time the proximal colon may become massively distended (megacolon), reaching diameters of as much as 20 cm. Dilation may stretch and thin the colonic wall to the point of rupture, which occurs most frequently near the cecum. Mucosal inflammation or shallow ulcers may also be present. These changes proximal to the diseased segment can make gross identification of the extent of aganglionosis difficult. Hence, intraoperative frozen-section analysis of transmural sections is commonly used to confirm the presence of ganglion cells at the anastamotic margin.

FIGURE 17-3 Hirschsprung disease. A, Preoperative barium enema study showing constricted rectum (bottom of the image) and dilated sigmoid colon. B, Corresponding intraoperative photograph showing constricted rectum and dilation of the sigmoid colon.

(Courtesy of Dr. Aliya Husain, The University of Chicago, Chicago, IL.)

Clinical Features.

Patients typically present neonatally, often with a failure to pass meconium in the immediate postnatal period. Obstructive constipation follows, although in cases where only a few centimeters of the rectum are involved there may be occasional passage of stool. The major threats to life are enterocolitis, fluid and electrolyte disturbances, perforation, and peritonitis. The primary mode of treatment is surgical resection of the aganglionic segment and anastamosis of the normal colon to the rectum. Even after successful surgery, it may take years for patients to attain normal bowel function and continence.

In contrast to the congenital megacolon of Hirschsprung disease, acquired megacolon may occur at any age as a result of Chagas disease, obstruction by a neoplasm or inflammatory stricture, toxic megacolon complicating ulcerative colitis, visceral myopathy, or in association with functional psychosomatic disorders. Of these, only Chagas disease (discussed later) is associated with loss of ganglia.

Pathogenesis.

Reflux of gastric juices is central to the development of mucosal injury in GERD. In severe cases, reflux of bile from the duodenum may exacerbate the damage. Conditions that decrease lower esophageal sphincter tone or increase abdominal pressure contribute to GERD and include alcohol and tobacco use, obesity, central nervous system depressants, pregnancy, hiatal hernia (discussed below), delayed gastric emptying, and increased gastric volume. In many cases, no definitive cause is identified.

Morphology. Simple hyperemia, evident to the endoscopist as redness, may be the only alteration. In mild GERD the mucosal histology is often unremarkable. With more significant disease, eosinophils are recruited into the squamous mucosa followed by neutrophils, which are usually associated with more severe injury (Fig. 17-5A). Basal zone hyperplasia exceeding 20% of the total epithelial thickness and elongation of lamina propria papillae, such that they extend into the upper third of the epithelium, may also be present.

FIGURE 17-5 Esophagitis. A, Reflux esophagitis with scattered intraepithelial eosinophils. Although mild basal zone expansion can be appreciated, squamous cell maturation is relatively normal. B, Eosinophilic esophagitis is characterized by numerous intraepithelial eosinophils. Abnormal squamous maturation is also apparent.

Clinical Features.

GERD is most common in adults over age 40 but also occurs in infants and children. The most common clinical symptoms are dysphagia, heartburn, and, less frequently, noticeable regurgitation of sour-tasting gastric contents. Rarely, chronic GERD is punctuated by attacks of severe chest pain that may be mistaken for heart disease. Treatment with proton pump inhibitors or H₂ histamine receptor antagonists, which reduce gastric acidity, typically provides symptomatic relief. While the severity of symptoms is not closely related to the degree of histologic damage, the latter tends to increase with disease duration. Complications of reflux esophagitis include esophageal ulceration, hematemesis, melena, stricture development, and Barrett esophagus.

Hiatal hernia is characterized by separation of the diaphragmatic crura and protrusion of the stomach into the thorax through the resulting gap. Congenital hiatal hernias are recognized in infants and children, but many are acquired in later life. Hiatal hernia is symptomatic in fewer than 10% of adults, and these cases are generally associated with other causes of LES incompetence. Symptoms, including heartburn and regurgitation of gastric juices, are similar to GERD.

Clinical Features.

Barrett esophagus can only be identified thorough endoscopy and biopsy, which are usually prompted by GERD symptoms. Once diagnosed, the best course of management in Barrett esophagus is a matter of debate. However, most agree that periodic endoscopy with biopsy, for detection of dysplasia, has an important role. Nevertheless, uncertainties about the potential of dysplasia to regress, either spontaneously or in response to therapy, complicate clinical decisions when dysplasia is identified. In contrast, intramucosal carcinoma requires therapeutic intervention. Treatment options include surgical resection, or esophagectomy, as well as newer modalities such as photodynamic therapy, laser ablation, and endoscopic mucosectomy. Multifocal high-grade dysplasia, which carries a significant risk of progression to intramucosal or invasive carcinoma, is treated similarly to intramucosal carcinoma. Many physicians follow low-grade dysplasia or a single focus of high-grade dysplasia with endoscopy and biopsy at frequent intervals. However, management of esophageal dysplasia is evolving, and it is hoped that improved molecular understanding of neoplastic progression may allow development of chemopreventive approaches that reduce incidence of esophageal adenocarcinoma.⁸

Pathogenesis.

Portal hypertension results in the development of collateral channels at sites where the portal and caval systems communicate. Although these collateral veins allow some drainage to occur, they lead to development of a congested subepithelial and submucosal venous plexus within the distal esophagus. These vessels, termed varices, develop in 90% of cirrhotic patients, most commonly in association with alcoholic liver disease. Worldwide, hepatic schistosomiasis is the second most common cause of varices. A more detailed consideration of portal hypertension is given in Chapter 18.

Morphology. Varices can be detected by venogram (Fig. 17-8A) and appear as tortuous dilated veins lying primarily within the submucosa of the distal esophagus and proximal stomach. Venous channels directly beneath the esophageal epithelium may also become massively dilated. Varices may not be grossly obvious in surgical or postmortem specimens, because they collapse in the absence of blood flow (Fig. 17-8B) and, when they are not ruptured, the overlying mucosa is intact (Fig. 17-8C). Variceal rupture results in hemorrhage into the lumen or esophageal wall, in which case the overlying mucosa appears ulcerated and necrotic. If rupture has occurred in the past, venous thrombosis, inflammation, and evidence of prior therapy may also be present.

FIGURE 17-8 Esophageal varices. A, This angiogram shows several tortuous esophageal varices. B, Collapsed varices are present in this postmortem specimen corresponding to the angiogram in A. The polypoid areas represent previous sites of variceal hemorrhage that have been ligated with bands. C, Dilated varice beneath intact squamous mucosa.

Clinical Features.

While varices are often asymptomatic, they may rupture, causing massive hematemesis. The factors that lead to rupture are not well defined, but inflammatory erosion of thinned overlying mucosa, increased tension in progressively dilated veins, and increased vascular hydrostatic pressure associated with vomiting are likely to contribute. In any case, hemorrhage due to variceal rupture is a medical emergency that is treated by any of several methods: sclerotherapy by endoscopic injection of thrombotic agents; endoscopic balloon tamponade; or endoscopic rubber band ligation. Despite these interventions, as many as half of patients die from the first bleeding episode either as a direct consequence of hemorrhage or following hepatic coma triggered by hypovolemic shock. Among those who survive, additional instances of hemorrhage occur in over 50% within 1 year. Each episode has a similar rate of mortality. Thus, over half of deaths among individuals with advanced cirrhosis result from variceal rupture. It must be remembered, however, that even when varices are present, they are only one of several causes of hematemesis.

Pathogenesis.

Molecular studies suggest that the progression of Barrett esophagus to adenocarcinoma occurs over an extended period through the stepwise acquisition of genetic and epigenetic changes. This model is supported by the observation that epithelial clones identified in nondysplastic Barrett metaplasia persist and accumulate mutations during progression to dysplasia and invasive carcinoma. Chromosomal abnormalities and mutation or overexpression of p53 are present at early stages of esophageal adenocarcinoma. Additional genetic changes include amplification of c-ERB-B2, cyclin D1, and cyclin E genes; mutation of the retinoblastoma tumor suppressor gene; and allelic loss of the cyclindependent kinase inhibitor p16/INK4a. In other instances p16/INK4a is epigenetically silenced by hypermethylation. Increased epithelial expression of tumor necrosis factor (TNF)- and nuclear factor (NF)-κB–dependent genes suggests that inflammation may also contribute to neoplastic progression.

Morphology. Esophageal adenocarcinoma usually occurs in the distal third of the esophagus and may invade the adjacent gastric cardia (Fig. 17-9A). Initially appearing as flat or raised patches in otherwise intact mucosa, large masses of 5 cm or more in diameter may develop. Alternatively, tumors may infiltrate diffusely or ulcerate and invade deeply. Microscopically, Barrett esophagus is frequently present adjacent to the tumor. Tumors most commonly produce mucin and form glands (Fig. 17-10A), often with intestinal-type morphology; less frequently tumors are composed of diffusely infiltrative signet-ring cells (similar to those seen in diffuse gastric cancers) or, in rare cases, small poorly differentiated cells (similar to small-cell carcinoma of the lung).

FIGURE 17-9 Esophageal cancer. A, Adenocarcinoma usually occurs distally and, as in this case, often involves the gastric cardia. B, Squamous cell carcinoma is most frequently found in the mid-esophagus, where it commonly causes strictures.

FIGURE 17-10 Esophageal cancer. A, Esophageal adenocarcinoma organized into back-to-back glands. B, Squamous cell carcinoma composed of nests of malignant cells that partially recapitulate the organization of squamous epithelium.

Clinical Features.

Although esophageal adenocarcinomas are occasionally discovered in evaluation of GERD or surveillance of Barrett esophagus, they more commonly present with pain or difficulty in swallowing, progressive weight loss, hematemesis, chest pain, or vomiting. By the time symptoms appear, the tumor has usually spread to submucosal lymphatic vessels. As a result of the advanced stage at diagnosis, overall 5-year survival is less than 25%. In contrast, 5-year survival approximates 80% in the few patients with adenocarcinoma limited to the mucosa or submucosa.

Pathogenesis.

The majority of esophageal squamous cell carcinomas in Europe and the United States are at least partially attributable to the use of alcohol and tobacco, which synergize to increase risk. However, esophageal squamous cell carcinoma is also common in some regions where alcohol and tobacco use is uncommon. Thus, nutritional deficiencies, as well as polycyclic hydrocarbons, nitrosamines, and other mutagenic compounds, such as those found in fungus-contaminated foods, must be considered. Human papillomavirus (HPV) infection has also been implicated in esophageal squamous cell carcinoma in high-risk areas but not in low-risk regions.¹² The molecular pathogenesis of esophageal squamous cell carcinoma remains incompletely defined, but loss of several tumor suppressor genes, including p53 and p16/INK4a, is involved.

Clinical Features.

The onset of esophageal squamous cell carcinoma is insidious and ultimately produces dysphagia, odynophagia (pain on swallowing), and obstruction. Patients subconsciously adjust to the progressively increasing obstruction by altering their diet from solid to liquid foods. Extreme weight loss and debilitation result from both impaired nutrition and effects of the tumor itself. Hemorrhage and sepsis may accompany tumor ulceration. Occasionally, the first symptoms are caused by aspiration of food via a tracheoesophageal fistula.

Increased prevalence of endoscopic screening has led to earlier detection of esophageal squamous cell carcinoma. This is critical, because 5-year survival rates are 75% in individuals with superficial esophageal carcinoma but much lower in patients with more advanced tumors. Lymph node metastases, which are common, are associated with poor prognosis. The overall 5-year survival remains a dismal 9%.

Pathogenesis.

The gastric lumen is strongly acidic with pH close to 1, more than a million times more acidic than the blood. This harsh environment contributes to digestion but also has the potential to damage the gastric mucosa. Multiple mechanisms have evolved to protect the gastric mucosa (Fig. 17-11). Mucin secreted by surface foveolar cells forms a thin layer of mucus that prevents large food particles from directly touching the epithelium. The mucus layer also promotes formation of an “unstirred” layer of fluid over the epithelium that protects the mucosa and has a neutral pH as a result of bicarbonate ion secretion by surface epithelial cells. Finally, the rich vascular supply to the gastric mucosa delivers oxygen, bicarbonate, and nutrients while washing away acid that has back-diffused into the lamina propria. Acute or chronic gastritis can occur following disruption of any of these protective mechanisms. For example, reduced mucin synthesis in the elderly has been suggested as one factor that may explain their increased susceptibility to gastritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with cytoprotection normally provided by prostaglandins or reduce bicarbonate secretion, either of which increases the susceptibility of the gastric mucosa to injury. Similarly, the gastric injury that occurs in uremic patients and those infected with urease-secreting H. pylori may be due to inhibition of gastric bicarbonate transporters by ammonium ions. Ingestion of harsh chemicals, particularly acids or bases, either accidentally or as a suicide attempt, also results in severe gastric injury, predominantly as a result of direct injury to mucosal epithelial and stromal cells. Direct cellular injury is also implicated in gastritis due to excessive alcohol consumption, NSAIDs, radiation therapy, and chemotherapy. Since the entire gastric mucosal surface is replaced every 2 to 6 days, mitotic inhibitors, including those used in cancer chemotherapy, cause generalized mucosal damage due to insufficient epithelial regeneration. Finally, decreased oxygen delivery may explain increased incidence of acute gastritis at high altitudes.

FIGURE 17-11 Mechanisms of gastric injury and protection. This diagram illustrates the progression from more mild forms of injury to ulceration that may occur with acute or chronic gastritis. Ulcers include layers of necrosis (N), inflammation (I), and granulation tissue (G), but a fibrotic scar (S), which takes time to develop, is only present in chronic lesions.

Pathogenesis.

The pathogenesis of acute ulceration is complex and incompletely understood. NSAID-induced ulcers are related to cyclooxygenase inhibition. This prevents synthesis of prostaglandins, which enhance bicarbonate secretion, inhibit acid secretion, promote mucin synthesis, and increase vascular perfusion. Lesions associated with intracranial injury are thought to be caused by direct stimulation of vagal nuclei, which causes hypersecretion of gastric acid. Systemic acidosis, a frequent finding in these settings, may also contribute to mucosal injury by lowering the intracellular pH of mucosal cells. Hypoxia and reduced blood flow caused by stress-induced splanchnic vasoconstriction also contribute to the pathogenesis of acute ulcers.

Clinical Features.

Most critically ill patients admitted to hospital intensive care units have histologic evidence of gastric mucosal damage. Bleeding from superficial gastric erosions or ulcers that may require transfusion develops in 1% to 4% of these patients. Other complications, including perforation, can also occur (Table 17-2). Prophylactic H₂ histamine receptor antagonists or proton pump inhibitors may blunt the impact of stress ulceration, but the most important determinant of clinical outcome is the ability to correct the underlying conditions. The gastric mucosa can recover completely if the patient does not succumb to their primary disease.

TABLE 17-2 Complications of Gastric Ulcers

Epidemiology.

In the United States, H. pylori infection is associated with poverty, household crowding, limited education, African-American or Mexican-American ethnicity, residence in rural areas, and birth outside of the United States. Colonization rates exceed 70% in some groups and vary from less than 10% to more than 80% worldwide. In high-prevalence areas infection is often acquired in childhood and then persists for decades, explaining the direct correlation between colonization rate and patient age.

The mode of H. pylori transmission is not well defined, but humans are the only known host, making oral-oral, fecal-oral, and environmental spread the most likely routes of infection. The related organism Helicobacter heilmannii causes similar disease and has reservoirs in cats, dogs, pigs, and nonhuman primates. While the morphologic differences between H. pylori and H. heilmannii organisms are subtle, recognition of H. heilmannii infection can be important since it may prompt treatment of household pets to prevent re-infection of the human companion.

Pathogenesis.

H. pylori infection is the most common cause of chronic gastritis. The disease most often presents as a predominantly antral gastritis with high acid production, despite hypogastrinemia. The risk of duodenal ulcer is increased in these patients and, in most, gastritis is limited to the antrum with occasional involvement of the cardia. In a subset of patients the gastritis progresses to involve the gastric body and fundus. This pangastritis is associated with multifocal mucosal atrophy, reduced acid secretion, intestinal metaplasia, and increased risk of gastric adenocarcinoma.

H. pylori organisms have adapted to the ecologic niche provided by gastric mucus. Although H. pylori may invade the gastric mucosa, this is not evident histologically and the contribution of invasion to disease is not known. Four features are linked to H. pylori virulence:

Although the mechanisms by which H. pylori cause gastritis are incompletely defined, it is clear that infection results in increased acid production and disruption of normal gastric and duodenal protective mechanisms, as described earlier (see Fig. 17-11). H. pylori gastritis is, therefore, the result of an imbalance between gastroduodenal mucosal defenses and damaging forces that overcome those defenses.

Over time chronic antral H. pylori gastritis may progress to pangastritis, resulting in multifocal atrophic gastritis. The underlying mechanisms contributing to this progression are not clear, but interactions between the host and bacterium seem to be critical. For example, particular polymorphisms in the gene encoding the pro-inflammatory cytokine interleukin-1β (IL-1β) correlate with the development of pangastritis after H. pylori infection. Polymorphisms in TNF and a variety of other genes associated with the inflammatory response also influence the clinical outcome in H. pylori infection.¹⁴ Severity of disease may also be influenced by genetic variation among H. pylori strains. For example, the CagA gene, a marker for a pathogenicity island of approximately 20 genes, is present in 50% of H. pylori isolates overall but in 90% of H. pylori isolates found in populations with elevated gastric cancer risk.

Morphology. Gastric biopsy specimens generally demonstrate H. pylori in infected individuals. The organism is concentrated within the superficial mucus overlying epithelial cells in the surface and neck regions. The distribution can be irregular, with areas of heavy colonization adjacent to those with few organisms. In extreme cases, the organisms carpet the luminal surfaces of foveolar and mucous neck cells, and can even extend into the gastric pits. Organisms are most easily demonstrated with a variety of special stains (Fig. 17-12A). H. pylori shows tropism for gastric epithelia and is generally not found in association with gastric intestinal metaplasia or duodenal epithelium. However, H. pylori may be present in foci of pyloric metaplasia within chronically injured duodenum or gastric-type mucosa within Barrett esophagus.

FIGURE 17-12 Helicobacter pylori gastritis. A, Spiral-shaped H. pylori are highlighted in this Warthin-Starry silver stain. Organisms are abundant within surface mucus. B, Intraepithelial and lamina propria neutrophils are prominent. C, Lymphoid aggregates with germinal centers and abundant subepithelial plasma cells within the superficial lamina propria are characteristic of H. pylori gastritis.

Within the stomach, H. pylori are typically found in the antrum (Table 17-3). Although there is a good concordance between colonization of the antrum and cardia, infection of the cardia occurs at somewhat lower rates. H. pylori are uncommon in oxyntic (acid-producing) mucosa of the fundus and body except in heavy colonization. Thus, an antral biopsy is preferred for evaluation of H. pylori gastritis. When viewed endoscopically, H. pylori–infected antral mucosa is usually erythematous and has a coarse or even nodular appearance. The inflammatory infiltrate generally includes variable numbers of neutrophils within the lamina propria, including some that cross the basement membrane to assume an intraepithelial location (Fig. 17-12B) and accumulate in the lumen of gastric pits to create pit abscesses. In addition, the superficial lamina propria includes large numbers of plasma cells, often in clusters or sheets, and increased numbers of lymphocytes and macrophages. Intraepithelial neutrophils and subepithelial plasma cells are characteristic of H. pylori gastritis. When intense, inflammatory infiltrates may create thickened rugal folds, mimicking early infiltrative lesions. Long-standing H. pylori gastritis may extend to involve the body and fundus, and the mucosa can become atrophic. Lymphoid aggregates, some with germinal centers, are frequently present (Fig. 17-12C) and represent an induced form of mucosa-associated lymphoid tissue, or MALT, that has the potential to transform into lymphoma.

TABLE 17-3 Characteristics of Helicobacter pylori–Associated and Autoimmune Gastritis

	H. pylori–Associated	Autoimmune
Location	Antrum	Body
Inflammatory infiltrate	Neutrophils, subepithelial plasma cells	Lymphocytes, macrophages
Acid production	Increased to slightly decreased	Decreased
Gastrin	Normal to decreased	Increased
Other lesions	Hyperplastic/inflammatory polyps	Neuroendocrine hyperplasia
Serology	Antibodies to H. pylori	Antibodies to parietal cells (H+, K+-ATPase, intrinsic factor)
Sequelae	Peptic ulcer, adenocarcinoma	Atrophy, pernicious anemia, adenocarcinoma, carcinoid tumor
Associations	Low socioeconomic status, poverty, residence in rural areas	Autoimmune disease; thyroiditis, diabetes mellitus, Graves disease

Clinical Features.

In addition to histologic identification of the organism, several diagnostic tests have been developed including a noninvasive serologic test for antibodies to H. pylori, fecal bacterial detection, and the urea breath test based on the generation of ammonia by the bacterial urease. Gastric biopsy specimens can also be analyzed by the rapid urease test, bacterial culture, or bacterial DNA detection by PCR.

Effective treatments for H. pylori infection include combinations of antibiotics and proton pump inhibitors. Individuals with H. pylori gastritis usually improve after treatment, although relapses can occur after incomplete eradication or re-infection. Prophylactic and therapeutic vaccine development is still at an early stage of development. Peptic ulcer disease, a complication of chronic H. pylori gastritis, is described later.

Pathogenesis.

Autoimmune gastritis is associated with loss of parietal cells, which are responsible for secretion of gastric acid and intrinsic factor. The absence of acid production stimulates gastrin release, resulting in hypergastrinemia and hyperplasia of antral gastrin-producing G cells. Lack of intrinsic factor disables ileal vitamin B₁₂ absorption, leading to B₁₂ deficiency and a slow-onset megaloblastic anemia (pernicious anemia). The reduced serum pepsinogen I concentration results from chief cell destruction. In contrast, although H. pylori can cause hypochlorhydria, it is not associated with achlorhydria or pernicious anemia because the parietal and chief cell damage is not as severe as in autoimmune gastritis.

It was initially thought that the autoantibodies to parietal cell components, most prominently the H⁺,K⁺-ATPase, or proton pump, and intrinsic factor were involved in the pathogenesis of autoimmune gastritis. However, this is unlikely because neither secreted intrinsic factor nor the luminally oriented proton pump are accessible to circulating antibodies, and passive transfer of these antibodies does not produce gastritis in experimental animals. It is more likely that CD4+ T cells directed against parietal cell components, including the H⁺,K⁺-ATPase, are the principal agents of injury. This is supported by the observation that transfer of H⁺,K⁺-ATPasereactive CD4+ T cells into naive mice results in gastritis and production of H⁺,K⁺-ATPase autoantibodies. There is no evidence of an autoimmune reaction to chief cells, suggesting that these are lost through gastric gland destruction during autoimmune attack on parietal cells. If autoimmune destruction is controlled by immunosuppression, the glands can repopulate, demonstrating that gastric stem cells survive and are able to differentiate into parietal and chief cells.

Morphology. Autoimmune gastritis is characterized by diffuse mucosal damage of the oxyntic (acid-producing) mucosa within the body and fundus. Damage to the antrum and cardia is typically absent or mild. With diffuse atrophy, the oxyntic mucosa of the body and fundus appears markedly thinned, and rugal folds are lost. If vitamin B₁₂ deficiency is severe, nuclear enlargement (megaloblastic change) occurs within epithelial cells. Neutrophils may be present, but the inflammatory infiltrate is more often composed of lymphocytes, macrophages, and plasma cells. Lymphoid aggregates may be present. The superficial lamina propria plasma cells of H. pylori gastritis are typically absent, and the inflammatory reaction is most often deep and centered on the gastric glands (Fig. 17-13A). Loss of parietal and chief cells can be extensive. When atrophy is incomplete residual islands of oxyntic mucosa may give the appearance of multiple small polyps or nodules. Small surface elevations may be apparent, and these correlate with areas of intestinal metaplasia, characterized by the presence of goblet cells and columnar absorptive cells (Fig. 17-13B). The antral endocrine cell hyperplasia that develops in most patients can be difficult to appreciate on H&E-stained sections, since the endocrine cells, which are also referred to as enterochromaffin-like (ECL) cells, are not easily recognized. This hyperplasia parallels the degree of mucosal atrophy and is a physiologic response to decreased acid production. Over time, hypergastrinemia can stimulate endocrine cell hyperplasia in the fundus and body. Rarely, this may progress to form small, multicentric, low-grade neuroendocrine, or carcinoid, tumors.

FIGURE 17-13 Autoimmune gastritis. A, Low-magnification image of gastric body demonstrating deep inflammatory infiltrates, primarily composed of lymphocytes, and glandular atrophy. B, Intestinal metaplasia, recognizable as the presence of goblet cells admixed with gastric foveolar epithelium.

Clinical Features.

Antibodies to parietal cells and to intrinsic factor are present early in the disease course. Progression to gastric atrophy probably occurs over 2 to 3 decades, and anemia is seen in only a few patients. Because of the slow onset and variable progression, patients are generally diagnosed only after being affected for many years; the median age at diagnosis is 60 years. Slightly more women than men are affected. Pernicious anemia and autoimmune gastritis are often associated with other autoimmune diseases including Hashimoto thyroiditis, insulin-dependent (type I) diabetes mellitus, Addison disease, primary ovarian failure, primary hypoparathyroidism, Graves disease, vitiligo, myasthenia gravis, and Lambert-Eaton syndrome. These associations, along with concordance in some monozygotic twins and clustering of disease in families, support a genetic predisposition. In general, about 20% of relatives of individuals with pernicious anemia also have autoimmune gastritis, although they may be asymptomatic. Despite this strong genetic influence, autoimmune gastritis stands apart from other autoimmune diseases in that there is little evidence of linkage to specific HLA alleles.

Clinical presentation may be linked to symptoms of anemia.¹⁵ In addition, vitamin B₁₂ deficiency may cause atrophic glossitis, in which the tongue becomes smooth and beefy red, epithelial megaloblastosis, and malabsorptive diarrhea. Vitamin B₁₂ deficiency may also cause peripheral neuropathy, spinal cord lesions, and cerebral dysfunction. Neuropathic changes include demyelination, axonal degeneration, and neuronal death. The most frequent manifestations of peripheral neuropathy are paresthesias and numbness. The spinal lesions may be associated with a mixture of loss of vibration and position sense, sensory ataxia with positive Romberg sign, limb weakness, spasticity, and extensor plantar responses. Cerebral manifestations range from mild personality changes and memory loss to psychosis. In contrast to anemia, neurologic changes are not reversed by vitamin B₁₂ replacement therapy.

Reactive Gastropathy.

This group of disorders is marked by foveolar hyperplasia, glandular regenerative changes, and mucosal edema. Neutrophils are not abundant. Causes of reactive gastropathy include chemical injury, NSAID use, bile reflux, and mucosal trauma secondary to prolapse. Notably, reactive gastropathy and bile reflux are common after gastric surgeries that bypass the pylorus. Gastric antral trauma induces a grossly characteristic lesion referred to as gastric antral vascular ectasia (GAVE). Endoscopy shows longitudinal stripes of edematous erythematous mucosa alternating with less severely injured mucosa that is sometimes referred to as watermelon stomach. Histologically, the antral mucosa shows reactive gastropathy with dilated capillaries containing fibrin thrombi.¹⁶

Eosinophilic Gastritis.

As indicated by the name, this form of gastritis is characterized by tissue damage associated with dense infiltrates of eosinophils in the mucosa and muscularis, usually in the antral or pyloric region. The lesion is often present in other areas of the GI tract as well and is associated with peripheral eosinophilia and increased serum IgE levels. Allergic reactions are one cause of eosinophilic gastritis. In children, the allergens include cow’s milk and soy protein, while drugs are common allergens in children and adults. Eosinophilic gastritis can also occur in association with systemic collagen-vascular disease, such as systemic sclerosis and polymyositis. Parasitic infections and H. pylori infection are other causes of eosinophilic gastritis.

Lymphocytic Gastritis.

This disease preferentially affects women and produces nonspecific symptoms such as abdominal pain, anorexia, nausea, and vomiting. It is idiopathic, but approximately 40% of cases are associated with celiac disease, suggesting an immune-mediated pathogenesis. Lymphocytic gastritis is also referred to as varioliform gastritis based on the distinctive endoscopic appearance (thickened folds covered by small nodules with central aphthous ulceration).¹⁷ The entire stomach is affected in most cases, but disease is occasionally limited to the body. Histologically there is a marked increase in the number of intraepithelial T lymphocytes, mostly CD8+ cells, within surface and pit regions.

Granulomatous Gastritis.

This descriptive term is applied to any gastritis that contains granulomas, or aggregates of epithelioid histiocytes (tissue macrophages). It encompasses a diverse group of diseases with widely varying clinical and pathologic features. Correlation with clinical, endoscopic, radiologic, and serologic data is generally necessary for diagnosis. In Western populations, gastric involvement by Crohn disease is the most common specific cause of granulomatous gastritis.¹⁸ Sarcoidosis is the second most common cause, followed by a variety of infections including mycobacteria, fungi, CMV, and H. pylori. In addition to the presence of histologically evident granulomas, narrowing and rigidity of the gastric antrum may occur secondary to transmural granulomatous inflammation.

Epidemiology.

PUD is common and ranks fourth in both annual physician visits and costs among all GI diseases.¹⁹ In the United States, the lifetime risk of developing an ulcer is approximately 10% for males and 4% for females; the latter are typically affected during or after menopause. PUD affects more than 300 million people and is responsible for treatment and ongoing care of over 3 million people, 190,000 hospitalizations, and 5000 deaths in the United States each year.¹⁹

Pathogenesis.

The imbalances of mucosal defenses and damaging forces that cause chronic gastritis are also responsible for PUD. Thus, PUD generally develops on a background of chronic gastritis. The reasons why some people develop only chronic gastritis while others develop PUD are poorly understood.

H. pylori infection and NSAID use are the primary underlying causes of PUD, and both compromise mucosal defense while causing mucosal damage. Although more than 70% of individuals with PUD are infected by H. pylori, fewer than 20% of H. pylori–infected individuals develop peptic ulcer. It is probable that host factors as well as variation among H. pylori strains determine the clinical outcomes.

The gastric hyperacidity that drives PUD may be caused by H. pylori infection, parietal cell hyperplasia, excessive secretory responses, or impaired inhibition of stimulatory mechanisms such as gastrin release. For example, Zollinger-Ellison syndrome, in which there are multiple peptic ulcerations in the stomach, duodenum, and even jejunum, is caused by uncontrolled release of gastrin by a tumor and the resulting massive acid production. More common cofactors in peptic ulcerogenesis include chronic NSAID use, which causes direct chemical irritation while suppressing prostaglandin synthesis necessary for mucosal protection; cigarette smoking, which impairs mucosal blood flow and healing; and high-dose corticosteroids that suppress prostaglandin synthesis and impair healing. Duodenal ulcers are more frequent in individuals with alcoholic cirrhosis, chronic obstructive pulmonary disease, chronic renal failure, and hyperparathyroidism. In the latter two conditions, hypercalcemia stimulates gastrin production and therefore increases acid secretion. Finally, self-imposed or exogenous psychologic stress may increase gastric acid production.

Morphology. Peptic ulcers are four times more common in the proximal duodenum than in the stomach. Duodenal ulcers usually occur within a few centimeters of the pyloric valve and involve the anterior duodenal wall. Gastric peptic ulcers are predominantly located along the lesser curvature near the interface of the body and antrum.

Peptic ulcers are solitary in more than 80% of patients. Lesions less than 0.3 cm in diameter tend to be shallow while those over 0.6 cm are likely to be deeper ulcers. The classic peptic ulcer is a round to oval, sharply punched-out defect (Fig. 17-14A). The mucosal margin may overhang the base slightly, particularly on the upstream side, but is usually level with the surrounding mucosa. In contrast, heaped-up margins are more characteristic of cancers. The depth of ulcers may be limited by the thick gastric muscularis propria or by adherent pancreas, omental fat, or the liver. Hemorrhage and fibrin deposition are often present on the gastric serosa. Perforation into the peritoneal cavity is a surgical emergency that may be identified by the presence of free air under the diaphragm on upright radiographs of the abdomen.

FIGURE 17-14 Acute gastric perforation in a patient presenting with free air under the diaphragm. A, Mucosal defect with clean edges. B, The necrotic ulcer base is composed of granulation tissue.

The base of peptic ulcers is smooth and clean as a result of peptic digestion of exudate, and blood vessels may be evident. In active ulcers the base may have a thin layer of fibrinoid debris underlaid by a predominantly neutrophilic inflammatory infiltrate. Beneath this, active granulation tissue infiltrated with mononuclear leukocytes and a fibrous or collagenous scar forms the ulcer base (Fig. 17-14B). Vessel walls within the scarred area are typically thickened and are occasionally thrombosed. Ongoing bleeding within the ulcer base may cause life-threatening hemorrhage. Scarring may involve the entire thickness of the wall and pucker the surrounding mucosa into folds that radiate outward.

Size and location do not differentiate benign and malignant ulcers. However, the gross appearance of chronic peptic ulcers is virtually diagnostic. Malignant transformation of peptic ulcers is very rare, and reports of transformation probably represent cases wherein a lesion thought to be benign was actually an ulcerated carcinoma from the start.

Clinical Features.

Peptic ulcers are notoriously chronic, recurring lesions with much greater morbidity than mortality. They may present in young adults but are most often diagnosed in middle-aged to older adults without obvious precipitating conditions. After a period of weeks to months of active disease, healing may occur with or without therapy, but the tendency to develop peptic ulcers remains. The majority of peptic ulcers come to clinical attention because of epigastric burning or aching pain, although a significant fraction present with complications such as iron deficiency anemia, frank hemorrhage, or perforation. The pain tends to occur 1 to 3 hours after meals during the day, is worse at night, and is relieved by alkali or food. Nausea, vomiting, bloating, belching, and significant weight loss are additional manifestations. With penetrating ulcers the pain is occasionally referred to the back, the left upper quadrant, or the chest, where it may be misinterpreted as cardiac in origin.

Current therapies for PUD are aimed at H. pylori eradication and neutralization of gastric acid, primarily with proton pump inhibitors or H₂ histamine receptor antagonists.²⁰ A variety of surgical approaches were formerly used, including antrectomy to remove gastrin-producing cells and vagotomy to remove the acid-stimulatory effects mediated by the vagus nerve. Proton pump inhibitors and H. pylori eradication have markedly reduced the need for surgical intervention, which is primarily reserved for treatment of bleeding or perforated peptic ulcers.

Epidemiology.

Gastric cancer incidence varies markedly with geography. In Japan, Chile, Costa Rica, and Eastern Europe the incidence is up to 20-fold higher than in North America, northern Europe, Africa, and Southeast Asia. Mass endoscopic screening programs can be successful in regions where the incidence is high, such as Japan, where 35% of newly detected cases are early gastric cancer, tumors limited to the mucosa and submucosa. Unfortunately, mass screening programs are not cost-effective in regions where the incidence is low, and fewer than 20% of cases are detected at an early stage in North America and northern Europe.

In the United States, gastric cancer rates dropped by over 85% during the twentieth century.²⁶ Adenocarcinoma of the stomach was the most common cause of cancer death in the United States in 1930 and remains a leading cause of cancer death worldwide, but now accounts for fewer than 2.5% of cancer deaths in the United States. Similar declines have been reported in many other Western countries, suggesting that environmental and dietary factors are responsible.²⁶ Consistent with this conclusion, studies of migrants from high-risk to low-risk regions have shown that gastric cancer rates in second-generation immigrants are similar to those in their new country of residence.

The cause of the overall reduction in gastric cancer is unknown. One possible explanation is the decreased consumption of dietary carcinogens, such as N-nitroso compounds and benzo[a]pyrene, because of reduced use of salt and smoking for food preservation and the widespread availability of food refrigeration. Conversely, intake of green, leafy vegetables and citrus fruits, which contain antioxidants such as vitamin C, vitamin E, and beta-carotene, and is correlated with reduced risk of gastric cancers, may have increased as a result of improved food transportation networks.

Gastric cancer is more common in lower socioeconomic groups and in individuals with multifocal mucosal atrophy and intestinal metaplasia. PUD does not impart an increased risk of gastric cancer, but patients who have had partial gastrectomies for PUD have a slightly higher risk of developing cancer in the residual gastric stump as a result of hypochlorhydria, bile reflux, and chronic gastritis.

Although overall incidence of gastric adenocarcinoma is falling, cancer of the gastric cardia is on the rise. This is probably related to Barrett esophagus and may reflect the increasing incidence of chronic GERD and obesity.¹⁰ Consistent with this presumed common pathogenesis, distal esophageal adenocarcinomas and gastric cardia adenocarcinomas are similar in morphology, clinical behavior, and therapeutic response.^27-29

Pathogenesis.

While the majority of gastric cancers are not hereditary, the mutations identified in familial gastric cancer have provided important insights into mechanisms of carcinogenesis in sporadic cases. Germline mutations in CDH1, which encodes E-cadherin, a protein that contributes to epithelial intercellular adhesion, are associated with familial gastric cancers, which are usually of the diffuse type. Mutations in CDH1 are present in about 50% of sporadic cases of diffuse gastric tumors, while E-cadherin expression is drastically decreased in the rest, often by methylation of the CDH1 promoter. Thus, the loss of E-cadherin function seems to be a key step in the development of diffuse gastric cancer. Notably, CDH1 mutations are also common in sporadic and familial lobular carcinoma of the breast, which also tends to infiltrate as single cells, and individuals with BRCA2 mutations are at increased risk of developing diffuse gastric cancer.

In contrast to diffuse gastric tumors, there is an increased risk of intestinal-type gastric cancer in individuals with FAP, particularly in Japan. This implies an interaction between host genetic background and environmental factors, since gastric cancer risk is less markedly elevated in individuals with FAP residing in areas of low gastric cancer incidence. Mutations in β-catenin, a protein that binds to both E-cadherin and adenomatous polyposis coli (APC), as well as microsatellite instability and hypermethylation of several genes including TGFβRII, BAX, IGFRII, and p16/INK4a have also been described in sporadic intestinal-type gastric cancer.

Genetic variants of pro-inflammatory and immune response genes, including those that encode IL-1β, TNF, IL-10, IL-8, and Toll-like receptor 4 (TLR4), are associated with elevated risk of gastric cancer when accompanied by H. pylori infection, and p53 mutations are present in the majority of sporadic gastric cancers of both histologic types. Thus, although specific sequences of events have not been defined, it is clear that chronic inflammation promotes neoplastic progression. Other associations between chronic inflammation and cancer were discussed in Chapter 7.

Morphology. Gastric adenocarcinomas are classified according to their location in the stomach, and most importantly, according to gross and histologic morphology. Most gastric adenocarcinomas involve the gastric antrum; the lesser curvature is involved more often than the greater curvature.²⁸ Gastric tumors with an intestinal morphology tend to form bulky tumors (Fig. 17-17A) composed of glandular structures (Fig. 17-18A), while cancers with a diffuse infiltrative growth pattern (see Fig. 17-17B) are more often composed of signet-ring cells (see Fig. 17-18B). Although intestinal-type adenocarcinomas may penetrate the gastric wall, they typically grow along broad cohesive fronts to form either an exophytic mass or an ulcerated tumor. The neoplastic cells often contain apical mucin vacuoles, and abundant mucin may be present in gland lumens. In contrast, diffuse gastric cancer is generally composed of discohesive cells that do not form glands but instead have large mucin vacuoles that expand the cytoplasm and push the nucleus to the periphery, creating a signet-ring cell morphology. These cells permeate the mucosa and stomach wall individually or in small clusters, which makes tumor cells easy to confuse with inflammatory cells, such as macrophages, at low magnification. Extracellular mucin release in either type of gastric cancer can result in formation of large mucin lakes that dissect tissue planes.

FIGURE 17-17 Gastric adenocarcinoma. A, Intestinal-type adenocarcinoma consisting of an elevated mass with heaped-up borders and central ulceration. Compare to the peptic ulcer in Figure 17-14A. B, Linitis plastica. The gastric wall is markedly thickened, and rugal folds are partially lost.

FIGURE 17-18 Gastric adenocarcinoma. A, Intestinal-type adenocarcinoma composed of columnar, gland-forming cells infiltrating through desmoplastic stroma. B, Signet-ring cells can be recognized by their large cytoplasmic mucin vacuoles and peripherally displaced, crescent-shaped nuclei.

A mass may be difficult to appreciate in diffuse gastric cancer, but these infiltrative tumors often evoke a desmoplastic reaction that stiffens the gastric wall and may provide a valuable diagnostic clue. When there are large areas of infitration, diffuse rugal flattening and a rigid, thickened wall may impart a leather bottle appearance termed linitis plastica (see Fig. 17-17B). Breast and lung cancers that metastasize to the stomach may also create a linitis plastica–like appearance.

Clinical Features.

Intestinal-type gastric cancer predominates in high-risk areas and develops from precursor lesions including flat dysplasia and adenomas. The mean age of presentation is 55 years, and the male-to-female ratio is 2 : 1. In contrast, the incidence of diffuse gastric cancer is relatively uniform across countries, there are no identified precursor lesions, and the disease occurs at similar frequencies in males and females. Notably, the remarkable decrease in gastric cancer incidence applies only to the intestinal type, which is most closely associated with atrophic gastritis and intestinal metaplasia. As a result, the incidences of intestinal and diffuse types of gastric cancers are now similar.

The depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis remain the most powerful prognostic indicators for gastric cancer.³⁰ In advanced cases gastric carcinoma may first be detected as metastases to the supraclavicular sentinel lymph node, also called Virchow’s node. Gastric tumors can also metastasize to the periumbilical region to form a subcutaneous nodule, termed a Sister Mary Joseph nodule, after the nurse who first noted this lesion as a marker of metastatic carcinoma. Local invasion into the duodenum, pancreas, and retroperitoneum is also characteristic. In such cases efforts are usually focused on chemotherapy or radiation therapy and palliative care. However, when possible, surgical resection remains the preferred treatment for gastric adenocarcinoma. After surgical resection, the 5-year survival rate of early gastric cancer can exceed 90%, even if lymph node metastases are present. In contrast, the 5-year survival rate for advanced gastric cancer remains below 20%.²⁸ Because of the advanced stage at which most gastric cancers are discovered in the United States, the overall 5-year survival is less than 30%.^28,31

Pathogenesis.

Extra-nodal marginal zone B-cell lymphomas usually arise at sites of chronic inflammation. They can originate in the GI tract at sites of preexisting MALT, such as the Peyer’s patches of the small intestine, but more commonly arise within tissues that are normally devoid of organized lymphoid tissue. The most common cause of “pro-lymphomatous” inflammation in the stomach is chronic H. pylori infection, which is found in association with most cases of gastric MALToma.³⁴ As with other low-grade lymphomas, MALTomas can transform into more aggressive tumors that are histologically identical to diffuse large B-cell lymphomas.

The most striking evidence linking H. pylori gastritis to MALToma is that eradication of the infection with antibiotics induces durable remissions with low rates of recurrence in most patients.³⁵ Histologic features that predict antibiotic treatment failures include transformation to large-cell lymphoma, tumor invasion to the muscularis propria or beyond, and lymph node involvement.

Three translocations are associated with gastric MALToma, the t(11;18)(q21;q21) and the less common t(1;14)(p22;q32) and t(14;18)(q32;q21). They are also highly predictive of response failure.^36,37 The t(11;18)(q21;q21) translocation brings together the apoptosis inhibitor 2 (API2) gene on chromosome 11 with the “mutated in MALT lymphoma,” or MLT, gene on chromosome 18. This creates a chimeric API2-MLT fusion gene that encodes an API2-MLT fusion protein. The t(14;18)(q32;q21) and t(1;14)(p22;q32) translocations cause increased expression of intact MLT and BCL-10 proteins, respectively.

Although some details remain uncertain, each of the three translocations has the same net effect, the constitutive activation of NF-κB, a transcription factor that promotes B-cell growth and survival. Remarkably, antigen-dependent activation of NF-κB in normal B and T cells requires both BCL-10 and MLT, which work together in a pathway down-stream of the B- and T-cell antigen receptors. In MALTomas that lack these translocations, H. pylori–induced inflammation may trigger NF-κB activation through the MLT/BCL-10 pathway. In these tumors elimination of the immune stimulus (H. pylori) down-regulates NF-κB, resulting in tumor regression. In contrast, NF-κB is constitutively active in tumors bearing translocations involving MLT or BCL10, and as a result the elimination of H. pylori has no effect. Additional genetic changes, such as inactivation of the tumor suppressor genes that encode p53 and p16, may lead to transformation of gastric MALToma into aggressive diffuse large B-cell lymphoma.³⁸

Morphology. Histologically, gastric MALToma takes the form of a dense lymphocytic infiltrate in the lamina propria (Fig. 17-19A). Characteristically, the neoplastic lymphocytes infiltrate the gastric glands focally to create diagnostic lymphoepithelial lesions (Fig. 17-19A, inset). Reactive-appearing B-cell follicles may be present, and, in about 40% of tumors, plasmacytic differentiation is observed. Occasionally the tumor cells accumulate large amounts of pale cytoplasm, a feature referred to as “monocytoid” change.

FIGURE 17-19 GI lymphoma. A, Gastric MALT lymphoma replacing much of the gastric epithelium. Inset shows lymphoepithelial lesions with neoplastic lymphocytes surrounding and infiltrating gastric glands. B, Disseminated lymphoma within the small intestine with numerous small serosal nodules. C, Large B-cell lymphoma infiltrating the small intestinal wall and producing diffuse thickening.

Like other tumors of mature B cells, MALTomas express the B-cell markers CD19 and CD20. They do not express CD5 and CD10, and are positive for CD43 in about 25% of cases, an unusual feature that can be diagnostically helpful. In cases lacking lymphoepithelial lesions, monoclonality may be demonstrated by restricted expression of either κ or γ immunoglobulin light chain or by molecular detection of clonal IgH rearrangements. Molecular cytogenetic analysis (e.g., fluorescent in situ hybridization) is being used increasingly to identify tumors with translocations that predict resistance to therapy.

Clinical Features.

The most common presenting symptoms are dyspepsia and epigastric pain. Hematemesis, melena, and constitutional symptoms such as weight loss can also be present. Because gastric MALTomas and H. pylori gastritis often coexist and have overlapping clinical symptoms and endoscopic appearances, diagnostic difficulties sometimes arise, particularly in small biopsy specimens. GI lymphomas may also disseminate as discrete small nodules (Fig. 17-19B) or infiltrate the wall diffusely (Fig. 17-19C).

Clinical Features.

The peak incidence of carcinoid tumors is in the sixth decade, but they may appear at any age. Symptoms are determined by the hormones produced. For example, tumors that produce gastrin may cause Zollinger-Ellison syndrome, while ileal tumors may cause carcinoid syndrome, which is characterized by cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, and right-sided cardiac valvular fibrosis. Carcinoid syndrome occurs in fewer than 10% of patients and is caused by vasoactive substances secreted by the tumor into the systemic circulation. When tumors are confined to the intestine, the vasoactive substances released are metabolized to inactive forms by the liver, a “first-pass” effect similar to that exerted on oral drugs. Carcinoid syndrome generally requires tumors to secrete hormones into a non-portal venous circulation and therefore is strongly associated with metastatic disease.

The most important prognostic factor for GI carcinoid tumors is location.

Epidemiology.

Overall, GISTs are slightly more common in males. The peak age of GIST diagnosis in the stomach is approximately 60 years, with fewer than 10% occurring in individuals under 40 years of age. Of the uncommon GISTs in children, some are related to the Carney triad, a nonhereditary syndrome seen primarily in young females that includes gastric GIST, paraganglioma, and pulmonary chondroma. There is also an increased incidence of GIST in individuals with neurofibromatosis type 1.⁴⁰

Pathogenesis.

Approximately 75% to 80% of all GISTs have oncogenic, gain-of-function mutations of the gene encoding the tyrosine kinase c-KIT, which is the receptor for stem cell factor. Approximately 8% of GISTs have mutations that activate a related tyrosine kinase, platelet-derived growth factor receptor α (PDGFRA).⁴¹ In sporadic GISTs, c-KIT and PDGFRA gene mutations are mutually exclusive.²¹ GISTs appear to arise from, or share a common stem cell with, the interstitial cells of Cajal, which are located in the muscularis propria and serve as pacemaker cells for gut peristalsis. Like GISTs, Cajal cells express c-KIT (also known as CD117) and CD34. Interestingly, familial GIST, which is rare, is associated with germline c-KIT or PDGFRA mutations; these patients, who develop multiple GISTs, may also have diffuse hyperplasia of Cajal cells.⁴² Mutation of c-KIT or PDGFRA is an early event in sporadic GISTs and is detectable in lesions as small as 3 mm. The constitutively active c-KIT and PDGFRA receptor tyrosine kinases produce intracellular signals that activate the RAS and PI3K/AKT pathways and thereby promote tumor cell proliferation and survival.²¹

Morphology. Primary gastric GISTs can be quite large, as much as 30 cm in diameter. They usually form a solitary, well-circumscribed, fleshy mass (Fig. 17-21A) covered by ulcerated or intact mucosa (Fig. 17-21B), but can also project outward toward the serosa. Metastases may take the form of multiple serosal nodules throughout the peritoneal cavity or as one or more nodules in the liver; spread outside of the abdomen is uncommon. GISTs composed of thin elongated cells are classified as spindle cell type (Fig. 17-21C), whereas tumors dominated by epithelial-appearing cells are termed epithelioid type; mixtures of the two patterns also occur. The most useful diagnostic marker is c-KIT, which is immunohistochemically detectable in 95% of gastric GISTs.

FIGURE 17-21 GI stromal tumor. A, On cross-section a whorled texture is evident within the white, fleshy tumor. B, The mass is covered by intact mucosa. C, Histologically the tumor is primarily composed of bundles, or fascicles, of spindle-shaped tumor cells.

(Courtesy of Dr. Christopher Weber, The University of Chicago, Chicago, IL.)

Clinical Features.

Symptoms of GISTs at presentation may be related to mass effects. Mucosal ulceration can cause blood loss, and approximately half of individuals with GIST present with anemia or related symptoms. GISTs may also be discovered as an incidental finding during radiologic imaging, endoscopy, or abdominal surgery performed for other reasons. Complete surgical resection is the primary treatment for localized gastric GIST. The prognosis correlates with tumor size, mitotic index, and location, with gastric GISTs being somewhat less aggressive than those arising in the small intestine. Recurrence or metastasis is rare for gastric GISTs under 5 cm but common for mitotically active tumors larger than 10 cm.

Patients with unresectable, recurrent, or metastatic disease often respond to imatinib, a tyrosine kinase inhibitor that inhibits c-KIT and PDGFRA, and is also effective in suppressing BCR-ABL kinase activity in chronic myeloid leukemia (Chapter 13).⁴³ Development of resistance to imatinib is most often related to secondary c-KIT mutations that limit drug efficacy.

Pathogenesis.

Intestinal responses to ischemia occur in two phases. The initial hypoxic injury occurs at the onset of vascular compromise. While some damage occurs during this phase, the epithelial cells lining the intestine are relatively resistant to transient hypoxia. The second phase, reperfusion injury, is initiated by restoration of the blood supply and it is at this time that the greatest damage occurs. In severe cases this may trigger multiorgan failure. While the underlying mechanisms of reperfusion injury are incompletely understood, they involve free radical production, neutrophil infiltration, and release of inflammatory mediators, such as complement proteins and TNF (Chapter 1). Activation of intracellular signaling molecules and transcription factors, including hypoxia-inducible factor 1 (HIF-1) and NF-κB, also contribute to intestinal ischemia-reperfusion injury.^44,45

The severity of vascular compromise, the time frame during which it develops, and the vessels affected are the major variables in ischemic bowel disease. Two aspects of intestinal vascular anatomy also contribute to the distribution of ischemic damage.

Morphology. Despite the increased susceptibility of watershed zones, mucosal and mural infarction may involve any level of the gut from stomach to anus. The lesions may be continuous but are more often segmental and patchy (Fig. 17-24A). The mucosa is hemorrhagic and may be ulcerated and dark red or purple as a result of luminal hemorrhage (Fig. 17-24B). The bowel wall is also thickened by edema that may involve the mucosa or extend into the submucosa and muscularis propria. When severe, there is extensive mucosal and submucosal hemorrhage and necrosis, but serosal hemorrhage and serositis are generally absent.

FIGURE 17-24 Ischemia. A, Jejunal resection with dusky serosa. B, Mucosa is stained with blood after hemorrhage. C, Characteristic attenuated villous epithelium in this case of acute jejunal ischemia. D, Chronic colonic ischemia with atrophic surface epithelium and fibrotic lamina propria.

Substantial portions of the bowel are generally involved in transmural infarction due to acute arterial obstruction. For reasons described above, the splenic flexure is the site at greatest risk. The demarcation between normal and ischemic bowel is sharply defined and the infarcted bowel is initially intensely congested and dusky to purple-red. Later, blood-tinged mucus or frank blood accumulates in the lumen and the wall becomes edematous, thickened, and rubbery. There is coagulative necrosis of the muscularis propria within 1 to 4 days, and perforation may occur. Serositis, with purulent exudates and fibrin deposition, may be prominent.

In mesenteric venous thrombosis arterial blood continues to flow for a time, resulting in a less abrupt transition from affected to normal bowel. However, propagation of the thrombus may lead to secondary involvement of the splanchnic bed. The ultimate result is similar to that produced by acute arterial obstruction because impaired venous drainage eventually prevents oxygenated arterial blood from entering the capillaries.

Microscopic examination of ischemic intestine demonstrates atrophy or sloughing of surface epithelium (Fig. 17-24C). In contrast, crypts may be hyperproliferative. Inflammatory infiltrates are initially absent in acute ischemia, but neutrophils are recruited within hours of reperfusion. Chronic ischemia is accompanied by fibrous scarring of the lamina propria (Fig. 17-24D) and, uncommonly, stricture formation. In acute phases of ischemic damage bacterial superinfection and enterotoxin release may induce pseudomembrane formation that can resemble Clostridium difficile–associated pseudomembranous colitis (discussed later).

Clinical Features.

Ischemic bowel disease tends to occur in older individuals with coexisting cardiac or vascular disease. Acute transmural infarction typically presents with sudden, severe abdominal pain and tenderness, sometimes accompanied by nausea, vomiting, bloody diarrhea, or grossly melanotic stool. Patients may progress to shock and vascular collapse within hours as a result of blood loss. Peristaltic sounds diminish or disappear, and muscular spasm creates board-like rigidity of the abdominal wall. Because these physical signs overlap with those of other abdominal emergencies, including acute appendicitis, perforated ulcer, and acute cholecystitis, the diagnosis of intestinal necrosis may be delayed or missed, with disastrous consequences. As the mucosal barrier breaks down, bacteria enter the circulation and sepsis can develop; mortality may exceed 50%. The overall progression of ischemic enteritis depends on the underlying cause and severity of injury.

Pathogenesis.

Celiac disease is a unique intestinal immune disorder because the environmental precipitant, gluten, is known. Gluten is the major storage protein of wheat and similar grains, and the alcohol-soluble fraction of gluten, gliadin, contains most of the disease-producing components. Gluten is digested by luminal and brush-border enzymes into amino acids and peptides, including a 33–amino acid α-gliadin peptide that is resistant to degradation by gastric, pancreatic, and small intestinal proteases (Fig. 17-25). The network of immune reactions to gliadin that are thought to result in celiac disease is illustrated below. Some gliadin peptides induce epithelial cells to express IL-15, which in turn triggers activation and proliferation of CD8+ intraepithelial lymphocytes that are induced to express NKG2D, a natural killer cell marker. These lymphocytes become cytotoxic and kill enterocytes with surface MIC-A, an HLA class I–like protein expressed in response to stress. NKG2D is the receptor for MIC-A. Thus, unlike the CD4+ T cells, these NKG2D+ CD8+ T cells do not recognize gliadin. The resulting epithelial damage may contribute to the process by which other gliadin peptides cross the epithelium to be deamidated by tissue transglutaminase. Deamidated gliadin peptides are then able to interact with HLA-DQ2 or HLA-DQ8 on antigen-presenting cells and be presented to CD4+ T cells. These T cells produce cytokines that contribute to tissue damage and the characteristic mucosal pathology.

FIGURE 17-25 The left panel illustrates the morphologic alterations that may be present celiac disease, including villous atrophy, increased numbers of intraepithelial lymphocytes (IELs), and epithelial proliferation with crypt elongation (compare to Fig. 17-26). The right panel depicts a model for the pathogenesis of celiac disease. Note that both innate and adaptive immune mechanisms are involved in the tissue responses to gliadin.

While nearly all people eat grain and are exposed to gluten and gliadin, most do not develop celiac disease. Thus, host factors determine whether disease develops. Among these, HLA proteins seem to be critical, since almost all people with celiac disease carry the class II HLA-DQ2 or HLA-DQ8 allele. However, the HLA locus accounts for less than half of the genetic component of celiac disease. Remaining genetic factors may include polymorphisms of immune-regulatory genes, such as those encoding IL-2, IL-21, CCR3, and SH2B3,⁴⁶ and genes that determine epithelial polarity.^47,48 There is also an association of celiac disease with other immune diseases including type 1 diabetes, thyroiditis, and Sjögren syndrome, as well as ataxia, autism, depression, some forms of epilepsy, IgA nephropathy, Down syndrome, and Turner syndrome.

Morphology. Biopsy specimens from the second portion of the duodenum or proximal jejunum, which are exposed to the highest concentrations of dietary gluten, are generally diagnostic in celiac disease. The histopathology is characterized by increased numbers of intraepithelial CD8+ T lymphocytes (intraepithelial lymphocytosis), crypt hyperplasia, and villous atrophy (Fig. 17-26). This loss of mucosal and brush-border surface area probably accounts for the malabsorption. In addition, increased rates of epithelial turnover, reflected in increased crypt mitotic activity, may limit the ability of absorptive enterocytes to fully differentiate and contribute to defects in terminal digestion and transepithelial transport. Other features of fully developed celiac disease include increased numbers of plasma cells, mast cells, and eosinophils, especially within the upper part of the lamina propria. With increased frequency of serologic screening and early detection of disease-associated antibodies, it is now appreciated that an increase in the number of intraepithelial lymphocytes, particularly within the villus, is a marker of less advanced celiac disease.⁴⁹ However, intraepithelial lymphocytosis and villous atrophy are not specific for celiac disease and can be present in other diseases, including viral enteritis. The combination of histology and serology is most specific for diagnosis of celiac disease.

FIGURE 17-26 Celiac disease. A, Advanced cases of celiac disease show complete loss of villi, or total villous atrophy. Note the dense plasma cell infiltrates in the lamina propria. B, Infiltration of the surface epithelium by T lymphocytes, which can be recognized by their densely stained nuclei (labelled T). Compare to elongated, pale-staining epithelial nuclei (labelled E).

Clinical Features.

In adults, celiac disease presents most commonly between the ages of 30 and 60. However, many cases escape clinical attention for extended periods because of atypical presentations. Some patients may have silent celiac disease, defined as positive serology and villous atrophy without symptoms, or latent celiac disease, in which positive serology is not accompanied by villous atrophy. Symptomatic adult celiac disease is often associated with anemia, chronic diarrhea, bloating, or chronic fatigue. Although there is no gender preference, celiac disease is detected two- to threefold more commonly in women, perhaps because monthly menstrual bleeding increases the demand for iron and vitamins and accentuates the effects of impaired absorption.

Pediatric celiac disease, which affects males and females equally, may present with malabsorption or atypical symptoms affecting almost any organ.⁵⁰ In those with classic symptoms, disease typically begins between ages of 6 and 24 months, after introduction of gluten to the diet, and includes irritability, abdominal distention, anorexia, chronic diarrhea, failure to thrive, weight loss, or muscle wasting.⁵⁰ Children with nonclassic symptoms tend to present at older ages with complaints of abdominal pain, nausea, vomiting, bloating, or constipation. Common extra-intestinal complaints include arthritis or joint pain, seizure disorders, aphthous stomatitis, iron deficiency anemia, pubertal delay, and short stature.

A characteristic itchy, blistering skin lesion, dermatitis herpetiformis, can be present in as many as 10% of patients, and the incidence of lymphocytic gastritis and lymphocytic colitis is also increased. Unfortunately, the only treatment currently available for celiac disease is a gluten-free diet, but, despite the challenges of adhering to this diet, it does result in symptomatic improvement for most patients. A gluten-free diet may also reduce the risk of long-term complications including anemia, female infertility, osteoporosis, and cancer.

Noninvasive serologic tests are generally performed prior to biopsy.⁵¹ The most sensitive tests are the presence of IgA antibodies to tissue transglutaminase or IgA or IgG antibodies to deamidated gliadin. Anti-endomysial antibodies are highly specific but less sensitive than other antibodies. In cases with negative IgA tests, IgA deficiency, which is more common in celiac patients, should be ruled out. If IgA deficiency is present, titers of IgG antibodies to tissue transglutaminase and deamidated gliadin should be measured. The absence of HLA-DQ2 or HLA-DQ8 is useful for its high negative predictive value, but the presence of these alleles is not helpful in confirming the diagnosis.

Individuals with celiac disease have a higher than normal rate of malignancy. The most common celiac disease–associated cancer is enteropathy-associated T-cell lymphoma, an aggressive lymphoma of intraepithelial T lymphocytes. Small intestinal adenocarcinoma is also more frequent in individuals with celiac disease. Thus, when symptoms such as abdominal pain, diarrhea, and weight loss develop despite a strict gluten-free diet, cancer or refractory sprue, in which the response to a gluten-free diet is lost, must be considered. It is, however, important to remember that failure to adhere to a gluten-free diet is the most common cause of recurrent symptoms, and that most people with celiac disease do well with dietary restrictions and die of unrelated causes.