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  1. 1. 797 Chapter 17 - The Gastrointestinal Tract Chen Liu MD, PhD James M. Crawford MD, PhD • Chapter 17 - The Gastrointestinal Tract – Esophagus • Normal • Pathology – Congenital Anomalies » ATRESIA AND FISTULAS » WEBS, RINGS, AND STENOSIS – Lesions Associated with Motor Dysfunction » ACHALASIA • Morphology. • Clinical Features. » HIATAL HERNIA » DIVERTICULA » LACERATIONS (MALLORY-WEISS SYNDROME) • Morphology. • Clinical Features. – Esophageal Varices • Morphology. • Clinical Features. – Esophagitis » REFLUX ESOPHAGITIS (GASTROESOPHAGEAL REFLUX DISEASE) • Morphology. • Clinical Features. » BARRETT ESOPHAGUS • Morphology. • Clinical Features. » INFECTIOUS AND CHEMICAL ESOPHAGITIS • Morphology. • Clinical Features. – Tumors » BENIGN TUMORS » MALIGNANT TUMORS • Squamous Cell Carcinoma • Etiology and Pathogenesis. • Morphology. • Clinical Features. • Adenocarcinoma
  2. 2. • Etiology and Pathogenesis. • Morphology. • Clinical Features. – Stomach • Normal – Gastric Mucosal Physiology » ACID SECRETION » MUCOSAL PROTECTION • Pathology – Congenital Anomalies » PYLORIC STENOSIS – Gastritis » ACUTE GASTRITIS • Pathogenesis. • Morphology. • Clinical Features. » CHRONIC GASTRITIS • Pathogenesis. • Helicobacter pylori Infection and Chronic Gastritis. • Autoimmune Gastritis. • Morphology. • Clinical Features. » SPECIAL FORMS OF GASTRITIS – Peptic Ulcer Disease » PEPTIC ULCERS • Epidemiology. • Pathogenesis. • Morphology. • Clinical Features. » ACUTE GASTRIC ULCERATION • Morphology. • Clinical Features. – Miscellaneous Conditions » HYPERTROPHIC GASTROPATHY » GASTRIC VARICES – Tumors » BENIGN TUMORS • Morphology. • Clinical Features. » GASTRIC CARCINOMA • Epidemiology. • Pathogenesis. • Helicobacter pylori Infection. • Environment. • Host.
  3. 3. • Other Risk Factors. • Morphology. • Clinical Features. » LESS COMMON GASTRIC TUMORS • Gastric Lymphoma. • Morphology. • Gastrointestinal Stromal Tumor. • Morphology. • Pathogenesis. • Gastric Neuroendocrine Cell (Carcinoid) Tumors. • Lipomas. • Metastatic Cancer. – Small and Large Intestines • Normal – Anatomy – Vasculature – Small Intestinal Mucosa – Colonic Mucosa – Endocrine Cells – Intestinal Immune System – Neuromuscular Function • Pathology – Congenital Anomalies » ATRESIA AND STENOSIS » MECKEL DIVERTICULUM » CONGENITAL AGANGLIONIC MEGACOLON —HIRSCHSPRUNG DISEASE • Morphology. • Clinical Features. – Enterocolitis » DIARRHEA AND DYSENTERY » INFECTIOUS ENTEROCOLITIS • Viral Gastroenteritis • Morphology. • Bacterial Enterocolitis • Bacterial Adhesion and Replication. • Bacterial Enterotoxins. • Bacterial Invasion. • Shigella Bacillary Dysentery • Pathogenesis. • Salmonellosis and Typhoid Fever • Pathogenesis. • Campylobacter Enterocolitis • Pathogenesis. • Cholera
  4. 4. • Pathogenesis. • Antibiotic-Associated Colitis (Pseudomembranous Colitis) • Morphology. • Bacterial Overgrowth Syndrome • Parasitic Enterocolitis • Nematodes • Cestodes • Amebiasis • Pathogenesis. • Morphology. • Clinical Features. • Giardiasis • Pathogenesis. • Morphology. • Clinical Features. • Necrotizing Enterocolitis • Collagenous and Lymphocytic Colitis » MISCELLANEOUS INTESTINAL INFLAMMATORY DISORDERS • Acquired Immunodeficiency Syndrome (AIDS) • Transplantation • Drug-Induced Intestinal Injury • Radiation Enterocolitis • Neutropenic Colitis (Typhlitis) • Diversion Colitis • Solitary Rectal Ulcer Syndrome – Malabsorption Syndromes » CELIAC DISEASE • Pathogenesis. • Morphology. • Clinical Features. » TROPICAL SPRUE (POSTINFECTIOUS SPRUE) • Morphology. » WHIPPLE DISEASE • Morphology. • Clinical Features. » DISACCHARIDASE (LACTASE) DEFICIENCY » ABETALIPOPROTEINEMIA – Idiopathic Inflammatory Bowel Disease » ETIOLOGY AND PATHOGENESIS • Genetic Susceptibility. • Role of Intestinal Flora. • Abnormal T-Cell Responses. • Diagnosis of IBD.
  5. 5. » CROHN DISEASE • Epidemiology. • Morphology. • Clinical Features. » ULCERATIVE COLITIS • Epidemiology. • Morphology. • Clinical Features. – Vascular Disorders » ISCHEMIC BOWEL DISEASE • Morphology. • Transmural Infarction. • Mucosal and Mural Infarction. • Chronic Ischemia. • Clinical Features. » ANGIODYSPLASIA » HEMORRHOIDS • Morphology. – Diverticular Disease • Morphology. • Pathogenesis. • Clinical Features. – Intestinal Obstruction » HERNIAS » ADHESIONS » INTUSSUSCEPTION » VOLVULUS – Tumors of the Small and Large Intestine » TUMORS OF THE SMALL INTESTINE • Adenomas • Adenocarcinoma » TUMORS OF THE COLON AND RECTUM • Non-Neoplastic Polyps • Morphology. • Hyperplastic Polyps. • Hamartomatous Polyps. • Adenomas • Morphology. • Clinical Features. • Familial Syndromes • Familial Adenomatous Polyposis (FAP) Syndrome. • Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome. • Colorectal Carcinogenesis • Molecular Carcinogenesis.
  6. 6. • Loss of Adenomatous Polyposis Coli (APC) Gene. • Mutation of K-RAS. • Loss of SMADs. • Loss of p53. • Activation of Telomerase. • Microsatellite Instability Pathway. • Colorectal Carcinoma • Epidemiology, Etiology, and Pathogenesis. • Morphology. • Clinical Features. • Carcinoid Tumors • Morphology. • Clinical Features. » GASTROINTESTINAL LYMPHOMA • Morphology. • Clinical Features. » MESENCHYMAL TUMORS • Morphology. • Clinical Features. » TUMORS OF THE ANAL CANAL – Appendix • Normal • Pathology – Acute Appendicitis » Morphology. » Clinical Features. – Tumors of the Appendix » MUCOCELE AND PSEUDOMYXOMA PERITONEI • Morphology. – Peritoneum – Inflammation » PERITONEAL INFECTION • Morphology. » SCLEROSING RETROPERITONITIS » MESENTERIC CYSTS – Tumors 798 Esophagus Normal
  7. 7. The esophagus develops from the cranial portion of the foregut and is recognizable by the third week of gestation. The normal esophagus is a hollow, highly distensible muscular tube that extends from the epiglottis in the pharynx, at about the level of the C6 vertebra, to the gastroesophageal junction at the level of the T11 or T12 vertebra. Measuring between 10 and 11 cm in the newborn, it grows to a length of about 25 cm in the adult. For the endoscopist, the esophagus is recorded as the anatomic distance between 15 and 40 cm from the incisor teeth, with the gastroesophageal junction located at the 40-cm point. Several points of luminal narrowing can be identified along its course—proximally at the cricoid cartilage, midway in its course alongside the aortic arch and at the anterior crossing of the left main bronchus and left atrium, and distally where it pierces the diaphragm. Although the pressure in the esophageal lumen is negative compared with the atmosphere, manometric recordings of intraluminal pressures have identified two higher- pressure areas that remain relatively contracted in the resting phase. A 3-cm segment in the proximal esophagus at the level of the cricopharyngeus muscle is referred to as the upper esophageal sphincter (UES). The 2- to 4-cm segment just proximal to the anatomic gastroesophageal junction, at the level of the diaphragm, is referred to as the lower esophageal sphincter (LES). Both "sphincters" are physiologic, in that there are no anatomic landmarks that delineate these higher-pressure regions from the intervening esophageal musculature. The wall of the esophagus consists of a mucosa, submucosa, muscularis propria, and adventitia, reflecting the general structural organization of the gastrointestinal tract.[1] The 799 mucosa has a smooth, glistening, and pink-tan surface. It has three components: a nonkeratinizing stratified squamous epithelial layer, lamina propria, and muscularis mucosa. The epithelial layer has mature squamous cells overlying basal cells. The basal cells, constituting 10% to 15 % of the mucosal thickness, are reserve cells with great proliferative potential. A small number of specialized cell types, such as melanocytes, endocrine cells, dendritic cells, and lymphocytes, are present in the deeper portion of the epithelial layer. The lamina propria is the nonepithelial portion of the mucosa, above the muscularis mucosae. It consists of areolar connective tissue and contains vascular structures and scattered leukocytes. Finger-like extensions of the lamina propria, called papillae, extend into the epithelial layer. The muscularis mucosae is a delicate layer of longitudinally oriented smooth-muscle bundles. The submucosa consists of loose connective tissue containing blood vessels, a rich network of lymphatics, a sprinkling of leukocytes with occasional lymphoid follicles, nerve fibers (including the ganglia of the Meissner plexus), and submucosal glands. Submucosal glands connected to the lumen by squamous epithelium-lined ducts are scattered along the entire esophagus but are more concentrated in the upper and lower portions. Their mucin-containing fluid secretions help lubricate the esophagus. As is true throughout the alimentary tract, the muscularis propria consists of an inner circular and an outer longitudinal coat of smooth muscle with an intervening, well-
  8. 8. developed myenteric plexus (Auerbach plexus). The muscularis propria of the proximal 6 to 8 cm of the esophagus also contains striated muscle fibers from the cricopharyngeus muscle. Besides creating a unique histologic interplay of smooth muscle and skeletal muscle fibers, this feature explains why skeletal muscle disorders can cause upper esophageal dysfunction. In sharp contrast to the rest of the gastrointestinal tract, the esophagus is mostly devoid of a serosal coat. Only small segments of the intra-abdominal esophagus are covered by serosa; the thoracic esophagus is surrounded by fascia that condenses around the esophagus to form a sheathlike structure. In the upper mediastinum, the esophagus is supported by this fascial tissue, which forms a similar sheath around adjacent structures, the great vessels and the tracheobronchial tree. This intimate anatomic proximity to important thoracic viscera is of significance in permitting the ready and widespread dissemination of infections and tumors of the esophagus into the posterior mediastinum. The rich network of mucosal and submucosal lymphatics that runs longitudinally along the esophagus further facilitates spread. The main functions of the esophagus are to conduct food and fluids from the pharynx to the stomach, to prevent passive diffusion of substances from the food into the blood, and to prevent reflux of gastric contents into the esophagus. These functions require motor activity coordinated with swallowing, namely a wave of peristaltic contraction, relaxation of the LES in anticipation of the peristaltic wave, and closure of the LES after the swallowing reflex. The mechanisms governing this motor function are complex, involving both extrinsic and intrinsic innervation, humoral regulation, and properties of the muscle wall itself. The control of the lower esophageal sphincter (LES) is critical to esophageal function.[2] Maintenance of sphincter tone is necessary to prevent reflux of gastric contents, which are under positive pressure relative to the esophagus. During deglutition, both active inhibition of the muscularis propria muscle fibers by inhibitory nonadrenergic/noncholinergic neurons and cessation of tonic excitation by cholinergic neurons enable the LES to relax. Many chemical agents (e.g., gastrin, acetylcholine, serotonin, prostaglandin F2α , motilin, substance P, histamine, and pancreatic polypeptide) increase LES tone, while some agents (nitric oxide, vasoactive intestinal peptide) decrease the tone. However, their precise roles in normal esophageal function remain unclear. Pathology Lesions of the esophagus run the gamut from highly lethal cancers to the merely annoying "heartburn" that has affected many a partaker of a large, spicy meal. Esophageal varices, the result of cirrhosis and portal hypertension, are of major importance, since their rupture is frequently followed by massive hematemesis (vomiting of blood) and even death by exsanguination. Esophagitis and hiatal hernias are far more frequent and rarely threaten life. Distressing to the physician is that all disorders of the
  9. 9. esophagus tend to produce similar symptoms, namely heartburn, dysphagia, pain, and/or hematemesis. Heartburn (retrosternal burning pain) usually reflects regurgitation of gastric contents into the lower esophagus. Dysphagia (difficulty in swallowing) is encountered both with deranged esophageal motor function and with diseases that narrow or obstruct the lumen. Pain and hematemesis are sometimes evoked by esophageal disease, particularly by those lesions associated with inflammation or ulceration of the esophageal mucosa. The clinical diagnosis of esophageal disorders often requires specialized procedures such as esophagoscopy, radiographic barium studies, and manometry. Congenital Anomalies Ectopic tissue rests are not uncommon in the esophagus. The most common is ectopic gastric mucosa in the upper third of the esophagus ("inlet patch"), occurring in up to 2% of individuals. Sebaceous glands or ectopic pancreatic tissue are much less frequent. The acid secretions of the ectopic gastric mucosa or pancreatic enzymatic secretions can produce localized inflammation and discomfort. Embryologic formation of the foregut can also give rise to congenital cysts. These are usually duplication cysts, containing double smooth muscle layers and derived from the lower esophagus in 60% of cases. Rarely, bronchial or parenchymal pulmonary tissue may arise from the upper gut and is denoted bronchogenic cyst or pulmonary sequestration, respectively. These lesions usually present as masses. Lastly, impaired formation of the diaphragm may permit herniation of abdominal viscera into the thorax. When severe, this lesion is incompatible with life, since the lungs are severely hypoplastic at the time of birth. This condition is to be distinguished from hiatal hernias, to be discussed presently. 800 ATRESIA AND FISTULAS Although developmental defects in the esophagus are uncommon, they must be corrected early because they are incompatible with life. Because they cause immediate regurgitation when feeding is attempted, they are usually discovered soon after birth. Absence (agenesis) of the esophagus is extremely rare; much more common are atresia and fistula formation ( Fig. 17-1 ). In atresia, a segment of the esophagus is represented by only a thin, noncanalized cord, with a proximal blind pouch connected to the pharynx and a lower pouch leading to the stomach. Atresia is most commonly located at or near the tracheal bifurcation. It rarely occurs alone, but is usually associated with a fistula connecting the lower or upper pouch with a bronchus or the trachea. Associated anomalies include congenital heart disease, neurologic disease, genitourinary disease, and other gastrointestinal malformations. Atresia sometimes is associated with the presence of a single umbilical artery.[3] Aspiration and paroxysmal suffocation from food are obvious hazards; pneumonia and severe fluid and electrolyte imbalances may also occur.
  10. 10. WEBS, RINGS, AND STENOSIS Esophageal mucosal webs are uncommon ledgelike protrusions of the mucosa into the esophageal lumen. These are semicircumferential, eccentric, and most common in the upper esophagus. Well-developed webs rarely protrude more than 5 mm into the lumen, with a thickness of 2 to 4 mm. The webs consist of squamous mucosa and a vascularized submucosal core. Webs can be congenital in origin, or they may arise in association with long-standing reflux esophagitis, chronic graft-versus-host disease (GVHD), or blistering skin diseases. When an upper esophageal web is accompanied by an iron-deficiency anemia, glossitis, and cheilosis, the condition is referred to as the Paterson-Brown-Kelly or Plummer-Vinson syndrome, with an attendant risk for postcricoid esophageal carcinoma. Esophageal rings are concentric plates of tissue protruding into the lumen of the distal esophagus. One occurring above the squamocolumnar junction of the esophagus and stomach is referred to as an A ring. One located at the squamocolumnar Figure 17-1 Esophageal atresia and tracheoesophageal fistula. A, Blind upper and lower esophageal segments. B, Fistula between blind upper segment and trachea. C, Blind upper segment, fistula between blind lower segment and trachea. D, Blind upper segment only. E, Fistula between patent esophagus and trachea. Type C is the most common variety. (Adapted from Morson BC, and Dawson IMP, eds., Gastrointestinal Pathology. Oxford, Blackwell Scientific Publications, 1972, p. 8.) junction of the lower esophagus is designated a Schatzki ring or a B ring. Histologically, these rings consist of mucosa, submucosa, and sometimes a hypertrophied muscularis propria. Schatzki rings may have columnar gastric epithelium on their undersurface. Esophageal webs and rings are encountered most frequently in women over age 40 and are of uncertain etiology. Episodic dysphagia is the main symptom associated with webs and rings, usually provoked when an individual bolts solid food. Pain is infrequent. Esophageal stenosis consists of fibrous thickening of the esophageal wall, particularly the submucosa, with atrophy of the muscularis propria. The lining epithelium is usually thin and sometimes ulcerated. Although occasionally of congenital origin, stenosis is more
  11. 11. frequently the result of severe esophageal injury with inflammatory scarring, as from gastroesophageal reflux, radiation, scleroderma, or caustic injury. Stenosis usually develops in adulthood and becomes manifest by progressive dysphagia, at first to solid foods only but eventually to all foods, which constitutes the major symptom. In severe stenosis, virtually total obstruction may result. Lesions Associated with Motor Dysfunction Coordinated motor function is critical to proper function of the esophagus; gravity alone is not sufficient to move food from the pharynx to the stomach, nor to prevent reflux of gastric contents—witness the blissful suckling of the supine infant. The major entities (achalasia, hiatal hernia, diverticulum and Mallory-Weiss tear) that are caused by or induce motor dysfunction of the esophagus are diagrammed in Figure 17-2 . ACHALASIA Achalasia means "failure to relax." It is characterized by three major abnormalities: (1) aperistalsis, (2) partial or incomplete relaxation of the LES with swallowing, and (3) increased resting tone of the LES. The pathogenesis of primary 801
  12. 12. Figure 17-2 Major conditions associated with esophageal motor dysfunction. achalasia is poorly understood. It is thought to involve dysfunction of inhibitory neurons containing nitric oxide and vasoactive intestinal polypeptide in the distal esophagus.[4] [5] Degenerative changes in neural innervation, either intrinsic to the esophagus or in the extraesophageal vagus nerves and the dorsal motor nucleus of the vagus, may also occur. Secondary achalasia may arise in Chagas disease, in which Trypanosoma cruzi causes destruction of the myenteric plexus of the esophagus, duodenum, colon, and ureter, with resultant dilation of these viscera. Disorders of the dorsal motor nuclei, particularly polio or surgical ablation, can cause an achalasia-like illness, as can diabetic autonomic neuropathy and infiltrative disorders such as malignancy, amyloidosis, and sarcoidosis. In most instances, however, achalasia occurs as a primary disorder of uncertain etiology. Morphology. In primary achalasia there is progressive dilation of the esophagus above the level of the LES. The wall of the esophagus may be of normal thickness, thicker than normal owing to hypertrophy of the muscularis, or markedly thinned by dilation. The myenteric ganglia are usually absent from the body of the esophagus, but may or may not be reduced in number in the region of the LES. The mucosal lining may be unaffected, but sometimes inflammation, ulceration, or fibrotic thickening may be evident just above the LES.
  13. 13. Clinical Features. Achalasia usually becomes manifest in young adulthood, but may appear in infancy or childhood. The classic clinical symptom of achalasia is progressive dysphagia. Nocturnal regurgitation and aspiration of undigested food may occur. The most serious aspect of this condition is the hazard of developing esophageal squamous cell carcinoma, said to occur in about 5% of patients, typically at an earlier age than those without this disease. Other complications include Candida esophagitis, lower esophageal diverticula (see below), and aspiration with pneumonia or airway obstruction. HIATAL HERNIA Hiatal hernia is characterized by separation of the diaphragmatic crura and widening of the space between the muscular crura and the esophageal wall. Two anatomic patterns are recognized (see Fig. 17-2 ): the axial, or sliding hernia, and the nonaxial, or paraesophageal hiatal hernia. The sliding hernia constitutes 95% of cases; protrusion of the stomach above the diaphragm creates a bell-shaped dilation, bounded below by the diaphragmatic narrowing. In paraesophageal hernias, a separate portion of the stomach, usually along the greater curvature, enters the thorax through the widened foramen. The cause of hiatal hernia is unknown. It is not clear whether it is a congenital malformation or is acquired during life. Based on barographic studies, hiatal hernias are reported 802 in 1% to 20% of adult subjects, with incidence increasing with age. However, hiatal hernias are well recognized in infants and children. Only about 9% of adults with a sliding hernia suffer from heartburn or regurgitation of gastric juices into the mouth. These symptoms are attributed to incompetence of the LES and are accentuated by positions favoring reflux (bending forward, lying supine) and obesity. Complications of hiatal hernias are numerous. Both types may ulcerate, causing bleeding and perforation. Paraesophageal hernias can become strangulated or obstructed, and early surgical repair has been advocated. Reflux esophagitis (discussed later) is frequently seen in association with sliding hernias, but compromise of the LES with regurgitation of peptic juices into the esophagus is probably the result of, rather than the cause of, a sliding hernia. The uncommon paraesophageal hernias may be caused by previous surgery, including operations for sliding hernia. DIVERTICULA A diverticulum is an outpouching of the alimentary tract that contains all visceral layers; a false diverticulum denotes an outpouching of mucosa and submucosa only ( Fig. 17-2 ). True diverticula are usually discovered in later life and may develop in three regions of the esophagus:
  14. 14. • Zenker diverticulum (pharyngoesophageal diverticulum) immediately above the UES • Traction diverticulum near the midpoint of the esophagus • Epiphrenic diverticulum immediately above the LES. Disordered cricopharyngeal motor dysfunction with or without gastroesophageal reflux disease (GERD) and diminished luminal size of the UES are implicated in the genesis of Zenker diverticulum. Scarring resulting from mediastinal lymphadenitis (as from tuberculosis) was presumed to be a cause of traction on the esophagus that gave rise to mid-esophageal diverticula. However, arguments have been advanced in favor of traction diverticula actually arising from motor dysfunction or being a congenital lesion. Dyscoordination of peristalsis and LES relaxation are the proposed cause of epiphrenic diverticula. Zenker diverticula may reach several centimeters in size and can accumulate significant amounts of food. Typical symptoms include dysphagia, food regurgitation, and a mass in the neck; aspiration with resultant pneumonia is a significant risk. While midesophageal diverticula are generally asymptomatic, epiphrenic diverticula can give rise to nocturnal regurgitation of massive amounts of fluid. LACERATIONS (MALLORY-WEISS SYNDROME) Longitudinal tears in the esophagus at the esophagogastric junction or gastric cardia are termed Mallory-Weiss tears and are believed to be the consequence of severe retching or vomiting.[6] They are encountered most commonly in alcoholics, in whom they are attributed to episodes of excessive vomiting in the setting of an alcoholic stupor. Normally, a reflex relaxation of the musculature of the gastrointestinal tract precedes the antiperistaltic wave of contraction. During episodes of prolonged vomiting, it is speculated that this reflex relaxation fails to occur. The refluxing gastric contents suddenly overwhelm the contraction of the musculature at the gastric inlet, and massive dilation with tearing of the stretched wall ensues. Since these tears may occur in persons who have no history of vomiting or alcoholism, other mechanisms must exist; underlying hiatal hernia is a known predisposing factor. Morphology. The linear irregular lacerations are oriented in the axis of the esophageal lumen and are several millimeters to several centimeters in length. They are usually found astride the esophagogastric junction or in the proximal gastric mucosa ( Fig. 17-3 ). The tears may involve only the mucosa or may penetrate deeply enough to perforate the wall. The histology is not distinctive and reflects trauma accompanied by fresh hemorrhage and a nonspecific inflammatory response. Infection of the mucosal defect may lead to an inflammatory ulcer or to mediastinitis. Clinical Features.
  15. 15. Esophageal lacerations account for 5% to 10% of bleeding episodes in the upper gastrointestinal tract. Most often, bleeding is not profuse and ceases without surgical intervention, although massive hematemesis may occur. Supportive therapy, such as vasoconstrictive medications and transfusions, and sometimes balloon tamponade, is usually all that is required. Healing tends to be prompt, with minimal to no residua. The rare instance of esophageal rupture is known as Boerhaave syndrome and may be a catastrophic event. Esophageal Varices Regardless of cause, portal hypertension, when sufficiently prolonged or severe, induces the formation of collateral bypass channels wherever the portal and caval systems communicate. The pathogenesis of portal hypertension and the Figure 17-3 Esophageal laceration (Mallory-Weiss tears). Gross view demonstrating longitudinal lacerations extending from esophageal mucosa into stomach mucosa (arrow). (Courtesy of Dr. Richard Harruff, King County Medical Examiner's Office, Seattle, WA.) 803 locations of these bypasses are considered in Chapter 18 . Here we are concerned with the collaterals that develop in the region of the lower esophagus when portal blood flow is diverted through the coronary veins of the stomach into the plexus of esophageal subepithelial and submucosal veins, thence into the azygos veins, and eventually into the systemic circulation. The increased pressure in the esophageal plexus produces dilated tortuous vessels called varices. Varices develop in 90% of cirrhotic patients and are most often associated with alcoholic cirrhosis. Worldwide, hepatic schistosomiasis is the second most common cause of variceal bleeding. Morphology.
  16. 16. Varices 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. The net effect is irregular protrusion of the overlying mucosa into the lumen, although varices are collapsed in surgical or postmortem specimens ( Fig. 17-4A ). When the varix is unruptured, the mucosa may be normal, but often it is eroded and inflamed because of its exposed position. Variceal rupture produces massive hemorrhage into the lumen, as well as suffusion of the esophageal wall with blood. In this instance the overlying mucosa appears ulcerated and necrotic ( Fig. 17-4B ). If rupture has occurred in the past, venous thrombosis and superimposed inflammation may be present. Varices can be detected by hepatic venogram ( Fig. 17-4C ). Clinical Features. Varices usually produce no symptoms until they rupture, causing massive hematemesis. Among Figure 17-4 Esophageal varices. A, A view of the everted esophagus and gastroesophageal junction, showing dilated submucosal veins (varices). The blue-colored varices have collapsed in this postmortem specimen. B, Low-power cross-section of a dilated submucosal varix that has ruptured through the mucosa. A small amount of thrombus is present within the point of rupture. C, Hepatic venogram after injection of dye into portal veins (PV) to show a large tortuous gastroesophageal varix (arrow) extending superiorly from the patent main portal vein. (C, courtesy of Dr. Emily Sedgwick, Brigham and Women's Hospital, Boston, MA.) patients with advanced cirrhosis of the liver, half the deaths result from rupture of a varix. Some patients die as a direct consequence of the hemorrhage and others of the hepatic coma triggered by the hemorrhage. It must be remembered, however, that even when varices are present, they account for less than half of all episodes of hematemesis.
  17. 17. Collectively, concomitant gastritis, esophageal laceration, or peptic ulcers are more common causes. Factors leading to rupture of a varix are unclear: silent inflammatory erosion of overlying thinned mucosa, increased tension in progressively dilated veins, and vomiting with increased vascular hydrostatic pressure are likely to play roles. Once begun, the hemorrhage rarely subsides spontaneously, and endoscopic injection of thrombotic agents ("sclerotherapy") or balloon tamponade is usually required. Forty to fifty percent of patients die in the first bleeding episode. Among those who survive, rebleeding occurs in over half within 1 year, with a similar rate of mortality for each episode. Esophagitis Inflammation of the esophageal mucosa is known as esophagitis. Injury to the esophageal mucosa with subsequent inflammation is common worldwide. In the United States and other Western countries, esophagitis is present in about 5% of the adult population; much higher prevalence is encountered in selected regions such as northern Iran and portions of China. Esophagitis may be caused by a variety of physical, chemical, or biologic agents. We review the common ones encountered in the clinical practice. 804 REFLUX ESOPHAGITIS (GASTROESOPHAGEAL REFLUX DISEASE) Reflux of gastric contents into the lower esophagus is the most important cause of esophagitis. Many causative factors are involved:[7] • Decreased efficacy of esophageal antireflux mechanisms, particularly LES tone. Central nervous system depressants, hypothyroidism, pregnancy, systemic sclerosing disorders, alcohol or tobacco exposure, or the presence of a nasogastric tube may be contributing causes. However, in most instances no antecedent etiology is identified. • Presence of a sliding hiatal hernia • Inadequate or slowed esophageal clearance of refluxed material • Delayed gastric emptying and increased gastric volume, contributing to the volume of refluxed material • Reduction in the reparative capacity of the esophageal mucosa by protracted exposure to gastric juices. Any one of these influences may assume primacy in an individual case, but more than one is likely to be involved in most instances. The action of gastric juices is critical to the development of esophageal mucosal injury; in severe cases refluxed bile from the duodenum also may contribute to the mucosal disruption. Morphology.
  18. 18. The anatomic changes depend on the causative agent and on the duration and severity of the exposure. Simple hyperemia ("redness") may be the only alteration. In uncomplicated reflux esophagitis, three histologic features are characteristic ( Fig. 17-5 ): • The presence of inflammatory cells, including eosinophils, neutrophils, and excessive numbers of lymphocytes, in the squamous epithelial layer • Basal zone hyperplasia exceeding 20% of the epithelial thickness • Elongation of lamina propria papillae with capillary congestion, extending into the top third of the epithelial layer. Infiltrates of intraepithelial eosinophils are believed to be an early histologic abnormality, since they occur even in the absence of basal zone hyperplasia. Intraepithelial neutrophils, on the other hand, are markers of more severe injury such as ulceration rather than reflux esophagitis per se. Clinical Features. Although largely limited to adults over age 40, reflux esophagitis is occasionally seen in infants and children. The clinical manifestations consist principally of dysphagia, heartburn, and sometimes regurgitation of a sour brash, hematemesis, or melena. The severity of symptoms is not closely related to the presence or degree of histologic esophagitis; most people experience reflux symptoms without damage to the distal esophageal mucosa, due to the short duration of the reflux. Anatomic damage appears best correlated with prolonged exposure of the lower esophagus to refluxed material. Rarely, chronic symptoms are punctuated by attacks of severe chest pain that may be mistaken for a "heart attack." The potential consequences of severe reflux esophagitis are bleeding, ulceration, development of stricture, and a tendency to develop Barrett esophagus, with its attendant risks. Figure 17-5 Reflux esophagitis. Low-power view of the superficial portion of the mucosa. Numerous eosinophils within the squamous epithelium, elongation of the lamina propria papillae, and basal zone hyperplasia are present. BARRETT ESOPHAGUS
  19. 19. Barrett esophagus is a complication of long-standing gastroesophageal reflux, occurring over time in up to 10% of patients with symptomatic gastroesophageal reflux disease (GERD). It is the single most important risk factor for esophageal adenocarcinoma. In Barrett esophagus, the distal squamous mucosa is replaced by metaplastic columnar epithelium, as a response to prolonged injury. Two criteria are required for the diagnosis of Barrett esophagus: (1) endoscopic evidence of columnar epithelial lining above the gastroesophageal junction and (2) histologic evidence of intestinal metaplasia in the biopsy specimens from the columnar epithelium.[8] Barrett esophagus is further classified as long segment (extending cephalad more than 3 cm from the manometric gastroesophageal junction) or short segment (extending less than 3 cm cephalad). Barrett esophagus patients tend to have a long history of heartburn and other reflux symptoms and appear to have more massive reflux with more and longer reflux episodes than most reflux patients. It is unknown why the columnar epithelium develops in some patients with reflux and not in others. The pathogenesis of Barrett esophagus remains unclear, but it appears to result from an alteration in the differentiation program of stem cells of the esophageal mucosa.[9] The concept of "intestinal metaplasia" in Barrett esophagus may be not entirely correct, since true absorptive enterocytes are not observed. Rather, admixed with intestinal mucin- secreting goblet cells are columnar cells exhibiting both secretory and absorptive ultrastructural features; this is a phenotype not observed elsewhere in the alimentary tract. Nevertheless the term "intestinal metaplasia" continues to be used to denote the altered histology of the mucosa. Morphology. Barrett esophagus is recognized as a red, velvety mucosa located between the smooth, pale pink esophageal squamous mucosa and the lusher light brown gastric mucosa. It may exist as tongues or patches (islands) extending up from the gastroesophageal junction or as a broad irregular circumferential band displacing the squamocolumnar junction several centimeters cephalad ( Fig. 17-6 ). A small zone of metaplastic mucosa may be present only at the esophagogastric junction (short-segment 805
  20. 20. Figure 17-6 Barrett esophagus. A, B, Gross view of distal esophagus (top) and proximal stomach (bottom), showing A, the normal gastroesophageal junction (arrow) and B, the granular zone of Barrett esophagus (arrow). C, Endoscopic view of Barrett esophagus showing red velvety gastrointestinal mucosa extending from the gastroesophageal orifice. Note the paler squamous esophageal mucosa. Barrett mucosa), sometimes less than 0.5 cm in length. Microscopically, the esophageal squamous epithelium is replaced by metaplastic columnar epithelium, complete with surface epithelium and mucosal glands. The metaplastic mucosa may contain only gastric surface and glandular mucus-secreting cells, making clinical distinction from a hiatal hernia difficult. Definitive diagnosis is made when the columnar mucosa contains intestinal goblet cells ( Fig. 17-7 ). Critical to the pathologic evaluation of patients with Barrett mucosa is the search for dysplasia, the presumed precursor of malignancy, in columnar epithelium with intestinal metaplasia. Dysplasia is recognized by the presence of cytologic and architectural abnormalities in the columnar epithelium, consisting of enlarged, crowded, and stratified hyperchromatic nuclei and loss of intervening stroma between adjacent glandular structures.[10] Dysplasia is classified as low-grade or high-grade, with the predominant distinction being a basal orientation of all nuclei in low-grade dysplasia versus nuclei consistently reaching the apex of epithelial cells in high-grade dysplasia. Approximately 50% of patients with high-grade dysplasia may already have adjacent adenocarcinoma, according to some studies;[11] therefore, persistent high-grade dysplasia demands clinical intervention. Clinical Features. Most of the patients with first diagnosis of Barrett esophagus are between ages 40 and 60, although children can also occasionally develop this condition. The incidence is highest among white males. In addition to the symptoms of reflux esophagitis, Barrett esophagus is clinically significant due to the secondary complications of local ulceration with bleeding and stricture. Of greatest importance is the development of adenocarcinoma,
  21. 21. which, in patients with over 3 cm of Barrett mucosa, occurs at an estimated 30- to 40-fold increased rate over the general population. The presence of short-segment Barrett esophagus also appears to impart risk for adenocarcinoma, but at what rate is not yet known. INFECTIOUS AND CHEMICAL ESOPHAGITIS In addition to gastroesophageal reflux (which is, in fact, a chemical injury), esophageal inflammation may have many origins, as follows: • Ingestion of mucosal irritants such as alcohol, corrosive acids or alkalis (in suicide attempts), excessively hot fluids (e.g., hot tea in Iran); or heavy smoking • Cytotoxic anticancer therapy, with or without superimposed infection • Infection following bacteremia or viremia; herpes simplex viruses and cytomegalovirus (CMV) are common offenders in immunosuppressed patients 806 • Fungal infection in debilitated or immunosuppressed patients or during broad- spectrum antimicrobial therapy; candidiasis by far the most common; mucormycosis and aspergillosis may occur • Uremia in the setting of renal failure. Figure 17-7 Barrett esophagus. Microscopic view showing squamous mucosa and intestinal-type columnar epithelial cells (goblet cells) in a glandular mucosa. Esophageal inflammation may also arise following radiation treatment and in association with systemic graft-versus-host disease (GVHD), autoimmune diseases, or the desquamative dermatologic conditions of pemphigoid and epidermolysis bullosa. On rare occasion, esophagitis occurs in the setting of Crohn disease. Morphology.
  22. 22. Esophagitis of different causes have their own characteristic features; the final common pathway for all is severe acute inflammation, superficial necrosis and ulceration with the formation of granulation tissue, and eventual fibrosis. • In candidiasis, patches of the entire esophagus become covered by adherent, gray-white pseudo-membranes teeming with densely matted fungal hyphae. • Herpesviruses typically cause punched-out ulcers; the nuclear inclusions of herpesvirus are found in a narrow rim of degenerating epithelial cells at the margin of the ulcer. CMV causes liner ulceration of the esophageal mucosa; the histologic findings of CMV-associated change with both intranuclear and cytoplasmic inclusions are found in capillary endothelium and stromal cells in the base of the ulcer. In both forms of infection, immunohistochemical staining for virus-specific antigens provides a sensitive and specific diagnostic tool if routine histology is equivocal. • Pathogenic bacteria account for 10% to 15% of cases of infectious esophagitis and exhibit bacterial invasion of the lamina propria with necrosis of the squamous epithelium. • Injury induced by chemicals (lye, acids, detergents) may produce only mild erythema and edema, sloughing of the mucosa, or outright necrosis of the entire esophageal wall. Localized esophageal ulceration may result from pharmaceutical tablets or capsules "sticking" in the esophagus. • Following irradiation of the esophagus, submucosal and mural blood vessels exhibit marked intimal proliferation with luminal narrowing. The submucosa becomes severely fibrotic, and the mucosa exhibits atrophy, with flattening of the papillae and thinning of the epithelium. • GVHD shares features with the skin manifestations (e.g., apoptosis of basal epithelial cells, separation of epithelium and lamina propria, atrophy, and fibrosis of the lamina propria with minimal inflammation). Clinical Features. Infections of the esophagus may occur in otherwise healthy individuals, but most often occur in the debilitated or immunosuppressed. Chemical injury in children is usually accidental, as opposed to attempted suicide, which is an adult phenomenon. Tumors BENIGN TUMORS Benign tumors of the esophagus are mostly mesenchymal in origin and lie within the esophageal wall. Most common are benign tumors of smooth muscle origin, called leiomyomas. Fibromas, lipomas, hemangiomas, neurofibromas, and lymphangiomas may also arise. Mucosal polyps are usually composed of a combination of fibrous, vascular, or adipose tissue covered by an intact mucosa, known as fibrovascular polyps or pedunculated lipomas. Squamous papillomas are sessile lesions with a central core of connective tissue and a hyperplastic papilliform squamous mucosa. When the papilloma is associated with human papillomavirus (HPV) infection, the term condyloma applies. In
  23. 23. rare instances a mesenchymal mass of inflamed granulation tissue, called an inflammatory polyp, may resemble a malignant lesion, hence its alternative name inflammatory pseudotumor. MALIGNANT TUMORS In the United States, carcinomas of the esophagus represent about 6% of all cancers of the gastrointestinal tract but cause a disproportionate number of cancer deaths. They remain asymptomatic during much of their development and are often discovered too late to permit cure. With rare exceptions, malignant esophageal tumors arise from the epithelial layer. In the United States, most esophageal cancers used to be of squamous cell origin, but the incidence of these tumors has declined with a steady increase of adenocarcinomas. Worldwide, squamous cell cancers constitute 90% of esophageal cancers, but in the United States squamous cell carcinoma and adenocarcinoma exhibit comparable incidence rates. Rare tumors (undifferentiated, carcinoid, malignant melanoma, lymphoma, sarcoma, and adenocarcinomas arising from the submucosal glands) are not discussed here. Squamous Cell Carcinoma Squamous cell carcinoma is the most common type of carcinoma in the esophagus. Most squamous cell carcinomas occur in adults over age 50. The male-to-female ratio varies, in different studies, from 2:1 to as high as 20:1. While squamous cell carcinoma of the esophagus occurs throughout the world, its incidence varies widely between countries and within regions of the same country. The regions with higher incidence are Iran, central China, South Africa, and southern Brazil, where annual incidence rates are as high as 100 per 100,000, with deaths from cancer of the esophagus constituting over 20% of all cancer deaths. Other areas of high incidence include Puerto Rico and Eastern Europe. In the United States, it affects from 2 to 8 persons per 100,000 yearly and is predominantly a disease of adult males (the male-to-female ratio is 4:1). Blacks throughout the world are at higher risk than are whites; incidence in this group in the United States is fourfold higher than for U.S. whites. Etiology and Pathogenesis. The marked differences in epidemiology strongly implicate dietary and environmental factors ( Table 17-1 ), with a contribution from genetic predisposition.[12] The majority of cancers in Europe and the United 807 TABLE 17-1 -- Factors Associated with the Development of Squamous Cell Carcinoma of the Esophagus Dietary
  24. 24. Deficiency of vitamins (A, C, riboflavin, thiamine, pyridoxine) Deficiency of trace elements (zinc, molybdenum) Fungal contamination of foodstuffs High content of nitrites/nitrosamines Betel chewing Lifestyle Burning-hot beverages or food Alcohol consumption Tobacco use Urban environment Esophageal Disorders Long-standing esophagitis Achalasia Plummer-Vinson syndrome Genetic Predisposition Long-standing celiac disease Ectodermal dysplasia Epidermolysis bullosa Racial disposition States are attributable to alcohol and tobacco usage. Some alcoholic drinks contain significant amounts of such carcinogens as polycyclic hydrocarbons, fuel oils, and nitrosamines, along with other mutagenic compounds. Nutritional deficiencies associated with alcoholism may contribute to the process of carcinogenesis. Alcohol and tobacco cannot be invoked as risk factors in many high-incidence regions of the world. The presence of carcinogens, such as fungus-contaminated and nitrosamine- containing foodstuffs in China, may play a significant role in the extraordinary high incidence of carcinoma in this region. Dietary deficiencies in vitamins and essential metals have been documented in China and South Africa. Human papillomavirus DNA is found frequently in esophageal squamous cell carcinomas from high-incidence regions, but is infrequent in cancer-bearing patients in North America. [13] Based on the above considerations, dietary and environmental factors have been proposed to increase risk, with nutritional deficiencies acting as promoters or potentiators of the tumorigenic effects of environmental carcinogens. For example, methylating nitroso
  25. 25. compounds in the diet and in tobacco smoke may be the reason for the broad spectrum of p53 point mutations present in over half of esophageal cancers. Other genetic alterations, such as mutations in p16INK4, and amplification of CYCLIN D1, C-MYC, and epithelial growth factor receptor (EGFR), are prevalent in these cancers as well. This is in keeping with the concept that stepwise acquisition and accumulation of genetic alterations ultimately give rise to cancer.[14] Notably rare in esophageal squamous cell carcinomas are K-RAS and adenomatous polyposis coli (APC) mutations. Finally, the chronic esophagitis so commonly observed in persons living in areas of high incidence may itself be the result of sustained exposure to the carcinogens listed earlier. This chronic esophagitis results in an increased epithelial cell turnover, which, over a length of time in a continuously carcinogenic environment, progresses to dysplasia and eventually to carcinoma. The rate of progression along the chronic esophagitis-dysplasia- cancer sequence may well be modified or modulated by genetic or racial factors. Morphology. Like squamous cell carcinomas arising in other locations, those of the esophagus begin as apparent in situ lesions (intraepithelial neoplasm or carcinoma in situ). When they become overt, about 20% of these tumors are located in the upper third, 50% in the middle third, and 30% in the lower third of the esophagus. Early lesions appear as small, gray-white, plaque-like thickenings or elevations of the mucosa. In months to years, these lesions become tumorous masses and may eventually encircle the lumen. Three morphologic patterns are described: (1) protruded (60%), a polypoid exophytic lesion that protrudes into the lumen; (2) flat (15%), a diffuse, infiltrative form that tends to spread within the wall of the esophagus, causing thickening, rigidity, and narrowing of the lumen; and (3) excavated (ulcerated, 25%; Fig. 17-8 ), a necrotic cancerous ulceration that excavates deeply into surrounding structures and may erode into the respiratory tree (with resultant fistula and pneumonia) or aorta (with catastrophic exsanguination) or may permeate the mediastinum and pericardium. The fortunate patient is found at the stage of superficial esophageal carcinoma, in which the malignant lesion is confined to the epithelial layer (in situ) or is superficially invading the lamina propria or submucosa ( Fig. 17-9 ). Most squamous cell carcinomas are moderately to well differentiated. Several histologic variants may be seen, such as verrucous squamous cell carcinoma, spindle cell carcinoma, and basaloid squamous cell carcinoma. Irrespective of their degree of differentiation, most symptomatic tumors are quite large by the time they are diagnosed and have already invaded the wall or beyond. The rich lymphatic network in the submucosa
  26. 26. Figure 17-8 Large ulcerated squamous cell carcinoma of the esophagus. 808 Figure 17-9 Squamous cell carcinoma of the esophagus: low-power microscopic view showing invasion into the submucosa. promotes extensive circumferential and longitudinal spread, and intramural tumor cell clusters may often be seen several centimeters away from the main mass. Local extension into adjacent mediastinal structures occurs early and often in this disease, possibly due to the absence of serosa for most of the esophagus. Tumors located in the upper third of the esophagus also metastasize to cervical lymph nodes; those in the middle third to the mediastinal, paratracheal, and tracheobronchial nodes; and those in the lower third most often spread to the gastric and celiac groups of nodes. Clinical Features.
  27. 27. Esophageal carcinoma is insidious in onset and produces dysphagia and obstruction gradually and late. Patients subconsciously adjust to their increasing difficulty in swallowing by progressively altering their diet from solid to liquid foods. Extreme weight loss and debilitation result from both the impaired nutrition and the effects of the tumor itself. Hemorrhage and sepsis may accompany ulceration of the tumor. Occasionally, the first alarming symptom of this neoplasm is aspiration of food via a cancerous tracheoesophageal fistula. Although the insidious growth of these neoplasms often leads to large lesions by the time a diagnosis is established, resectability rates have improved modestly (from less than half to over 80%) with the advent of endoscopic screening in patient populations at risk and accurate staging by endoscopic ultrasonography. The five- year survival rate in patients with superficial esophageal carcinoma is about 75%, compared to 25% in patients who undergo "curative" surgery for more advanced disease and 9% for all patients with esophageal squamous cell carcinoma. Local and distant recurrence following surgery is common. The presence of lymph node metastases at the time of resection significantly reduces five-year survival. Adenocarcinoma Adenocarcinoma of the esophagus is a malignant epithelial tumor with glandular differentiation. Because of confusion in the past with gastric cancers arising at the gastroesophageal junction, true esophageal adenocarcinomas were thought to be unusual. With increasing recognition of Barrett mucosa, it is apparent that most adenocarcinomas in the lower third of the esophagus are true esophageal cancers, rather than gastric cancers straddling the esophagogastric junction. Accordingly, adenocarcinoma now represents up to half of all esophageal cancers reported in the United States, and the incidence has been increasing in recent decades, particularly among white men. The majority of cases arise from the Barrett mucosa. In rare instances, adenocarcinoma originates from heterotopic gastric mucosa or submucosal glands. Etiology and Pathogenesis. The discussion of adenocarcinoma focuses on Barrett esophagus. The lifetime risk for cancer development from Barrett esophagus is approximately 10%. Tobacco exposure and obesity are risk factors, but there is no close association between alcohol ingestion and the development of adenocarcinoma of the esophagus. Helicobacter pylori infection may be a contributing factor, but there is no general agreement about this issue. Molecular studies have suggested that the pathogenesis of adenocarcinoma from Barrett esophagus is a multistep process with a long latency period associated with many genetic changes. The development of dysplasia seems to be a critical step in this process ( Fig. 17-10 ). Barrett epithelial cells have higher proliferative activity, and dysplastic epithelial cells have lost cell-cycle control. Several growth factors, oncogenes, and tumor suppressor genes are implicated in this process.[15] Overexpression of p53 and an increased proportion of cycling cells are present in the dysplastic epithelium, presumably the result of chronic cell and DNA damage induced by gastric reflux. In high-grade dysplasia, chromosomal abnormalities, such as chromosome 4 amplification, are generally present.[16] When the dysplastic epithelium develops into adenocarcinoma, additional genetic
  28. 28. changes, including nuclear translocation of β-catenin and amplification of c-ERB-B2, are present. Although specific genetic abnormalities associated with the Barrett esophagus- carcinoma transition have not been identified, p53 mutations, along with tetraploidy and aneuploidy, seem to occur early. These genetic alterations may be suitable biomarkers of disease progression. Morphology. Adenocarcinomas arising in the setting of Barrett esophagus are usually located in the distal esophagus and may invade the adjacent gastric cardia. Initially appearing as flat or raised patches of an otherwise intact mucosa, they may develop into large nodular masses up to 5 cm in diameter or may exhibit diffusely infiltrative or deeply ulcerative features ( Fig. 17-11A ). Microscopically, most tumors are mucin-producing glandular tumors exhibiting intestinal-type features ( Fig. 17-11B ); less often they are made up of diffusely infiltrative signet-ring cells of a gastric type or even poorly differentiated small cell-type tumor. Multiple foci of dysplastic mucosa are frequently adjacent to the tumor, which is the basis for the recommendation of multisite biopsy when performing endoscopic screening for dysplasia and malignancy. 809 Figure 17-10 Transition from Barrett esophagus to adenocarcinoma. Clinical Features. Adenocarcinomas arising in Barrett esophagus chiefly occur in patients over age 40, with a median age in the sixth decade. Similar to Barrett esophagus, adenocarcinoma is more common in men than in women, and whites are affected more frequently than blacks, in contrast to squamous cell carcinomas. As in other forms of esophageal carcinoma, patients usually present because of difficulty swallowing, progressive weight loss, bleeding, chest pain, and vomiting. Long-term symptoms of heartburn, regurgitation, and epigastric pain related to concurrent gastroesophageal reflux disease and sliding hiatal hernias are present in less than half of newly diagnosed patients.
  29. 29. Figure 17-11 Adenocarcinoma of the esophagus. A, Gross view of an ulcerated, exophytic mass at the gastroesophageal junction, arising from the granular mucosa of Barrett esophagus. The gray-white esophageal mucosa is on the top, and the folds of gastric mucosa are below. (A, courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.) B, Microscopic view of malignant intestinal-type glands in adenocarcinoma arising from Barrett esophagus. The prognosis for esophageal adenocarcinoma is as poor as that for other forms of esophageal cancer, with under 20% overall five-year survival. Identification and resection of early cancers with invasion limited to the mucosa or submucosa improves five-year survival to over 80%. Although dysplasia appears to be a requisite for the development of adenocarcinoma, patients with low-grade dysplasia may not progress to cancer over long periods of follow-up, and apparent regression may occur. Regression or ablation of Barrett esophagus has not yet been shown to eliminate the risk for adenocarcinoma. 810 Stomach Normal
  30. 30. The stomach develops from the distal part of the foregut. It is a saccular organ with a volume of 1200 to 1500 mL, but a capacity of over 3000 mL. It extends from just left of the midline where it is joined to the esophagus, to just right of the midline where it connects to the duodenum. The concavity of the right, inner curve is called the lesser curvature, and the convexity of the left, outer curve is the greater curvature. An angle along the lesser curve, the incisura angularis, marks the approximate point at which the stomach narrows prior to its junction with the duodenum. The entire stomach is covered by peritoneum; an exaggerated peritoneal fold, the greater omentum, extends beyond the greater curvature to the transverse colon. The stomach is divided into five anatomic regions ( Fig. 17-12A ). The cardia is the narrow conical portion of the stomach immediately distal to the gastroesophageal junction. The fundus is the dome-shaped portion of the proximal stomach that extends superolateral to the gastroesophageal junction. The body, or corpus, comprises the remainder of the stomach proximal to the incisura angularis. The stomach distal to this angle is the antrum, demarcated from the duodenum by the muscular pyloric sphincter. The gastric wall, like the rest of the gastrointestinal tract, consists of mucosa, submucosa, muscularis propria, and serosa. The interior surface of the stomach exhibits coarse rugae (meaning "folds"). These infoldings of mucosa and submucosa extend longitudinally and are most prominent in the proximal stomach, flattening out when the stomach is distended. A finer mosaic-like pattern is delineated by small furrows in the mucosa. The delicate texture of the mucosa is punctuated by millions of gastric foveolae, or pits, leading to the mucosal glands. The normal gastric mucosa has two compartments: the superficial foveolar (meaning leaflike) compartment and the deeper glandular compartment. The foveolar compartment is relatively uniform throughout the stomach. In contrast, the glandular compartment exhibits major differences in thickness and in glandular composition in different regions of the stomach ( Fig. 17-12B, C ). The foveolar compartment consists of surface epithelial cells (the foveolar cells) lining the entire mucosal surface as well as the gastric pits. The lush undulation of the mucosal surface and pits imparts the leaflike texture to the gastric mucosa. The tall, columnar mucin-secreting foveolar cells have basal nuclei and crowded, small, relatively clear mucin-containing granules in the supranuclear region. Deeper in the gastric pits are so-called mucous neck cells, which have a lower content of mucin granules and are thought to be the progenitors of both the surface epithelium and the cells of the gastric glands. [17] Mitoses are extremely common in this region, as the entire gastric mucosal surface is totally replaced every 2 to 6 days. The glandular compartment consists of gastric glands, which vary between anatomic regions: • Cardia glands contain mucus-secreting cells only. • Oxyntic (also called gastric or fundic) glands are found in the fundus and body and contain parietal cells, chief cells, and scattered endocrine cells. The term oxyntic means acid-forming (derived from Greek, oxynein). • Antral or pyloric glands contain mucus-secreting cells and endocrine cells.
  31. 31. The main cell types in these glands are the following: • Mucous cells populate the glands of the cardia and antral regions and secrete mucus and pepsinogen II. The mucous neck cells in the glands of the body and fundus secrete mucus as well as group I and II pepsinogens. • Parietal cells line predominantly the upper half of the oxyntic glands in the fundus and body. They are recognizable 811 by their bright eosinophilia on H & E stained preparations, which are attributable to their abundant mitochondria. The apical membrane of the parietal cell is invaginated, forming an extensive intracellular canalicular system complete with microvilli. In the resting state, vesicles lie in close approximation to the canalicular system. These vesicles contain the proton pump, a unique hydrogen- potassium-ATPase (H+ ,K+ -ATPase) that pumps hydrogen across membranes in exchange for potassium ions. Within minutes of parietal cell stimulation, the vesicles fuse with the canalicular system, thereby creating an apically directed acid-secreting membrane of enormous surface area. Parietal cells also secrete intrinsic factor, which binds luminal vitamin B12 in the duodenum and permits its absorption in the ileum. • Chief cells, concentrated more at the base of gastric glands, are responsible for the secretion of the proteolytic proenzymes pepsinogen I and II. Chief cells are notable for their basophilic cytoplasm, and ultrastructurally are classic protein- synthesizing cells, having an extensive rough endoplasmic reticulum, a prominent supranuclear Golgi apparatus, and numerous apical secretory granules. Upon stimulation of chief cells, the pepsinogens contained in the granules are released by exocytosis. The pepsinogens are activated to pepsin by the low luminal pH and inactivated above pH 6.0 upon entry into the duodenum. • Endocrine or enteroendocrine cells are scattered among the epithelial cells of gastric and antral glands. The cytoplasm of these triangular cells contains small brightly eosinophilic granules, which are concentrated on the basal aspect of the cell. These cells can act in an endocrine mode, releasing their products into the circulation, or a paracrine mode, via secretion into the local tissue. In the antral mucosa, most of the endocrine cells are the gastrin-producing cells, or G cells. In the body (gastric) mucosa, the endocrine cells produce histamine, which binds the histamine-2 (H2 ) receptor on the parietal cells to increase acid production. These cells are also referred as enterochromaffin-like (ECL) cells. Other ECL cells in the gastric mucosa include D cells (producing somatostatin) and X cells (producing endothelin). These cells play an important role in modulating acid production.
  32. 32. Figure 17-12 Anatomy and histology of the stomach. A, Gross anatomy. B, Microscopic view of antral mucosa. C, Microscopic view of fundic mucosa. Gastric Mucosal Physiology ACID SECRETION The hallmark of gastric physiology is secretion of hydrochloric acid, divided into three phases. • The cephalic phase, initiated by the sight, taste, smell, chewing, and swallowing of palatable food, is mediated by vagal activity. • The gastric phase involves stimulation of stretch receptors by gastric distention and is mediated by vagal impulses; it also involves gastrin release from endocrine cells, the G cells, in the antral glands. Gastrin release is promoted by luminal amino acids and peptides and possibly by vagal stimulation.
  33. 33. • The intestinal phase, initiated when food containing digested protein enters the proximal small intestine, involves a number of polypeptides besides gastrin. All signals converge on the gastric parietal cell to activate the proton pump: • Acetylcholine released from cephalic-vagal or gastric-vagal afferents stimulates the parietal cell via the muscarine-3 cholinergic receptor, resulting in an increase in cytosolic Ca2+ and subsequent activation of the proton pump. • Gastrin activates a gastrin receptor, resulting in an increase of cytosolic Ca2+ within the parietal cells. • An oxyntic gland ECL cell plays a central role: gastrin and vagal afferents induce the release of histamine from the ECL cell, thereby stimulating the H2 receptor on parietal cells. This pathway is considered to be the most important for activation of the proton pump. Activation of some receptors on the parietal cell surface inhibit acid production. They include receptors for somatostatin, prostaglandins of the E series, and epidermal growth factor. MUCOSAL PROTECTION At maximal secretory rates the intraluminal concentration of hydrogen ion is 3 million times greater than that of the blood and tissues. The "mucosal barrier" protects the gastric mucosa from autodigestion and consists of: • Mucus secretion: The thin layer of surface mucus in the stomach and duodenum exhibits a diffusion coefficient for H+ that is one quarter that of water. Acid- and pepsin-containing fluid exits the gastric glands as "jets" passing through the surface mucus layer, entering the lumen directly without contacting surface epithelial cells. • Bicarbonate secretion: Surface epithelial cells in both the stomach and duodenum secrete bicarbonate into the boundary zone of adherent mucus, creating an essentially pH-neutral microenvironment immediately adjacent to the cell surface. • The epithelial barrier: Intercellular tight junctions provide a barrier to the back- diffusion of hydrogen ions. Epithelial disruption is followed rapidly by restitution, in which existing cells migrate along the exposed basement membrane to fill in the defects and restore epithelial barrier integrity. • Mucosal blood flow: The rich mucosal blood supply provides oxygen, bicarbonate, and nutrients to epithelial cells and removes back-diffused acid. • Prostaglandin synthesis: Production of prostglandins by the mucosal cells impacts on many other components of mucosal defense. For example, prostglandins favor production of mucus and bicarbonates, and they inhibit acid secretion by parietal cells. In addition, by their vasodilatory action, prostglandins E and I improve mucosal blood flow. Drugs that block postglandin synthesis reduce this cytoprotection and thus promote gastric mucosal injury and ulceration.
  34. 34. When the mucosal barrier is breached, the muscularis mucosa limits injury. Superficial damage limited to the mucosa can heal within hours to days. When damage extends into the submucosa, weeks are required for complete healing. Imperfect as our understanding of these defensive mechanisms may be, they are clearly a physiologic marvel, or our gastric walls would suffer the same fate as a piece of swallowed meat. In addition to the well-characterized barrier function and digestive function of the gastric mucosa, mucosal endocrine 812 cells also produce hormones that are involved in growth regulation. Ghrelin is a recently identified growth hormone that regulates body growth and appetite via a possible effect on the gastrointestinal-hypothalamic-pituitary axis.[18] Pathology Gastric lesions are frequent causes of clinical disease. In Western industrialized nations, peptic ulcers develop in up to 10% of the general population at some point during life. Chronic infection of the gastric mucosa by the bacterium H. pylori is the most common infection worldwide. Lastly, gastric cancer remains a leading cause of death in the United States, despite its decreasing incidence. Congenital Anomalies Heterotopic rests of normal tissue may be present in the stomach, and are usually asymptomatic. With pancreatic heterotopia, nodules of essentially normal pancreatic tissue up to 1 cm in diameter may be present in the gastric submucosa, muscle wall, or at a subserosal location. When in the pylorus, localized inflammation may lead to pyloric obstruction. With gastric heterotopia, small patches of ectopic gastric mucosa in the duodenum or in more distal sites may present as perplexing sources of bleeding, due to peptic ulceration of adjacent mucosa. Defective closure of the diaphragm leads to weakness or partial to total absence of a region of the diaphragm, usually on the left. Resultant herniation of abdominal contents into the thorax in utero produces a diaphragmatic hernia. Usually, the stomach or a portion of it insinuates into the pouch, but occasionally small bowel and even a portion of the liver accompany it. The herniation may be asymptomatic or may engender potentially lethal respiratory problems in the newborn. Rarely, and in keeping with the foregut origin of the stomach, a bud of pulmonary tissue complete with bronchial structures may be attached to the stomach. This pulmonary sequestrum may become infected or present as a mass lesion. PYLORIC STENOSIS
  35. 35. Congenital hypertrophic pyloric stenosis is encountered in infants as a disorder that affects males three to four times more often than females, occurring in 1 in 300 to 900 live births. Familial occurrence implicates a multifactorial pattern of inheritance; monozygotic twins have a high rate of concordance of the condition. Pyloric stenosis also may occur in association with Turner syndrome, trisomy 18, and esophageal atresia. Regurgitation and persistent, projectile, nonbilious vomiting usually appear in the second or third week of life. Physical examination reveals visible peristalsis and a firm, ovoid palpable mass in the region of the pylorus or distal stomach, the result of hypertrophy, and possibly hyperplasia, of the muscularis propria of the pylorus. Edema and inflammatory changes in the mucosa and submucosa may aggravate the narrowing. Surgical muscle splitting is curative. Acquired pyloric stenosis in adults is one of the long-term risks of antral gastritis or peptic ulcers close to the pylorus. Carcinomas of the pyloric region, lymphomas, or adjacent carcinomas of the pancreas are more ominous causes. In these cases, inflammatory fibrosis or malignant infiltration narrow the pyloric channel, producing pyloric outlet obstruction. In rare instances, hypertrophic pyloric stenosis is the result of prolonged pyloric spasm. Gastritis This diagnosis is both overused and often missed—overused when it is applied loosely to any transient upper abdominal complaint in the absence of validating evidence, and missed because most patients with chronic gastritis are asymptomatic. Gastritis is simply defined as inflammation of the gastric mucosa. It is a histologic diagnosis. Inflammation may be predominantly acute, with neutrophilic infiltration, or chronic, with lymphocytes and/or plasma cells predominating and associated intestinal metaplasia and atrophy.[19] ACUTE GASTRITIS Acute gastritis is an acute mucosal inflammatory process, usually of a transient nature. The inflammation may be accompanied by hemorrhage into the mucosa and, in more severe circumstances, by sloughing of the superficial mucosa (mucosal erosion). This severe erosive form of the disease is an important cause of acute gastrointestinal bleeding. Pathogenesis. The pathogenesis is poorly understood, in part because the normal mechanisms for gastric mucosal protection are not entirely clear. Acute gastritis is frequently associated with: • Heavy use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin • Excessive alcohol consumption • Heavy smoking • Treatment with cancer chemotherapeutic drugs
  36. 36. • Uremia • Systemic bacterial or viral infections (e.g., salmonellosis or CMV infection) • Severe stress (e.g., trauma, burns, surgery) • Ischemia and shock • Suicidal attempts, as with acids and alkali • Gastric irradiation or freezing • Mechanical trauma (e.g., nasogastric intubation) • Distal gastrectomy. One or more of the following influences are thought to be operative in these varied settings: increased acid secretion with back-diffusion, decreased production of bicarbonate buffer, reduced blood flow, disruption of the adherent mucus layer, and direct damage to the epithelium. Not surprisingly, mucosal insults can act synergistically. Thus, ischemic injury worsens the effects of back-diffusion of hydrogen ions. Other mucosal insults have been identified, such as regurgitation of detergent bile acids and lysolecithins from the proximal duodenum, and inadequate mucosal synthesis of prostaglandins. It must be emphasized that a substantial portion of patients has idiopathic gastritis, with no associated disorders. 813 Morphology. In the mildest form of acute gastritis, the lamina propria exhibits only moderate edema and slight vascular congestion. The surface epithelium is intact, and scattered neutrophils are present among the surface epithelial cells or within the epithelial layer and lumen of mucosal glands. The presence of neutrophils above the basement membrane (within the epithelial space) is abnormal and signifies active inflammation ("activity"). With more severe mucosal damage, erosion and hemorrhage develop. "Erosion" denotes loss of the superficial epithelium, generating a defect in the mucosa that does not cross the muscularis mucosa. It is accompanied by a robust acute inflammatory infiltrate and extrusion of a fibrin-containing purulent exudate into the lumen. Hemorrhage may occur independently, generating punctate dark spots in an otherwise hyperemic mucosa or in association with erosion. Concurrent erosion and hemorrhage is termed acute erosive hemorrhagic gastritis ( Fig. 17-13A ). Large areas of the gastric mucosa may be denuded, but the involvement is superficial and rarely affects the entire depth of the mucosa ( Fig. 17-13B ). These lesions are but one step removed from stress ulcers, to be described later. Clinical Features. Depending on the severity of the anatomic changes, acute gastritis may be entirely asymptomatic; may cause variable epigastric pain, nausea, and vomiting; or may present with overt hemorrhage, massive hematemesis, melena, and potentially fatal blood loss. Overall, it is one of the major causes of massive hematemesis, as in alcoholics. In
  37. 37. particular settings, the condition is quite common. As many as 25% of persons who take daily aspirin for rheumatoid arthritis develop acute gastritis, many with bleeding. CHRONIC GASTRITIS Chronic gastritis is defined as the presence of chronic mucosal inflammatory changes leading eventually to mucosal atrophy and intestinal metaplasia, usually in the absence of erosions. The Figure 17-13 Acute gastritis. A, Gross view showing punctate erosions in an otherwise unremarkable mucosa; adherent blood is dark due to exposure to gastric acid. B, Low-power microscopic view of focal mucosal disruption with hemorrhage; the adjacent mucosa is normal. epithelial changes may become dysplastic and constitute a background for the development of carcinoma. Chronic gastritis is notable for distinct causal subgroups and for patterns of histologic alterations that vary in different parts of the world. In the Western world, the prevalence of histologic changes indicative of chronic gastritis in the later decades of life is higher than 50%. Pathogenesis. The major etiologic associations of chronic gastritis are: • Chronic infection by H. pylori • Immunologic (autoimmune), in association with pernicious anemia • Toxic, as with alcohol and cigarette smoking • Postsurgical, especially following antrectomy with gastroenterostomy with reflux of bilious duodenal secretions • Motor and mechanical, including obstruction, bezoars (luminal concretions), and gastric atony • Radiation • Granulomatous conditions (e.g., Crohn disease) • Miscellaneous—amyloidosis, graft-versus-host disease, uremia.
  38. 38. Helicobacter pylori Infection and Chronic Gastritis. By far the most important etiologic association with chronic gastritis is chronic infection by the bacillus H. pylori. The link was discovered in 1983, when the bacterium was called Campylobacter pyloridis.[20] Since then, studies on H. pylori have yielded tremendous knowledge on the property of the bacteria and their role in the pathogenesis of gastric diseases. The complete genome of this bacterium has now been sequenced.[21] Effective treatment with antibiotics has revolutionized the way chronic gastritis and peptic ulcer disease are managed.[22] In addition to chronic gastritis, this organism plays a critical role in other major gastric and duodenal diseases ( Table 17-2 ). Peptic ulcer disease is now approached as an infectious disease that can be treated by antibiotics. H. pylori is present in 90% of patients with chronic gastritis affecting the antrum. Colonization rates increase with age, reaching 50% in asymptomatic American adults over age 50. Prevalence of infection among adults in Puerto Rico exceeds 80%. In this and other 814 TABLE 17-2 -- Diseases Associated with Helicobacter pylori Infection Disease Association Chronic gastritis Strong causal association Peptic ulcer disease Strong causal association Gastric carcinoma Strong causal association Gastric MALT lymphoma* Definitive etiologic role * MALT, mucosa-associated lymphoid tissue areas where infection is endemic, the organism seems to be acquired in childhood and persists for decades. The mode of transmission of H. pylori has not been well defined, although oral-oral transmission, fecal-oral transmission, and environmental spread are among the possible routes. Most infected persons also have the associated gastritis but are asymptomatic. Nevertheless, infected persons are at increased risk for the development of peptic ulcer disease and possibly gastric cancer. H. pylori is a nonsporing, curvilinear gram-negative rod measuring approximately 3.5 × 0.5 µm. H. pylori is part of a genus of bacteria that have adapted to the ecologic niche provided by gastric mucus, which is lethal to most bacteria. The specialized traits that allow it to flourish include: • Motility (via flagella), allowing it to swim through viscous mucus
  39. 39. • Elaboration of a urease, which produces ammonia and carbon dioxide from endogenous urea, thereby buffering gastric acid in the immediate vicinity of the organism • Expression of bacterial adhesins, such as BabA, which binds to the fucosylated Lewis B blood-group antigens, enhances binding to blood group O antigen bearing cells.[23] • Expression of bacterial toxins, such as cytotoxin association gene A (CagA) and vacuolating cytotoxin gene A (VacA).[24] These are discussed later under "Peptic Ulcer." The H. pylori genome is 1.65 million base pairs and encodes approximately 1500 proteins. Extensive molecular studies suggest that the bacteria cause gastritis by stimulating production of pro-inflammatory cytokines and by directly injuring epithelial cells (discussed later). After initial exposure to H. pylori, gastritis occurs in two patterns: a predominantly antral-type gastritis with high acid production and elevated risk for duodenal ulcer, and a pangastritis that is followed by multifocal atrophy (multifocal atrophic gastritis) with lower gastric acid secretion and higher risk for adenocarcinoma. The underlying mechanisms contributing to this difference are not completely clear, but host- microorganism interplay appears to be critical. IL-1β is a potent pro-inflammatory cytokine and a powerful gastric acid inhibitor. Patients who have higher IL-1β production in response to H. pylori infection tend to develop pangastritis, while patients who have lower IL-1β production exhibit antral-type gastritis. [25] A number of diagnostic tests have been developed for the detection of H. pylori. Noninvasive tests include a serologic test for antibodies, fecal bacterial detection, and a urea breath test. The breath test is based on the generation of ammonia by bacterial urease. Invasive tests are based on the identification of H. pylori in gastric biopsy tissue. Detection methods in gastric tissue include visualization of the bacteria in histologic sections, bacterial culture, a rapid urease test, and bacterial DNA detection by the polymerase chain reaction. Patients with chronic gastritis and H. pylori usually improve when treated with antibiotics. Relapses are associated with reappearance of the organism. The current treatment regimens include antibiotics and hydrogen pump inhibitors.[22] Prophylactic and therapeutic vaccine development is still in the early research stage, but it holds the promise to eradicate or at least greatly reduce the worldwide prevalence of H. pylori infection. In addition to H. pylori, humans can also be infected by Helicobacter heilmannii, a spiral bacterium found in dogs, cats, and nonhuman primates.[26] This bacterium causes a relatively mild gastritis. Autoimmune Gastritis.
  40. 40. This form of gastritis accounts for less than 10% of cases of chronic gastritis. It results from the presence of autoantibodies to components of gastric gland parietal cells, including antibodies against the acidproducing enzyme H+ ,K+ -ATPase,[27] gastrin receptor, and intrinsic factor. Gland destruction and mucosal atrophy lead to loss of acid production. In the most severe cases, production of intrinsic factor is lost, leading to pernicious anemia. This uncommon form of gastritis is seen in association with other autoimmune disorders such as Hashimoto thyroiditis, Addison disease, and type 1 diabetes. Patients with autoimmune gastritis have a significant risk for developing gastric carcinoma and endocrine tumors (carcinoid tumor). Morphology. Chronic gastritis may affect different regions of the stomach and exhibit varying degrees of mucosal damage.[19] Autoimmune gastritis is characterized by diffuse mucosal damage of the body-fundic mucosa, with less intense to absent antral damage, probably due to the autoantibodies against parietal cells. Gastritis in the setting of environmental etiologies (including infection by H. pylori) tends to affect antral mucosa or both antral and body- fundic mucosa (pangastritis). The mucosa is usually reddened and has a coarser texture than normal. The inflammatory infiltrate may create a mucosa with thickened rugal folds, mimicking early infiltrative lesions. Alternatively, with long-standing atrophic disease, the mucosa may become thinned and flattened. Irrespective of cause or location, the histologic changes are similar. An inflammatory infiltrate of lymphocytes and plasma cells is present within the lamina propria ( Fig. 17-14 ). "Active" inflammation is signified by the presence of neutrophils within the glandular and surface epithelial layer. Active inflammation may be prominent or absent. Lymphoid aggregates, some with germinal centers, are frequently observed within the mucosa. Several additional histologic features are characteristic: • Regenerative Change. A proliferative response to the epithelial injury is a constant feature of chronic gastritis. In the neck region of the gastric glands mitotic figures are increased. Epithelial cells of the 815 surface mucosa, and to a lesser extent the glands, exhibit enlarged, hyperchromatic nuclei and a higher nuclear-cytoplasmic ratio. Mucus vacuoles are diminished or absent in the superficial cells. When regenerative changes are severe, particularly with ongoing active inflammation, distinguishing regenerative change from dysplasia may be difficult. • Metaplasia. The antral, body, and fundic mucosa may become partially replaced by metaplastic columnar absorptive cells and goblet cells of intestinal morphology (intestinal metaplasia), both along the surface epithelium and in rudimentary glands. Occasionally, villus-like projections may appear. Although small intestinal features predominate, in some instances, features of colonic epithelium may be present. • Atrophy. Atrophic change is evident by marked loss in glandular structures. Atrophy is quite frequently associated with autoimmune gastritis and
  41. 41. pangastritis caused by H. pylori. Parietal cells, in particular, may be conspicuously absent in the autoimmune form. Persisting glands frequently undergo cystic dilatation. A particular feature of atrophic gastritis of autoimmune origin or chronic gastritis treated by inhibitors of acid secretion is hyperplasia of gastrin-producing G-cells in the antral mucosa. This is attributed to the hypochlorhydria or achlorhydria arising from severe parietal cell loss. The G-cell hyperplasia is responsible for the increased gastrinemia, which stimulates hyperplasia of enterochromaffin-like cells in the gastric body. As will be discussed later, the ECL cell hyperplasia is the frequent background for gastric carcinoid tumor formation. • Dysplasia. With long-standing chronic gastritis, the epithelium develops cytologic alterations, including variation in size, shape, and orientation of epithelial cells, and nuclear enlargement and atypia. Intestinal metaplasia may precede the development of dysplasia. Dysplastic alterations may become so severe as to constitute in situ carcinoma. The development of dysplasia is thought to be a precursor lesion of gastric cancer in atrophic forms of gastritis, particularly in association with pernicious anemia (autoimmune gastritis) and H. pylori- associated chronic gastritis. Figure 17-14 Chronic gastritis, showing partial replacement of the gastric mucosal epithelium by intestinal metaplasia (upper left) and inflammation of the lamina propria (right) containing lymphocytes and plasma cells. In those individuals infected by H. pylori, the organism lies in the superficial mucus layer and among the microvilli of epithelial cells. The distribution of organisms can be very patchy and irregular, with areas of heavy colonization adjacent to those with no organisms. In extreme cases, the organisms carpet the luminal surfaces of surface epithelial cells, the mucous neck cells, and the epithelial cells lining the gastric pits; they do not invade the mucosa. This is most easily demonstrated with silver stains ( Fig. 17-15 ), although organisms can be seen on Giemsa- and routine H & E-stained tissue. Even in heavily colonized stomachs, the organisms are absent from areas with intestinal
  42. 42. metaplasia. Conversely, organisms may be present in foci of pyloric metaplasia in an inflamed duodenum and in the gastric-type mucosa of Barrett esophagus. Clinical Features. Chronic gastritis usually causes few symptoms. Nausea, vomiting, and upper abdominal discomfort may occur. Individuals with advanced gastritis from H. pylori or other environmental causes are often hypochlorhydric, owing to parietal cell damage and atrophy of body and fundic mucosa. However, since parietal cells are never completely destroyed, these patients do not develop achlorhydria or pernicious anemia. Serum gastrin levels are usually within the normal range or only modestly elevated. Figure 17-15 Helicobacter pylori. A Steiner silver stain demonstrates the numerous darkly stained Helicobacter organisms along the luminal surface of the gastric epithelial cells. Note that there is no tissue invasion by bacteria. 816 When severe parietal cell loss occurs in the setting of autoimmune gastritis, hypochlorhydria or achlorhydria and hypergastrinemia are characteristically present. Circulating autoantibodies to a diverse array of parietal cell antigens may be detected. A small subset of these patients (10%) may develop overt pernicious anemia after a period of years. The familial occurrence of pernicious anemia is well established; a high prevalence of gastric autoantibodies is also found in asymptomatic relatives of patients with pernicious anemia. The distribution suggests that the inheritance of autoimmune gastritis is autosomal dominant.
  43. 43. Most important is the relationship of chronic gastritis to the development of peptic ulcer and gastric carcinoma. Most patients with a peptic ulcer, whether duodenal or gastric, have H. pylori infection. H. pylori is thought to contribute to the pathogenesis of both gastric carcinoma and lymphoma. The long-term risk of gastric cancer in patients with autoimmune gastritis is 2% to 4%, which is considerably greater than that of the normal population. SPECIAL FORMS OF GASTRITIS Eosinophilic gastritis is an idiopathic condition that features a prominent eosinophilic infiltrate of the mucosa, muscle wall, or all layers of the stomach, usually in the antral or pyloric region. This disorder typically affects middle-aged women, and the primary symptom is abdominal pain, although swelling of the pylorus may produce gastric outlet obstruction. It may occur in association with eosinophilic enteritis and is often accompanied by a peripheral eosinophilia. Steroid therapy is usually effective. Allergic gastroenteropathy is a disorder of children that may produce symptoms of diarrhea, vomiting, and growth failure. An infiltrate of eosinophils limited to the mucosa can usually be demonstrated in antral biopsies. Lymphocytic gastritis is a condition in which lymphocytes densely populate the epithelial layer of the mucosal surface and gastric pits and suffuse the lamina propria. The intraepithelial lymphocytes are exclusively T lymphocytes, mostly CD8+ cells. The gastritis is generally restricted to the body of the stomach. This condition produces indistinct symptoms such as abdominal pain, anorexia, nausea, and vomiting. Although idiopathic in nature, 45% to 60% of cases are associated with celiac disease. Therefore, an immune-mediated pathogenesis is most likely. Granulomatous gastritis. The presence of intramucosal epithelioid granulomas can usually be attributed to Crohn disease, sarcoidosis, infection (tuberculosis, histoplasmosis, anisakiasis), a systemic vasculitis, or as a reaction to foreign materials. Granulomatous gastritis is the term reserved for patients without these concurrent conditions. This idiopathic disorder is clinically benign. The predominant pathologic finding is narrowing and rigidity of the gastric antrum due to transmural granulomatous inflammation. Graft-versus-Host Disease. Gastritis associated with GVHD can be encountered in the setting of bone marrow transplantation. Histologically, there is a relatively mild lymphocytic infiltrate in the lamina propria and apoptosis of glandular epithelial cells, in particular the mucous neck cells. Reactive gastropathy is a group of disorders that exhibit characteristic mucosal histologic changes ( Fig. 17-16 ) that may include: foveolar hyperplasia with loss of mucin and glandular regenerative changes, mucosal edema and dilation of mucosal capillaries, and smooth muscle fibers extending into the lamina propria between the glands. The key to the definition is the absence of active (neutrophilic) inflammation of the epithelium. Reactive gastropathy is fairly common. The etiology is related to chemical injury from
  44. 44. cyclooxygenase inhibition (aspirin and NSAIDs) or bile reflux, and from mucosal trauma resulting from prolapse. In particular, gastric antral trauma or prolapse induce a characteristic lesion referred to as gastric antral vascular ectasia. Endoscopy shows longitudinal stripes of edematous erythematous mucosa alternating with less severely injured mucosa (watermelon stomach). Histologically, the antral mucosa exhibits reactive gastropathy and dilated capillaries containing fibrin thrombi. Peptic Ulcer Disease Ulcers are defined histologically as a breach in the mucosa of the alimentary tract that extends through the muscularis mucosa into the submucosa or deeper. Although they may occur anywhere in the alimentary tract, none are as prevalent as the peptic ulcers that occur in the duodenum and stomach. Acute gastric ulcers may also appear under conditions of severe systemic stress or ingestion of NSAIDs. Ulcers are to be distinguished from erosions, in which there is epithelial disruption within the mucosa but no breach of the muscularis mucosa. PEPTIC ULCERS Peptic ulcers are chronic, most often solitary, lesions that occur in any portion of the gastrointestinal tract exposed to the aggressive action of acid/peptic juices. Peptic ulcers are usually solitary lesions less than 4 cm in diameter, located in the following sites, in order of decreasing frequency:[28] Figure 17-16 Reactive gastropathy. Gastric mucosa, showing hyperplasia of foveolar surface epithelial cells, glandular regenerative changes, and smooth muscle fibers extending into lamina propria. 817 • Duodenum, first portion
  45. 45. • Stomach, usually antrum • At the gastroesophageal junction, in the setting of gastroesophageal reflux or Barrett esophagus • Within the margins of a gastrojejunostomy • In the duodenum, stomach, and/or jejunum of patients with Zollinger-Ellison syndrome • Within or adjacent to an ileal Meckel diverticulum that contains ectopic gastric mucosa. Epidemiology. In the United States, approximately 4 million people have peptic ulcers (duodenal and gastric), and 350,000 new cases are diagnosed each year. Around 180,000 patients are hospitalized yearly, and about 5000 people die each year as a result of peptic ulcer disease.[28] The lifetime likelihood of developing a peptic ulcer is about 10% for American males and 4% for females. Peptic ulcers are relapsing lesions that are most often diagnosed in middle-aged to older adults, but they may first become evident in young adult life. They often appear without obvious precipitating conditions and may then, after a period of weeks to months of active disease, heal with or without therapy. Even with healing, however, the tendency to develop peptic ulcers remains, in part because of recurrent infections with H. pylori. Although it is difficult to obtain estimates of the prevalence of active disease, autopsy studies and population surveys indicate a prevalence of 6% to 14% for men and 2% to 6% for women. The male-to-female ratio for duodenal ulcers is about 3:1, and for gastric ulcers about 1.5 to 2:1. Women are most often affected at or after menopause. For
  46. 46. Figure 17-17 Diagram of causes of, and defense mechanisms against, peptic ulceration. Diagram of the base of a nonperforated peptic ulcer, demonstrating the layers of necrosis (N), inflammation (I), granulation tissue (G), and scar (S), moving from the luminal surface at the top to the muscle wall at the bottom. unknown reasons, there has been a significant decrease in the prevalence of duodenal ulcers over the past decades but little change in the prevalence of gastric ulcers. Pathogenesis. Peptic ulcers are produced by an imbalance between gastroduodenal mucosal defense mechanisms and the damaging forces, [29] particularly gastric acid and pepsin ( Fig. 17-17 ). However, hyperacidity is not a prerequisite, as only a minority of patients with duodenal ulcers has hyperacidity, and it is even less common in those with gastric ulcers. Rather, gastric ulceration occurs when mucosal defenses fail, as when mucosal blood flow drops, gastric emptying is delayed, or epithelial restitution is impaired. H. pylori infection is a major factor in the pathogenesis of peptic ulcer. It is present in virtually all patients with duodenal ulcers and in about 70% of those with gastric ulcers. Furthermore, antibiotic treatment of H. pylori infection promotes healing of ulcers and tends to prevent their recurrence. Hence, much interest is focused on the possible mechanisms by which this tiny spiral organism tips the balance of mucosal defenses. Some likely possibilities include: • Although H. pylori does not invade the tissues, it induces an intense inflammatory and immune response. There is increased production of pro- inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), and, most notably, IL-8. This cytokine is produced by the mucosal epithelial cells, and it recruits and activates neutrophils. • Several bacterial gene products are involved in causing epithelial cell injury and induction of inflammation. H. 818 pylori secretes a urease that breaks down urea to form toxic compounds such as ammonium chloride and monochloramine. The organisms also elaborate phospholipases that damage surface epithelial cells. Bacterial proteases and phospholipases break down the glycoprotein-lipid complexes in the gastric mucus, thus weakening the first line of mucosal defense. • H. pylori enhances gastric acid secretion and impairs duodenal bicarbonate production, thus reducing luminal pH in the duodenum. This altered milieu seems to favor gastric metaplasia (the presence of gastric epithelium) in the first part of the duodenum. Such metaplastic foci provide areas for H. pylori colonization. • Several H. pylori proteins are immunogenic, and they evoke a robust immune response in the mucosa. Both activated T cells and B cells can be seen in chronic gastritis caused by H. pylori. The B lymphocytes aggregate to form follicles. The role of T and B cells in causing epithelial injury is not established, but T-cell-
  47. 47. driven activation of B cells may be involved in the pathogenesis of gastric lymphomas. • Thrombotic occlusion of surface capillaries is promoted by a bacterial platelet- activating factor. • Other antigens (including lipopolysaccharide) recruit inflammatory cells to the mucosa. The chronically inflamed mucosa is more susceptible to acid injury. • Damage to the mucosa is thought to permit leakage of tissue nutrients into the surface microenvironment, thereby sustaining the bacillus. With the unraveling of the H. pylori genome, the basis of the pathogenicity of this organism is beginning to be understood. [22] [30] Over 80% of patients with duodenal ulcers are infected by strains that are cytotoxin-associated antigen (CagA) positive. This antigen elicits a strong serologic response, but more importantly it is a marker for the Cag pathogenicity island, a 37 kb DNA fragment that encodes 29 genes, some of which are involved in the pro-inflammatory and tissue damaging effects of H. pylori. In keeping with this, infection with Cag positive strains is associated with greater number of organisms in the tissue, more severe epithelial damage, greater acute and chronic inflammation, higher likelihood of peptic ulceration and an increased risk for gastric cancer (discussed later). One of the important genes regulated by CagA is the vacuolating toxin (VacA); the CagA gene is essential for the expression of VacA. This toxin causes cell injury (characterized by vacuole formation) in vitro and gastric tissue damage in vivo. VacA also behaves as a passive urea transporter thereby increasing the permeability of the epithelium to urea. As discussed above, urea is broken down into toxic intermediates by bacterial urease. Only 10% to 20% of individuals worldwide infected with H. pylori actually develop peptic ulcer. Why most infected persons are spared and some are susceptible remains an enigma. Perhaps there are unknown interactions between H. pylori and the mucosa that occur only in some individuals. Another perplexing observation is that in patients with duodenal ulcer, the actual infection by H. pylori is limited to the stomach. Increased acid production by H. pylori infection seems to play a role. Suffice it to say that while the link between H. pylori infection and gastric and duodenal ulcers is well established, the interactions leading to ulceration remain to be defined. Other events may act alone or in concert with H. pylori to promote peptic ulceration. Gastric hyperacidity, when present, may be strongly ulcerogenic. Hyperacidity may arise from increased parietal cell mass, increased sensitivity to secretory stimuli, increased basal acid secretory drive, or impaired inhibition of stimulatory mechanisms such as gastrin release. The classic example is Zollinger-Ellison syndrome, in which there are multiple peptic ulcerations in the stomach, duodenum, and even jejunum, owing to excess gastrin secretion by a tumor and, hence, excess gastric acid production. Chronic use of NSAIDs suppresses mucosal prostaglandin synthesis; aspirin also is a direct irritant. Cigarette smoking impairs mucosal blood flow and healing. Alcohol has not been proved to directly cause peptic ulceration, but alcoholic cirrhosis is associated with an increased incidence of peptic ulcers. Corticosteroids in high dose and with