• 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 798EsophagusNormal
The esophagus develops from the cranial portion of the foregut and is recognizable by thethird week of gestation. The normal esophagus is a hollow, highly distensible musculartube 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. Measuringbetween 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 and40 cm from the incisor teeth, with the gastroesophageal junction located at the 40-cmpoint. Several points of luminal narrowing can be identified along its course—proximallyat the cricoid cartilage, midway in its course alongside the aortic arch and at the anteriorcrossing of the left main bronchus and left atrium, and distally where it pierces thediaphragm. Although the pressure in the esophageal lumen is negative compared with theatmosphere, manometric recordings of intraluminal pressures have identified two higher-pressure areas that remain relatively contracted in the resting phase. A 3-cm segment inthe proximal esophagus at the level of the cricopharyngeus muscle is referred to as theupper esophageal sphincter (UES). The 2- to 4-cm segment just proximal to the anatomicgastroesophageal junction, at the level of the diaphragm, is referred to as the loweresophageal sphincter (LES). Both "sphincters" are physiologic, in that there are noanatomic landmarks that delineate these higher-pressure regions from the interveningesophageal musculature.The wall of the esophagus consists of a mucosa, submucosa, muscularis propria, andadventitia, reflecting the general structural organization of the gastrointestinal tract. The  799mucosa has a smooth, glistening, and pink-tan surface. It has three components: anonkeratinizing stratified squamous epithelial layer, lamina propria, and muscularismucosa. The epithelial layer has mature squamous cells overlying basal cells. The basalcells, constituting 10% to 15 % of the mucosal thickness, are reserve cells with greatproliferative potential. A small number of specialized cell types, such as melanocytes,endocrine cells, dendritic cells, and lymphocytes, are present in the deeper portion of theepithelial layer. The lamina propria is the nonepithelial portion of the mucosa, above themuscularis mucosae. It consists of areolar connective tissue and contains vascularstructures and scattered leukocytes. Finger-like extensions of the lamina propria, calledpapillae, extend into the epithelial layer. The muscularis mucosae is a delicate layer oflongitudinally oriented smooth-muscle bundles.The submucosa consists of loose connective tissue containing blood vessels, a richnetwork 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 arescattered along the entire esophagus but are more concentrated in the upper and lowerportions. Their mucin-containing fluid secretions help lubricate the esophagus.As is true throughout the alimentary tract, the muscularis propria consists of an innercircular and an outer longitudinal coat of smooth muscle with an intervening, well-
developed myenteric plexus (Auerbach plexus). The muscularis propria of the proximal 6to 8 cm of the esophagus also contains striated muscle fibers from the cricopharyngeusmuscle. Besides creating a unique histologic interplay of smooth muscle and skeletalmuscle fibers, this feature explains why skeletal muscle disorders can cause upperesophageal dysfunction.In sharp contrast to the rest of the gastrointestinal tract, the esophagus is mostly devoid ofa serosal coat. Only small segments of the intra-abdominal esophagus are covered byserosa; the thoracic esophagus is surrounded by fascia that condenses around theesophagus to form a sheathlike structure. In the upper mediastinum, the esophagus issupported by this fascial tissue, which forms a similar sheath around adjacent structures,the great vessels and the tracheobronchial tree. This intimate anatomic proximity toimportant thoracic viscera is of significance in permitting the ready and widespreaddissemination of infections and tumors of the esophagus into the posterior mediastinum.The rich network of mucosal and submucosal lymphatics that runs longitudinally alongthe esophagus further facilitates spread.The main functions of the esophagus are to conduct food and fluids from the pharynx tothe stomach, to prevent passive diffusion of substances from the food into the blood, andto prevent reflux of gastric contents into the esophagus. These functions require motoractivity coordinated with swallowing, namely a wave of peristaltic contraction, relaxationof the LES in anticipation of the peristaltic wave, and closure of the LES after theswallowing reflex. The mechanisms governing this motor function are complex,involving both extrinsic and intrinsic innervation, humoral regulation, and properties ofthe muscle wall itself.The control of the lower esophageal sphincter (LES) is critical to esophageal function. Maintenance of sphincter tone is necessary to prevent reflux of gastric contents, whichare under positive pressure relative to the esophagus. During deglutition, both activeinhibition of the muscularis propria muscle fibers by inhibitorynonadrenergic/noncholinergic neurons and cessation of tonic excitation by cholinergicneurons 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 remainunclear.PathologyLesions of the esophagus run the gamut from highly lethal cancers to the merelyannoying "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 (vomitingof blood) and even death by exsanguination. Esophagitis and hiatal hernias are far morefrequent and rarely threaten life. Distressing to the physician is that all disorders of theesophagus tend to produce similar symptoms, namely heartburn, dysphagia, pain, and/orhematemesis.Heartburn (retrosternal burning pain) usually reflects regurgitation of gastric contentsinto the lower esophagus. Dysphagia (difficulty in swallowing) is encountered both withderanged esophageal motor function and with diseases that narrow or obstruct the lumen.Pain and hematemesis are sometimes evoked by esophageal disease, particularly by thoselesions associated with inflammation or ulceration of the esophageal mucosa. The clinicaldiagnosis of esophageal disorders often requires specialized procedures such asesophagoscopy, radiographic barium studies, and manometry.Congenital AnomaliesEctopic tissue rests are not uncommon in the esophagus. The most common is ectopicgastric 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. Theacid secretions of the ectopic gastric mucosa or pancreatic enzymatic secretions canproduce localized inflammation and discomfort.Embryologic formation of the foregut can also give rise to congenital cysts. These areusually duplication cysts, containing double smooth muscle layers and derived from thelower esophagus in 60% of cases. Rarely, bronchial or parenchymal pulmonary tissuemay arise from the upper gut and is denoted bronchogenic cyst or pulmonarysequestration, respectively. These lesions usually present as masses. Lastly, impairedformation of the diaphragm may permit herniation of abdominal viscera into the thorax.When severe, this lesion is incompatible with life, since the lungs are severelyhypoplastic at the time of birth. This condition is to be distinguished from hiatal hernias,to be discussed presently. 800ATRESIA AND FISTULASAlthough developmental defects in the esophagus are uncommon, they must be correctedearly because they are incompatible with life. Because they cause immediateregurgitation when feeding is attempted, they are usually discovered soon after birth.Absence (agenesis) of the esophagus is extremely rare; much more common are atresiaand fistula formation ( Fig. 17-1 ). In atresia, a segment of the esophagus is representedby only a thin, noncanalized cord, with a proximal blind pouch connected to the pharynxand a lower pouch leading to the stomach. Atresia is most commonly located at or nearthe tracheal bifurcation. It rarely occurs alone, but is usually associated with a fistulaconnecting the lower or upper pouch with a bronchus or the trachea. Associatedanomalies include congenital heart disease, neurologic disease, genitourinary disease, and
other gastrointestinal malformations. Atresia sometimes is associated with the presenceof a single umbilical artery. Aspiration and paroxysmal suffocation from food are obvious hazards; pneumonia and severe fluid and electrolyte imbalances may also occur.WEBS, RINGS, AND STENOSISEsophageal mucosal webs are uncommon ledgelike protrusions of the mucosa into theesophageal lumen. These are semicircumferential, eccentric, and most common in theupper 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 vascularizedsubmucosal core. Webs can be congenital in origin, or they may arise in association withlong-standing reflux esophagitis, chronic graft-versus-host disease (GVHD), or blisteringskin diseases. When an upper esophageal web is accompanied by an iron-deficiencyanemia, glossitis, and cheilosis, the condition is referred to as the Paterson-Brown-Kellyor Plummer-Vinson syndrome, with an attendant risk for postcricoid esophagealcarcinoma.Esophageal rings are concentric plates of tissue protruding into the lumen of the distalesophagus. One occurring above the squamocolumnar junction of the esophagus andstomach is referred to as an A ring. One located at the squamocolumnarFigure 17-1 Esophageal atresia and tracheoesophageal fistula. A, Blind upper and lower esophagealsegments. B, Fistula between blind upper segment and trachea. C, Blind upper segment, fistula betweenblind lower segment and trachea. D, Blind upper segment only. E, Fistula between patent esophagus andtrachea. 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 muscularispropria. Schatzki rings may have columnar gastric epithelium on their undersurface.Esophageal webs and rings are encountered most frequently in women over age 40 andare of uncertain etiology. Episodic dysphagia is the main symptom associated with websand rings, usually provoked when an individual bolts solid food. Pain is infrequent.
Esophageal stenosis consists of fibrous thickening of the esophageal wall, particularly thesubmucosa, with atrophy of the muscularis propria. The lining epithelium is usually thinand sometimes ulcerated. Although occasionally of congenital origin, stenosis is morefrequently the result of severe esophageal injury with inflammatory scarring, as fromgastroesophageal reflux, radiation, scleroderma, or caustic injury. Stenosis usuallydevelops in adulthood and becomes manifest by progressive dysphagia, at first to solidfoods only but eventually to all foods, which constitutes the major symptom. In severestenosis, virtually total obstruction may result.Lesions Associated with Motor DysfunctionCoordinated motor function is critical to proper function of the esophagus; gravity aloneis not sufficient to move food from the pharynx to the stomach, nor to prevent reflux ofgastric contents—witness the blissful suckling of the supine infant. The major entities(achalasia, hiatal hernia, diverticulum and Mallory-Weiss tear) that are caused by orinduce motor dysfunction of the esophagus are diagrammed in Figure 17-2 .ACHALASIAAchalasia 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
Figure 17-2 Major conditions associated with esophageal motor dysfunction.achalasia is poorly understood. It is thought to involve dysfunction of inhibitory neuronscontaining nitric oxide and vasoactive intestinal polypeptide in the distal esophagus.  Degenerative changes in neural innervation, either intrinsic to the esophagus or in theextraesophageal vagus nerves and the dorsal motor nucleus of the vagus, may also occur.Secondary achalasia may arise in Chagas disease, in which Trypanosoma cruzi causesdestruction of the myenteric plexus of the esophagus, duodenum, colon, and ureter, withresultant dilation of these viscera. Disorders of the dorsal motor nuclei, particularly polioor surgical ablation, can cause an achalasia-like illness, as can diabetic autonomicneuropathy and infiltrative disorders such as malignancy, amyloidosis, and sarcoidosis.In most instances, however, achalasia occurs as a primary disorder of uncertainetiology.Morphology.In primary achalasia there is progressive dilation of the esophagus above the level of theLES. The wall of the esophagus may be of normal thickness, thicker than normal owingto hypertrophy of the muscularis, or markedly thinned by dilation. The myenteric gangliaare usually absent from the body of the esophagus, but may or may not be reduced innumber in the region of the LES. The mucosal lining may be unaffected, but sometimesinflammation, ulceration, or fibrotic thickening may be evident just above the LES.
Clinical Features.Achalasia usually becomes manifest in young adulthood, but may appear in infancy orchildhood. The classic clinical symptom of achalasia is progressive dysphagia. Nocturnalregurgitation and aspiration of undigested food may occur. The most serious aspect ofthis condition is the hazard of developing esophageal squamous cell carcinoma, said tooccur in about 5% of patients, typically at an earlier age than those without this disease.Other complications include Candida esophagitis, lower esophageal diverticula (seebelow), and aspiration with pneumonia or airway obstruction.HIATAL HERNIAHiatal hernia is characterized by separation of the diaphragmatic crura and widening ofthe space between the muscular crura and the esophageal wall. Two anatomic patterns arerecognized (see Fig. 17-2 ): the axial, or sliding hernia, and the nonaxial, orparaesophageal hiatal hernia. The sliding hernia constitutes 95% of cases; protrusion ofthe stomach above the diaphragm creates a bell-shaped dilation, bounded below by thediaphragmatic 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 congenitalmalformation or is acquired during life. Based on barographic studies, hiatal hernias arereported 802in 1% to 20% of adult subjects, with incidence increasing with age. However, hiatalhernias are well recognized in infants and children. Only about 9% of adults with asliding hernia suffer from heartburn or regurgitation of gastric juices into the mouth.These symptoms are attributed to incompetence of the LES and are accentuated bypositions favoring reflux (bending forward, lying supine) and obesity.Complications of hiatal hernias are numerous. Both types may ulcerate, causing bleedingand perforation. Paraesophageal hernias can become strangulated or obstructed, and earlysurgical repair has been advocated. Reflux esophagitis (discussed later) is frequently seenin association with sliding hernias, but compromise of the LES with regurgitation ofpeptic juices into the esophagus is probably the result of, rather than the cause of, asliding hernia. The uncommon paraesophageal hernias may be caused by previoussurgery, including operations for sliding hernia.DIVERTICULAA 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 ofthe esophagus:
• 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 refluxdisease (GERD) and diminished luminal size of the UES are implicated in the genesis ofZenker diverticulum. Scarring resulting from mediastinal lymphadenitis (as fromtuberculosis) was presumed to be a cause of traction on the esophagus that gave rise tomid-esophageal diverticula. However, arguments have been advanced in favor of tractiondiverticula actually arising from motor dysfunction or being a congenital lesion.Dyscoordination of peristalsis and LES relaxation are the proposed cause of epiphrenicdiverticula.Zenker diverticula may reach several centimeters in size and can accumulate significantamounts of food. Typical symptoms include dysphagia, food regurgitation, and a mass inthe neck; aspiration with resultant pneumonia is a significant risk. While midesophagealdiverticula are generally asymptomatic, epiphrenic diverticula can give rise to nocturnalregurgitation of massive amounts of fluid.LACERATIONS (MALLORY-WEISS SYNDROME)Longitudinal tears in the esophagus at the esophagogastric junction or gastric cardia aretermed Mallory-Weiss tears and are believed to be the consequence of severe retching orvomiting. 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 theantiperistaltic wave of contraction. During episodes of prolonged vomiting, it isspeculated that this reflex relaxation fails to occur. The refluxing gastric contentssuddenly overwhelm the contraction of the musculature at the gastric inlet, and massivedilation with tearing of the stretched wall ensues. Since these tears may occur in personswho have no history of vomiting or alcoholism, other mechanisms must exist; underlyinghiatal hernia is a known predisposing factor.Morphology.The linear irregular lacerations are oriented in the axis of the esophageal lumen and areseveral millimeters to several centimeters in length. They are usually found astride theesophagogastric junction or in the proximal gastric mucosa ( Fig. 17-3 ). The tearsmay involve only the mucosa or may penetrate deeply enough to perforate the wall. Thehistology is not distinctive and reflects trauma accompanied by fresh hemorrhage and anonspecific inflammatory response. Infection of the mucosal defect may lead to aninflammatory ulcer or to mediastinitis.Clinical Features.
Esophageal lacerations account for 5% to 10% of bleeding episodes in the uppergastrointestinal tract. Most often, bleeding is not profuse and ceases without surgicalintervention, although massive hematemesis may occur. Supportive therapy, such asvasoconstrictive medications and transfusions, and sometimes balloon tamponade, isusually all that is required. Healing tends to be prompt, with minimal to no residua. Therare instance of esophageal rupture is known as Boerhaave syndrome and may be acatastrophic event.Esophageal VaricesRegardless of cause, portal hypertension, when sufficiently prolonged or severe, inducesthe formation of collateral bypass channels wherever the portal and caval systemscommunicate. The pathogenesis of portal hypertension and theFigure 17-3 Esophageal laceration (Mallory-Weiss tears). Gross view demonstrating longitudinallacerations extending from esophageal mucosa into stomach mucosa (arrow). (Courtesy of Dr. RichardHarruff, King County Medical Examiners Office, Seattle, WA.) 803locations of these bypasses are considered in Chapter 18 . Here we are concerned with thecollaterals that develop in the region of the lower esophagus when portal blood flow isdiverted through the coronary veins of the stomach into the plexus of esophagealsubepithelial and submucosal veins, thence into the azygos veins, and eventually into thesystemic circulation. The increased pressure in the esophageal plexus produces dilatedtortuous vessels called varices. Varices develop in 90% of cirrhotic patients and are most
often associated with alcoholic cirrhosis. Worldwide, hepatic schistosomiasis is thesecond most common cause of variceal bleeding.Morphology.Varices appear as tortuous dilated veins lying primarily within the submucosa of thedistal esophagus and proximal stomach; venous channels directly beneath the esophagealepithelium may also become massively dilated. The net effect is irregular protrusion ofthe overlying mucosa into the lumen, although varices are collapsed in surgical orpostmortem specimens ( Fig. 17-4A ). When the varix is unruptured, the mucosa may benormal, but often it is eroded and inflamed because of its exposed position. Varicealrupture produces massive hemorrhage into the lumen, as well as suffusion of theesophageal wall with blood. In this instance the overlying mucosa appears ulcerated andnecrotic ( Fig. 17-4B ). If rupture has occurred in the past, venous thrombosis andsuperimposed inflammation may be present. Varices can be detected by hepaticvenogram ( Fig. 17-4C ).Clinical Features.Varices usually produce no symptoms until they rupture, causing massive hematemesis.AmongFigure 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 postmortemspecimen. 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 ofdye into portal veins (PV) to show a large tortuous gastroesophageal varix (arrow) extending superiorlyfrom the patent main portal vein. (C, courtesy of Dr. Emily Sedgwick, Brigham and Womens 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 hepaticcoma triggered by the hemorrhage. It must be remembered, however, that even whenvarices are present, they account for less than half of all episodes of hematemesis.Collectively, concomitant gastritis, esophageal laceration, or peptic ulcers are morecommon causes. Factors leading to rupture of a varix are unclear: silent inflammatoryerosion of overlying thinned mucosa, increased tension in progressively dilated veins,and vomiting with increased vascular hydrostatic pressure are likely to play roles. Oncebegun, the hemorrhage rarely subsides spontaneously, and endoscopic injection ofthrombotic agents ("sclerotherapy") or balloon tamponade is usually required. Forty tofifty 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 eachepisode.EsophagitisInflammation of the esophageal mucosa is known as esophagitis. Injury to the esophagealmucosa with subsequent inflammation is common worldwide. In the United States andother Western countries, esophagitis is present in about 5% of the adult population; muchhigher prevalence is encountered in selected regions such as northern Iran and portions ofChina. Esophagitis may be caused by a variety of physical, chemical, or biologic agents.We review the common ones encountered in the clinical practice. 804REFLUX ESOPHAGITIS (GASTROESOPHAGEAL REFLUX DISEASE)Reflux of gastric contents into the lower esophagus is the most important cause ofesophagitis. Many causative factors are involved:  • 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 thanone is likely to be involved in most instances. The action of gastric juices is critical tothe development of esophageal mucosal injury; in severe cases refluxed bile from theduodenum also may contribute to the mucosal disruption.Morphology.The anatomic changes depend on the causative agent and on the duration and severity ofthe exposure. Simple hyperemia ("redness") may be the only alteration. In uncomplicatedreflux 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. Intraepithelialneutrophils, on the other hand, are markers of more severe injury such as ulceration ratherthan reflux esophagitis per se.Clinical Features.Although largely limited to adults over age 40, reflux esophagitis is occasionally seen ininfants and children. The clinical manifestations consist principally of dysphagia,heartburn, and sometimes regurgitation of a sour brash, hematemesis, or melena. Theseverity of symptoms is not closely related to the presence or degree of histologicesophagitis; most people experience reflux symptoms without damage to the distalesophageal mucosa, due to the short duration of the reflux. Anatomic damage appearsbest correlated with prolonged exposure of the lower esophagus to refluxed material.Rarely, chronic symptoms are punctuated by attacks of severe chest pain that may bemistaken for a "heart attack." The potential consequences of severe reflux esophagitis arebleeding, ulceration, development of stricture, and a tendency to develop Barrettesophagus, with its attendant risks.
Figure 17-5 Reflux esophagitis. Low-power view of the superficial portion of the mucosa. Numerouseosinophils within the squamous epithelium, elongation of the lamina propria papillae, and basal zonehyperplasia are present.BARRETT ESOPHAGUSBarrett esophagus is a complication of long-standing gastroesophageal reflux, occurringover time in up to 10% of patients with symptomatic gastroesophageal reflux disease(GERD). It is the single most important risk factor for esophageal adenocarcinoma. InBarrett esophagus, the distal squamous mucosa is replaced by metaplastic columnarepithelium, as a response to prolonged injury. Two criteria are required for the diagnosisof Barrett esophagus: (1) endoscopic evidence of columnar epithelial lining above thegastroesophageal junction and (2) histologic evidence of intestinal metaplasia in thebiopsy specimens from the columnar epithelium. Barrett esophagus is further classified as long segment (extending cephalad more than 3 cm from the manometricgastroesophageal junction) or short segment (extending less than 3 cm cephalad). Barrettesophagus patients tend to have a long history of heartburn and other reflux symptomsand appear to have more massive reflux with more and longer reflux episodes than mostreflux patients. It is unknown why the columnar epithelium develops in some patientswith reflux and not in others.The pathogenesis of Barrett esophagus remains unclear, but it appears to result from analteration in the differentiation program of stem cells of the esophageal mucosa. The concept of "intestinal metaplasia" in Barrett esophagus may be not entirely correct, sincetrue absorptive enterocytes are not observed. Rather, admixed with intestinal mucin-secreting goblet cells are columnar cells exhibiting both secretory and absorptiveultrastructural features; this is a phenotype not observed elsewhere in the alimentary tract.Nevertheless the term "intestinal metaplasia" continues to be used to denote the alteredhistology 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 mayexist as tongues or patches (islands) extending up from the gastroesophageal junction oras a broad irregular circumferential band displacing the squamocolumnar junction severalcentimeters cephalad ( Fig. 17-6 ). A small zone of metaplastic mucosa may be presentonly at the esophagogastric junction (short-segment 805
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 extendingfrom the gastroesophageal orifice. Note the paler squamous esophageal mucosa.Barrett mucosa), sometimes less than 0.5 cm in length. Microscopically, the esophagealsquamous epithelium is replaced by metaplastic columnar epithelium, complete withsurface epithelium and mucosal glands. The metaplastic mucosa may contain only gastricsurface and glandular mucus-secreting cells, making clinical distinction from a hiatalhernia difficult. Definitive diagnosis is made when the columnar mucosa containsintestinal goblet cells ( Fig. 17-7 ).Critical to the pathologic evaluation of patients with Barrett mucosa is the search fordysplasia, the presumed precursor of malignancy, in columnar epithelium with intestinalmetaplasia. Dysplasia is recognized by the presence of cytologic and architecturalabnormalities in the columnar epithelium, consisting of enlarged, crowded, and stratifiedhyperchromatic nuclei and loss of intervening stroma between adjacent glandularstructures. 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 nucleiconsistently reaching the apex of epithelial cells in high-grade dysplasia. Approximately50% of patients with high-grade dysplasia may already have adjacent adenocarcinoma,according to some studies; 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 highestamong white males. In addition to the symptoms of reflux esophagitis, Barrett esophagusis clinically significant due to the secondary complications of local ulceration withbleeding and stricture. Of greatest importance is the development of adenocarcinoma,
which, in patients with over 3 cm of Barrett mucosa, occurs at an estimated 30- to 40-foldincreased rate over the general population. The presence of short-segment Barrettesophagus also appears to impart risk for adenocarcinoma, but at what rate is not yetknown.INFECTIOUS AND CHEMICAL ESOPHAGITISIn addition to gastroesophageal reflux (which is, in fact, a chemical injury), esophagealinflammation 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 columnarepithelial cells (goblet cells) in a glandular mucosa.Esophageal inflammation may also arise following radiation treatment and in associationwith systemic graft-versus-host disease (GVHD), autoimmune diseases, or thedesquamative dermatologic conditions of pemphigoid and epidermolysis bullosa. On rareoccasion, esophagitis occurs in the setting of Crohn disease.Morphology.
Esophagitis of different causes have their own characteristic features; the final commonpathway for all is severe acute inflammation, superficial necrosis and ulceration with theformation 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 oftenoccur in the debilitated or immunosuppressed. Chemical injury in children is usuallyaccidental, as opposed to attempted suicide, which is an adult phenomenon.TumorsBENIGN TUMORSBenign tumors of the esophagus are mostly mesenchymal in origin and lie within theesophageal wall. Most common are benign tumors of smooth muscle origin, calledleiomyomas. Fibromas, lipomas, hemangiomas, neurofibromas, and lymphangiomas mayalso arise. Mucosal polyps are usually composed of a combination of fibrous, vascular, oradipose tissue covered by an intact mucosa, known as fibrovascular polyps orpedunculated lipomas. Squamous papillomas are sessile lesions with a central core ofconnective tissue and a hyperplastic papilliform squamous mucosa. When the papillomais associated with human papillomavirus (HPV) infection, the term condyloma applies. In
rare instances a mesenchymal mass of inflamed granulation tissue, called aninflammatory polyp, may resemble a malignant lesion, hence its alternative nameinflammatory pseudotumor.MALIGNANT TUMORSIn the United States, carcinomas of the esophagus represent about 6% of all cancers ofthe gastrointestinal tract but cause a disproportionate number of cancer deaths. Theyremain asymptomatic during much of their development and are often discovered too lateto permit cure. With rare exceptions, malignant esophageal tumors arise from theepithelial layer. In the United States, most esophageal cancers used to be of squamouscell origin, but the incidence of these tumors has declined with a steady increase ofadenocarcinomas. Worldwide, squamous cell cancers constitute 90% of esophagealcancers, but in the United States squamous cell carcinoma and adenocarcinoma exhibitcomparable incidence rates. Rare tumors (undifferentiated, carcinoid, malignantmelanoma, lymphoma, sarcoma, and adenocarcinomas arising from the submucosalglands) are not discussed here.Squamous Cell CarcinomaSquamous cell carcinoma is the most common type of carcinoma in the esophagus. Mostsquamous cell carcinomas occur in adults over age 50. The male-to-female ratio varies, indifferent studies, from 2:1 to as high as 20:1. While squamous cell carcinoma of theesophagus occurs throughout the world, its incidence varies widely between countriesand 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 highas 100 per 100,000, with deaths from cancer of the esophagus constituting over 20% ofall 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 ispredominantly a disease of adult males (the male-to-female ratio is 4:1). Blacksthroughout the world are at higher risk than are whites; incidence in this group in theUnited States is fourfold higher than for U.S. whites.Etiology and Pathogenesis.The marked differences in epidemiology strongly implicate dietary and environmentalfactors ( Table 17-1 ), with a contribution from genetic predisposition. The majority of cancers in Europe and the United 807 TABLE 17-1 -- Factors Associated with the Development of Squamous Cell Carcinoma of the EsophagusDietary
Deficiency of vitamins (A, C, riboflavin, thiamine, pyridoxine)Deficiency of trace elements (zinc, molybdenum)Fungal contamination of foodstuffsHigh content of nitrites/nitrosaminesBetel chewingLifestyleBurning-hot beverages or foodAlcohol consumptionTobacco useUrban environmentEsophageal DisordersLong-standing esophagitisAchalasiaPlummer-Vinson syndromeGenetic PredispositionLong-standing celiac diseaseEctodermal dysplasiaEpidermolysis bullosaRacial dispositionStates are attributable to alcohol and tobacco usage. Some alcoholic drinks containsignificant amounts of such carcinogens as polycyclic hydrocarbons, fuel oils, andnitrosamines, along with other mutagenic compounds. Nutritional deficiencies associatedwith alcoholism may contribute to the process of carcinogenesis.Alcohol and tobacco cannot be invoked as risk factors in many high-incidence regions ofthe world. The presence of carcinogens, such as fungus-contaminated and nitrosamine-containing foodstuffs in China, may play a significant role in the extraordinary highincidence of carcinoma in this region. Dietary deficiencies in vitamins and essentialmetals have been documented in China and South Africa. Human papillomavirus DNA isfound frequently in esophageal squamous cell carcinomas from high-incidence regions,but is infrequent in cancer-bearing patients in North America.Based on the above considerations, dietary and environmental factors have been proposedto increase risk, with nutritional deficiencies acting as promoters or potentiators of thetumorigenic effects of environmental carcinogens. For example, methylating nitroso
compounds in the diet and in tobacco smoke may be the reason for the broad spectrum ofp53 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 epithelialgrowth factor receptor (EGFR), are prevalent in these cancers as well. This is in keepingwith the concept that stepwise acquisition and accumulation of genetic alterationsultimately give rise to cancer. 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 highincidence 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 alength of time in a continuously carcinogenic environment, progresses to dysplasia andeventually 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 asapparent in situ lesions (intraepithelial neoplasm or carcinoma in situ). When theybecome overt, about 20% of these tumors are located in the upper third, 50% in themiddle 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, theselesions become tumorous masses and may eventually encircle the lumen. Threemorphologic patterns are described: (1) protruded (60%), a polypoid exophytic lesion thatprotrudes into the lumen; (2) flat (15%), a diffuse, infiltrative form that tends to spreadwithin the wall of the esophagus, causing thickening, rigidity, and narrowing of thelumen; and (3) excavated (ulcerated, 25%; Fig. 17-8 ), a necrotic cancerous ulcerationthat excavates deeply into surrounding structures and may erode into the respiratory tree(with resultant fistula and pneumonia) or aorta (with catastrophic exsanguination) or maypermeate the mediastinum and pericardium. The fortunate patient is found at the stage ofsuperficial esophageal carcinoma, in which the malignant lesion is confined to theepithelial 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 histologicvariants may be seen, such as verrucous squamous cell carcinoma, spindle cellcarcinoma, and basaloid squamous cell carcinoma. Irrespective of their degree ofdifferentiation, most symptomatic tumors are quite large by the time they are diagnosedand have already invaded the wall or beyond. The rich lymphatic network in thesubmucosa
Figure 17-8 Large ulcerated squamous cell carcinoma of the esophagus. 808Figure 17-9 Squamous cell carcinoma of the esophagus: low-power microscopic view showing invasioninto the submucosa.promotes extensive circumferential and longitudinal spread, and intramural tumor cellclusters may often be seen several centimeters away from the main mass. Local extensioninto adjacent mediastinal structures occurs early and often in this disease, possibly due tothe absence of serosa for most of the esophagus. Tumors located in the upper third of theesophagus also metastasize to cervical lymph nodes; those in the middle third to themediastinal, paratracheal, and tracheobronchial nodes; and those in the lower third mostoften spread to the gastric and celiac groups of nodes.Clinical Features.
Esophageal carcinoma is insidious in onset and produces dysphagia and obstructiongradually and late. Patients subconsciously adjust to their increasing difficulty inswallowing by progressively altering their diet from solid to liquid foods. Extreme weightloss and debilitation result from both the impaired nutrition and the effects of the tumoritself. Hemorrhage and sepsis may accompany ulceration of the tumor. Occasionally, thefirst alarming symptom of this neoplasm is aspiration of food via a canceroustracheoesophageal fistula. Although the insidious growth of these neoplasms often leadsto large lesions by the time a diagnosis is established, resectability rates have improvedmodestly (from less than half to over 80%) with the advent of endoscopic screening inpatient 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 diseaseand 9% for all patients with esophageal squamous cell carcinoma. Local and distantrecurrence following surgery is common. The presence of lymph node metastases at thetime of resection significantly reduces five-year survival.AdenocarcinomaAdenocarcinoma of the esophagus is a malignant epithelial tumor with glandulardifferentiation. Because of confusion in the past with gastric cancers arising at thegastroesophageal junction, true esophageal adenocarcinomas were thought to be unusual.With increasing recognition of Barrett mucosa, it is apparent that most adenocarcinomasin the lower third of the esophagus are true esophageal cancers, rather than gastriccancers straddling the esophagogastric junction. Accordingly, adenocarcinoma nowrepresents up to half of all esophageal cancers reported in the United States, and theincidence has been increasing in recent decades, particularly among white men. Themajority of cases arise from the Barrett mucosa. In rare instances, adenocarcinomaoriginates from heterotopic gastric mucosa or submucosal glands.Etiology and Pathogenesis.The discussion of adenocarcinoma focuses on Barrett esophagus. The lifetime risk forcancer development from Barrett esophagus is approximately 10%. Tobacco exposureand obesity are risk factors, but there is no close association between alcohol ingestionand the development of adenocarcinoma of the esophagus. Helicobacter pylori infectionmay be a contributing factor, but there is no general agreement about this issue.Molecular studies have suggested that the pathogenesis of adenocarcinoma from Barrettesophagus is a multistep process with a long latency period associated with many geneticchanges. 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 epithelialcells have lost cell-cycle control. Several growth factors, oncogenes, and tumorsuppressor genes are implicated in this process. Overexpression of p53 and an increased proportion of cycling cells are present in the dysplastic epithelium, presumably the resultof chronic cell and DNA damage induced by gastric reflux. In high-grade dysplasia,chromosomal abnormalities, such as chromosome 4 amplification, are generally present. When the dysplastic epithelium develops into adenocarcinoma, additional genetic
changes, including nuclear translocation of β-catenin and amplification of c-ERB-B2, arepresent. Although specific genetic abnormalities associated with the Barrett esophagus-carcinoma transition have not been identified, p53 mutations, along with tetraploidy andaneuploidy, seem to occur early. These genetic alterations may be suitable biomarkers ofdisease progression.Morphology.Adenocarcinomas arising in the setting of Barrett esophagus are usually located in thedistal esophagus and may invade the adjacent gastric cardia. Initially appearing as flat orraised patches of an otherwise intact mucosa, they may develop into large nodular massesup to 5 cm in diameter or may exhibit diffusely infiltrative or deeply ulcerative features( Fig. 17-11A ). Microscopically, most tumors are mucin-producing glandular tumorsexhibiting intestinal-type features ( Fig. 17-11B ); less often they are made up of diffuselyinfiltrative signet-ring cells of a gastric type or even poorly differentiated small cell-typetumor. Multiple foci of dysplastic mucosa are frequently adjacent to the tumor, which isthe basis for the recommendation of multisite biopsy when performing endoscopicscreening for dysplasia and malignancy. 809Figure 17-10 Transition from Barrett esophagus to adenocarcinoma.Clinical Features.Adenocarcinomas arising in Barrett esophagus chiefly occur in patients over age 40, witha median age in the sixth decade. Similar to Barrett esophagus, adenocarcinoma is morecommon in men than in women, and whites are affected more frequently than blacks, incontrast 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, andepigastric pain related to concurrent gastroesophageal reflux disease and sliding hiatalhernias are present in less than half of newly diagnosed patients.
Figure 17-11 Adenocarcinoma of the esophagus. A, Gross view of an ulcerated, exophytic mass at thegastroesophageal junction, arising from the granular mucosa of Barrett esophagus. The gray-whiteesophageal mucosa is on the top, and the folds of gastric mucosa are below. (A, courtesy of Dr. JamesGulizia, Brigham and Womens Hospital, Boston, MA.) B, Microscopic view of malignant intestinal-typeglands in adenocarcinoma arising from Barrett esophagus.The prognosis for esophageal adenocarcinoma is as poor as that for other forms ofesophageal cancer, with under 20% overall five-year survival. Identification and resectionof early cancers with invasion limited to the mucosa or submucosa improves five-yearsurvival to over 80%. Although dysplasia appears to be a requisite for the development ofadenocarcinoma, patients with low-grade dysplasia may not progress to cancer over longperiods of follow-up, and apparent regression may occur. Regression or ablation ofBarrett esophagus has not yet been shown to eliminate the risk for adenocarcinoma. 810StomachNormal
The stomach develops from the distal part of the foregut. It is a saccular organ with avolume of 1200 to 1500 mL, but a capacity of over 3000 mL. It extends from just left ofthe midline where it is joined to the esophagus, to just right of the midline where itconnects to the duodenum. The concavity of the right, inner curve is called the lessercurvature, and the convexity of the left, outer curve is the greater curvature. An anglealong the lesser curve, the incisura angularis, marks the approximate point at which thestomach narrows prior to its junction with the duodenum. The entire stomach is coveredby peritoneum; an exaggerated peritoneal fold, the greater omentum, extends beyond thegreater curvature to the transverse colon.The stomach is divided into five anatomic regions ( Fig. 17-12A ). The cardia is thenarrow conical portion of the stomach immediately distal to the gastroesophagealjunction. The fundus is the dome-shaped portion of the proximal stomach that extendssuperolateral to the gastroesophageal junction. The body, or corpus, comprises theremainder of the stomach proximal to the incisura angularis. The stomach distal to thisangle 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 andare most prominent in the proximal stomach, flattening out when the stomach isdistended. A finer mosaic-like pattern is delineated by small furrows in the mucosa. Thedelicate 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 (meaningleaflike) compartment and the deeper glandular compartment. The foveolar compartmentis relatively uniform throughout the stomach. In contrast, the glandular compartmentexhibits major differences in thickness and in glandular composition in different regionsof the stomach ( Fig. 17-12B, C ). The foveolar compartment consists of surfaceepithelial cells (the foveolar cells) lining the entire mucosal surface as well as the gastricpits. The lush undulation of the mucosal surface and pits imparts the leaflike texture tothe gastric mucosa. The tall, columnar mucin-secreting foveolar cells have basal nucleiand crowded, small, relatively clear mucin-containing granules in the supranuclearregion. Deeper in the gastric pits are so-called mucous neck cells, which have a lowercontent of mucin granules and are thought to be the progenitors of both the surfaceepithelium and the cells of the gastric glands. Mitoses are extremely common in this region, as the entire gastric mucosal surface is totally replaced every 2 to 6 days. Theglandular 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.
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.
Figure 17-12 Anatomy and histology of the stomach. A, Gross anatomy. B, Microscopic view of antralmucosa. C, Microscopic view of fundic mucosa.Gastric Mucosal PhysiologyACID SECRETIONThe hallmark of gastric physiology is secretion of hydrochloric acid, divided into threephases. • 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.
• 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. Theyinclude receptors for somatostatin, prostaglandins of the E series, and epidermal growthfactor.MUCOSAL PROTECTIONAt maximal secretory rates the intraluminal concentration of hydrogen ion is 3 milliontimes greater than that of the blood and tissues. The "mucosal barrier" protects the gastricmucosa 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.
When the mucosal barrier is breached, the muscularis mucosa limits injury. Superficialdamage limited to the mucosa can heal within hours to days. When damage extends intothe submucosa, weeks are required for complete healing. Imperfect as our understandingof these defensive mechanisms may be, they are clearly a physiologic marvel, or ourgastric 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 gastricmucosa, mucosal endocrine 812cells also produce hormones that are involved in growth regulation. Ghrelin is a recentlyidentified growth hormone that regulates body growth and appetite via a possible effecton the gastrointestinal-hypothalamic-pituitary axis.PathologyGastric 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 commoninfection worldwide. Lastly, gastric cancer remains a leading cause of death in the UnitedStates, despite its decreasing incidence.Congenital AnomaliesHeterotopic rests of normal tissue may be present in the stomach, and are usuallyasymptomatic. With pancreatic heterotopia, nodules of essentially normal pancreatictissue up to 1 cm in diameter may be present in the gastric submucosa, muscle wall, or ata subserosal location. When in the pylorus, localized inflammation may lead to pyloricobstruction. With gastric heterotopia, small patches of ectopic gastric mucosa in theduodenum or in more distal sites may present as perplexing sources of bleeding, due topeptic ulceration of adjacent mucosa.Defective closure of the diaphragm leads to weakness or partial to total absence of aregion of the diaphragm, usually on the left. Resultant herniation of abdominal contentsinto the thorax in utero produces a diaphragmatic hernia. Usually, the stomach or aportion of it insinuates into the pouch, but occasionally small bowel and even a portion ofthe liver accompany it. The herniation may be asymptomatic or may engender potentiallylethal respiratory problems in the newborn.Rarely, and in keeping with the foregut origin of the stomach, a bud of pulmonary tissuecomplete with bronchial structures may be attached to the stomach. This pulmonarysequestrum may become infected or present as a mass lesion.PYLORIC STENOSIS
Congenital hypertrophic pyloric stenosis is encountered in infants as a disorder thataffects males three to four times more often than females, occurring in 1 in 300 to 900live births. Familial occurrence implicates a multifactorial pattern of inheritance;monozygotic twins have a high rate of concordance of the condition. Pyloric stenosis alsomay occur in association with Turner syndrome, trisomy 18, and esophageal atresia.Regurgitation and persistent, projectile, nonbilious vomiting usually appear in the secondor third week of life. Physical examination reveals visible peristalsis and a firm, ovoidpalpable 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 andinflammatory 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 orpeptic ulcers close to the pylorus. Carcinomas of the pyloric region, lymphomas, oradjacent carcinomas of the pancreas are more ominous causes. In these cases,inflammatory fibrosis or malignant infiltration narrow the pyloric channel, producingpyloric outlet obstruction. In rare instances, hypertrophic pyloric stenosis is the result ofprolonged pyloric spasm.GastritisThis diagnosis is both overused and often missed—overused when it is applied loosely toany transient upper abdominal complaint in the absence of validating evidence, andmissed because most patients with chronic gastritis are asymptomatic. Gastritis is simplydefined as inflammation of the gastric mucosa. It is a histologic diagnosis. Inflammationmay be predominantly acute, with neutrophilic infiltration, or chronic, with lymphocytesand/or plasma cells predominating and associated intestinal metaplasia and atrophy. ACUTE GASTRITISAcute gastritis is an acute mucosal inflammatory process, usually of a transient nature.The inflammation may be accompanied by hemorrhage into the mucosa and, in moresevere circumstances, by sloughing of the superficial mucosa (mucosal erosion). Thissevere erosive form of the disease is an important cause of acute gastrointestinalbleeding.Pathogenesis.The pathogenesis is poorly understood, in part because the normal mechanisms forgastric mucosal protection are not entirely clear. Acute gastritis is frequently associatedwith: • Heavy use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin • Excessive alcohol consumption • Heavy smoking • Treatment with cancer chemotherapeutic drugs
• 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 variedsettings: increased acid secretion with back-diffusion, decreased production ofbicarbonate buffer, reduced blood flow, disruption of the adherent mucus layer, anddirect damage to the epithelium. Not surprisingly, mucosal insults can act synergistically.Thus, ischemic injury worsens the effects of back-diffusion of hydrogen ions. Othermucosal insults have been identified, such as regurgitation of detergent bile acids andlysolecithins from the proximal duodenum, and inadequate mucosal synthesis ofprostaglandins. It must be emphasized that a substantial portion of patients has idiopathicgastritis, with no associated disorders. 813Morphology.In the mildest form of acute gastritis, the lamina propria exhibits only moderate edemaand slight vascular congestion. The surface epithelium is intact, and scattered neutrophilsare present among the surface epithelial cells or within the epithelial layer and lumen ofmucosal glands. The presence of neutrophils above the basement membrane (withinthe epithelial space) is abnormal and signifies active inflammation ("activity"). Withmore severe mucosal damage, erosion and hemorrhage develop. "Erosion" denotes lossof the superficial epithelium, generating a defect in the mucosa that does not crossthe muscularis mucosa. It is accompanied by a robust acute inflammatory infiltrate andextrusion of a fibrin-containing purulent exudate into the lumen. Hemorrhage may occurindependently, generating punctate dark spots in an otherwise hyperemic mucosa or inassociation with erosion. Concurrent erosion and hemorrhage is termed acute erosivehemorrhagic gastritis ( Fig. 17-13A ). Large areas of the gastric mucosa may bedenuded, but the involvement is superficial and rarely affects the entire depth of themucosa ( Fig. 17-13B ). These lesions are but one step removed from stress ulcers, to bedescribed later.Clinical Features.Depending on the severity of the anatomic changes, acute gastritis may be entirelyasymptomatic; may cause variable epigastric pain, nausea, and vomiting; or may presentwith 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
particular settings, the condition is quite common. As many as 25% of persons who takedaily aspirin for rheumatoid arthritis develop acute gastritis, many with bleeding.CHRONIC GASTRITISChronic gastritis is defined as the presence of chronic mucosal inflammatory changesleading eventually to mucosal atrophy and intestinal metaplasia, usually in the absenceof erosions. TheFigure 17-13 Acute gastritis. A, Gross view showing punctate erosions in an otherwise unremarkablemucosa; adherent blood is dark due to exposure to gastric acid. B, Low-power microscopic view of focalmucosal disruption with hemorrhage; the adjacent mucosa is normal.epithelial changes may become dysplastic and constitute a background for thedevelopment of carcinoma. Chronic gastritis is notable for distinct causal subgroups andfor patterns of histologic alterations that vary in different parts of the world. In theWestern world, the prevalence of histologic changes indicative of chronic gastritis in thelater 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.
Helicobacter pylori Infection and Chronic Gastritis.By far the most important etiologic association with chronic gastritis is chronic infectionby the bacillus H. pylori. The link was discovered in 1983, when the bacterium wascalled Campylobacter pyloridis. Since then, studies on H. pylori have yielded tremendous knowledge on the property of the bacteria and their role in the pathogenesisof gastric diseases. The complete genome of this bacterium has now been sequenced. Effective treatment with antibiotics has revolutionized the way chronic gastritis andpeptic ulcer disease are managed. In addition to chronic gastritis, this organism plays a critical role in other major gastricand duodenal diseases ( Table 17-2 ). Peptic ulcer disease is now approached as aninfectious disease that can be treated by antibiotics. H. pylori is present in 90% ofpatients with chronic gastritis affecting the antrum. Colonization rates increase with age,reaching 50% in asymptomatic American adults over age 50. Prevalence of infectionamong adults in Puerto Rico exceeds 80%. In this and other 814 TABLE 17-2 -- Diseases Associated with Helicobacter pylori InfectionDisease AssociationChronic gastritis Strong causal associationPeptic ulcer disease Strong causal associationGastric carcinoma Strong causal associationGastric MALT lymphoma * Definitive etiologic role* MALT, mucosa-associated lymphoid tissueareas where infection is endemic, the organism seems to be acquired in childhood andpersists for decades. The mode of transmission of H. pylori has not been well defined,although oral-oral transmission, fecal-oral transmission, and environmental spread areamong the possible routes. Most infected persons also have the associated gastritis butare asymptomatic. Nevertheless, infected persons are at increased risk for thedevelopment 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 nicheprovided by gastric mucus, which is lethal to most bacteria. The specialized traits thatallow it to flourish include: • Motility (via flagella), allowing it to swim through viscous mucus
• 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. • Expression of bacterial toxins, such as cytotoxin association gene A (CagA) and vacuolating cytotoxin gene A (VacA). These are discussed later under "Peptic  Ulcer."The H. pylori genome is 1.65 million base pairs and encodes approximately 1500proteins. Extensive molecular studies suggest that the bacteria cause gastritis bystimulating production of pro-inflammatory cytokines and by directly injuring epithelialcells (discussed later).After initial exposure to H. pylori, gastritis occurs in two patterns: a predominantlyantral-type gastritis with high acid production and elevated risk for duodenal ulcer, and apangastritis that is followed by multifocal atrophy (multifocal atrophic gastritis) withlower gastric acid secretion and higher risk for adenocarcinoma. The underlyingmechanisms contributing to this difference are not completely clear, but host-microorganism interplay appears to be critical. IL-1β is a potent pro-inflammatorycytokine and a powerful gastric acid inhibitor. Patients who have higher IL-1β productionin response to H. pylori infection tend to develop pangastritis, while patients who havelower IL-1β production exhibit antral-type gastritis. 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 aurea breath test. The breath test is based on the generation of ammonia by bacterialurease. 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 histologicsections, bacterial culture, a rapid urease test, and bacterial DNA detection by thepolymerase chain reaction.Patients with chronic gastritis and H. pylori usually improve when treated withantibiotics. Relapses are associated with reappearance of the organism. The currenttreatment regimens include antibiotics and hydrogen pump inhibitors. Prophylactic and therapeutic vaccine development is still in the early research stage, but it holds thepromise to eradicate or at least greatly reduce the worldwide prevalence of H. pyloriinfection.In addition to H. pylori, humans can also be infected by Helicobacter heilmannii, a spiralbacterium found in dogs, cats, and nonhuman primates. This bacterium causes a relatively mild gastritis.Autoimmune Gastritis.
This form of gastritis accounts for less than 10% of cases of chronic gastritis. It resultsfrom the presence of autoantibodies to components of gastric gland parietal cells,including antibodies against the acidproducing enzyme H+ ,K+ -ATPase, gastrin receptor, and intrinsic factor. Gland destruction and mucosal atrophy lead to loss of acidproduction. In the most severe cases, production of intrinsic factor is lost, leading topernicious anemia. This uncommon form of gastritis is seen in association with otherautoimmune disorders such as Hashimoto thyroiditis, Addison disease, and type 1diabetes. Patients with autoimmune gastritis have a significant risk for developing gastriccarcinoma and endocrine tumors (carcinoid tumor).Morphology.Chronic gastritis may affect different regions of the stomach and exhibit varying degreesof mucosal damage. Autoimmune gastritis is characterized by diffuse mucosal damage of the body-fundic mucosa, with less intense to absent antral damage, probably due to theautoantibodies 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 texturethan 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, thehistologic changes are similar. An inflammatory infiltrate of lymphocytes and plasmacells is present within the lamina propria ( Fig. 17-14 ). "Active" inflammation issignified by the presence of neutrophils within the glandular and surface epitheliallayer. Active inflammation may be prominent or absent. Lymphoid aggregates, somewith germinal centers, are frequently observed within the mucosa. Several additionalhistologic 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
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 intestinalmetaplasia (upper left) and inflammation of the lamina propria (right) containing lymphocytes and plasmacells.In those individuals infected by H. pylori, the organism lies in the superficial mucus layerand among the microvilli of epithelial cells. The distribution of organisms can be verypatchy and irregular, with areas of heavy colonization adjacent to those with noorganisms. In extreme cases, the organisms carpet the luminal surfaces of surfaceepithelial cells, the mucous neck cells, and the epithelial cells lining the gastric pits; theydo 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 inheavily colonized stomachs, the organisms are absent from areas with intestinal
metaplasia. Conversely, organisms may be present in foci of pyloric metaplasia in aninflamed duodenum and in the gastric-type mucosa of Barrett esophagus.Clinical Features.Chronic gastritis usually causes few symptoms. Nausea, vomiting, and upper abdominaldiscomfort may occur. Individuals with advanced gastritis from H. pylori or otherenvironmental causes are often hypochlorhydric, owing to parietal cell damage andatrophy of body and fundic mucosa. However, since parietal cells are never completelydestroyed, these patients do not develop achlorhydria or pernicious anemia. Serumgastrin levels are usually within the normal range or only modestly elevated.Figure 17-15 Helicobacter pylori. A Steiner silver stain demonstrates the numerous darkly stainedHelicobacter organisms along the luminal surface of the gastric epithelial cells. Note that there is no tissueinvasion by bacteria. 816When 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. Asmall subset of these patients (10%) may develop overt pernicious anemia after a periodof years. The familial occurrence of pernicious anemia is well established; a highprevalence of gastric autoantibodies is also found in asymptomatic relatives of patientswith pernicious anemia. The distribution suggests that the inheritance of autoimmunegastritis is autosomal dominant.
Most important is the relationship of chronic gastritis to the development of peptic ulcerand 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 bothgastric carcinoma and lymphoma. The long-term risk of gastric cancer in patients withautoimmune gastritis is 2% to 4%, which is considerably greater than that of the normalpopulation.SPECIAL FORMS OF GASTRITISEosinophilic gastritis is an idiopathic condition that features a prominent eosinophilicinfiltrate of the mucosa, muscle wall, or all layers of the stomach, usually in the antral orpyloric region. This disorder typically affects middle-aged women, and the primarysymptom is abdominal pain, although swelling of the pylorus may produce gastric outletobstruction. It may occur in association with eosinophilic enteritis and is oftenaccompanied by a peripheral eosinophilia. Steroid therapy is usually effective.Allergic gastroenteropathy is a disorder of children that may produce symptoms ofdiarrhea, vomiting, and growth failure. An infiltrate of eosinophils limited to the mucosacan usually be demonstrated in antral biopsies.Lymphocytic gastritis is a condition in which lymphocytes densely populate the epitheliallayer of the mucosal surface and gastric pits and suffuse the lamina propria. Theintraepithelial lymphocytes are exclusively T lymphocytes, mostly CD8+ cells. Thegastritis is generally restricted to the body of the stomach. This condition producesindistinct symptoms such as abdominal pain, anorexia, nausea, and vomiting. Althoughidiopathic 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 canusually 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 concurrentconditions. This idiopathic disorder is clinically benign. The predominant pathologicfinding is narrowing and rigidity of the gastric antrum due to transmural granulomatousinflammation.Graft-versus-Host Disease. Gastritis associated with GVHD can be encountered in thesetting of bone marrow transplantation. Histologically, there is a relatively mildlymphocytic infiltrate in the lamina propria and apoptosis of glandular epithelial cells, inparticular the mucous neck cells.Reactive gastropathy is a group of disorders that exhibit characteristic mucosal histologicchanges ( Fig. 17-16 ) that may include: foveolar hyperplasia with loss of mucin andglandular regenerative changes, mucosal edema and dilation of mucosal capillaries, andsmooth muscle fibers extending into the lamina propria between the glands. The key tothe definition is the absence of active (neutrophilic) inflammation of the epithelium.Reactive gastropathy is fairly common. The etiology is related to chemical injury from
cyclooxygenase inhibition (aspirin and NSAIDs) or bile reflux, and from mucosal traumaresulting from prolapse. In particular, gastric antral trauma or prolapse induce acharacteristic lesion referred to as gastric antral vascular ectasia. Endoscopy showslongitudinal stripes of edematous erythematous mucosa alternating with less severelyinjured mucosa (watermelon stomach). Histologically, the antral mucosa exhibits reactivegastropathy and dilated capillaries containing fibrin thrombi.Peptic Ulcer DiseaseUlcers are defined histologically as a breach in the mucosa of the alimentary tract thatextends through the muscularis mucosa into the submucosa or deeper. Although theymay occur anywhere in the alimentary tract, none are as prevalent as the peptic ulcers thatoccur in the duodenum and stomach. Acute gastric ulcers may also appear underconditions of severe systemic stress or ingestion of NSAIDs. Ulcers are to bedistinguished from erosions, in which there is epithelial disruption within the mucosa butno breach of the muscularis mucosa.PEPTIC ULCERSPeptic ulcers are chronic, most often solitary, lesions that occur in any portion of thegastrointestinal tract exposed to the aggressive action of acid/peptic juices. Peptic ulcersare usually solitary lesions less than 4 cm in diameter, located in the following sites, inorder of decreasing frequency: Figure 17-16 Reactive gastropathy. Gastric mucosa, showing hyperplasia of foveolar surface epithelialcells, glandular regenerative changes, and smooth muscle fibers extending into lamina propria.
817 • Duodenum, first portion • 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 andgastric), and 350,000 new cases are diagnosed each year. Around 180,000 patients arehospitalized yearly, and about 5000 people die each year as a result of peptic ulcerdisease. 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 olderadults, but they may first become evident in young adult life. They often appear withoutobvious precipitating conditions and may then, after a period of weeks to months ofactive disease, heal with or without therapy. Even with healing, however, the tendency todevelop 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, autopsystudies and population surveys indicate a prevalence of 6% to 14% for men and 2% to6% for women. The male-to-female ratio for duodenal ulcers is about 3:1, and for gastriculcers about 1.5 to 2:1. Women are most often affected at or after menopause. For
Figure 17-17 Diagram of causes of, and defense mechanisms against, peptic ulceration. Diagram of thebase of a nonperforated peptic ulcer, demonstrating the layers of necrosis (N), inflammation (I), granulationtissue (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 duodenalulcers over the past decades but little change in the prevalence of gastric ulcers.Pathogenesis.Peptic ulcers are produced by an imbalance between gastroduodenal mucosal defensemechanisms and the damaging forces, particularly gastric acid and pepsin ( Fig. 17-17 ). However, hyperacidity is not a prerequisite, as only a minority of patients withduodenal 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 bloodflow 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 invirtually 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 andtends to prevent their recurrence. Hence, much interest is focused on the possiblemechanisms 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- 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 thisorganism is beginning to be understood. Over 80% of patients with duodenal ulcers  are infected by strains that are cytotoxin-associated antigen (CagA) positive. This antigenelicits a strong serologic response, but more importantly it is a marker for the Cagpathogenicity island, a 37 kb DNA fragment that encodes 29 genes, some of which areinvolved in the pro-inflammatory and tissue damaging effects of H. pylori. In keepingwith this, infection with Cag positive strains is associated with greater number oforganisms in the tissue, more severe epithelial damage, greater acute and chronicinflammation, higher likelihood of peptic ulceration and an increased risk for gastriccancer (discussed later). One of the important genes regulated by CagA is thevacuolating toxin (VacA); the CagA gene is essential for the expression of VacA. Thistoxin causes cell injury (characterized by vacuole formation) in vitro and gastric tissuedamage in vivo. VacA also behaves as a passive urea transporter thereby increasing thepermeability of the epithelium to urea. As discussed above, urea is broken down intotoxic intermediates by bacterial urease.Only 10% to 20% of individuals worldwide infected with H. pylori actually developpeptic 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 thatoccur only in some individuals. Another perplexing observation is that in patients withduodenal ulcer, the actual infection by H. pylori is limited to the stomach. Increased acidproduction by H. pylori infection seems to play a role. Suffice it to say that while the linkbetween H. pylori infection and gastric and duodenal ulcers is well established, theinteractions 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 arisefrom increased parietal cell mass, increased sensitivity to secretory stimuli, increasedbasal acid secretory drive, or impaired inhibition of stimulatory mechanisms such asgastrin release. The classic example is Zollinger-Ellison syndrome, in which there aremultiple peptic ulcerations in the stomach, duodenum, and even jejunum, owing to excessgastrin secretion by a tumor and, hence, excess gastric acid production.Chronic use of NSAIDs suppresses mucosal prostaglandin synthesis; aspirin also is adirect irritant. Cigarette smoking impairs mucosal blood flow and healing. Alcohol hasnot been proved to directly cause peptic ulceration, but alcoholic cirrhosis is associatedwith an increased incidence of peptic ulcers. Corticosteroids in high dose and withrepeated use promote ulcer formation. In some patients with duodenal ulcers, there istoo-rapid gastric emptying, exposing the duodenal mucosa to an excessive acid load.Duodenal ulcer also is more frequent in patients with alcoholic cirrhosis, chronicobstructive pulmonary disease, chronic renal failure, and hyperparathyroidism. In thelatter two conditions, hypercalcemia stimulates gastrin production and therefore acidsecretion. Genetic influences appear to play no major role in peptic ulceration. Finally,there are compelling arguments that personality and psychological stress are importantcontributing factors, even though hard data on cause and effect are lacking. Indeed, wemight develop ulcers by trying to fathom their cause(s).Morphology.At least 98% of peptic ulcers are located in the first portion of the duodenum or in thestomach, in a ratio of about 4:1. Most duodenal ulcers occur within a few centimeters ofthe pyloric ring. The anterior wall of the duodenum is affected more often than theposterior wall. Gastric ulcers are predominantly located along the lesser curvature, in oraround the border zone between the oxyntic mucosa and the antral mucosa. Lesscommonly, gastric ulcers may occur on the anterior or posterior walls, or along thegreater curvature. Although the great majority of individuals have a single ulcer, in 10%to 20% of patients with gastric ulceration there may be a coexistent duodenal ulcer.Wherever they occur, chronic peptic ulcers have a fairly standard, virtually diagnosticgross appearance ( Fig. 17-18 ). Small lesions (<0.3 cm) are most likely to be shallowerosions; those over 0.6 cm are likely to be ulcers. Although over 50% of peptic ulcershave a diameter less than 2 cm, about 10% of benign ulcers are greater than 4 cm. Sincecarcinomatous ulcers may be less than 4 cm in diameter and may be located anywhere inthe stomach, size and location do not differentiate a benign from a malignant ulcer.
The classic peptic ulcer is a round to oval, sharply punched-out defect with relativelystraight walls. The mucosal margin may overhang the base slightly, particularly on theupstream portion of the circumference. The margins are usually level with thesurrounding mucosa or only slightly elevated. Heaping-up of these margins is rare in thebenign ulcer but is characteristic of the malignant lesion. The depth of these ulcers varies,from superficial lesions involving only the mucosa and muscularis mucosa to 819Figure 17-18 Peptic ulcer of the duodenum. Note that the ulcer is small (2 cm) with a sharply punched-outappearance. Unlike cancerous ulcers, the margins are not elevated. The ulcer base is clean. (Courtesy ofRobin Foss, University of Florida, Gainesville, FL.)deeply excavated ulcers having their bases on the muscularis propria. When the entirewall is penetrated, the base of the ulcer may be formed by adherent pancreas, omental fat,or liver. Free perforation into the peritoneal cavity may occur.The base of a peptic ulcer is smooth and clean, owing to peptic digestion of any exudatethat may form. At times, thrombosed or even patent blood vessels (the source of life-threatening hemorrhage) are evident in the base of the ulcer. Scarring may involve theentire thickness of the stomach; puckering of the surrounding mucosa creates mucosalfolds that radiate from the crater in spokelike fashion. The gastric mucosa surrounding agastric ulcer is somewhat edematous and reddened, owing to the almost invariablegastritis.The histologic appearance varies from active necrosis, to chronic inflammation andscarring, to healing (see Fig. 2-26 , Chapter 2). In active ulcers with ongoing necrosis,four zones are demonstrable: (1) the base and margins have a superficial thin layer ofnecrotic fibrinoid debris not visible to the naked eye; (2) beneath this layer is a zone ofnon-specific inflammatory infiltrate, with neutrophils predominating; (3) in the deeperlayers, especially in the base of the ulcer, there is active granulation tissue infiltrated withmononuclear leukocytes; and (4) the granulation tissue rests on a more solid fibrous or
collagenous scar. Vessel walls within the scarred area are typically thickened by thesurrounding inflammation and are occasionally thrombosed.Chronic gastritis is virtually universal among patients with peptic ulcer disease, occurringin 85% to 100% of patients with duodenal ulcers and in 65% with gastric ulcers. H.pylori infection is almost always demonstrable in patients with gastritis. Gastritis remainsafter the ulcer has healed; recurrence of the ulcer does not appear to be related toprogression of the gastritis. This feature is helpful in distinguishing peptic ulcers fromacute erosive gastritis or stress ulcers, since the adjacent mucosa is generally normal inthe latter two conditions.Clinical Features.The great majority of peptic ulcers cause epigastric gnawing, burning, or aching pain. Asignificant minority first comes to light with complications such as iron-deficiencyanemia, frank hemorrhage, or perforation. The pain tends to be worse at night and occursusually 1 to 3 hours after meals during the day. Classically, the pain is relieved by alkalisor food, but there are many exceptions. Nausea, vomiting, bloating, belching, andsignificant weight loss (raising the possibility of some hidden malignancy) are additionalmanifestations. With penetrating ulcers, the pain is occasionally referred to the back, theleft upper quadrant, or chest. This type of pain may be misinterpreted as being of cardiacorigin.Peptic ulcers are notoriously chronic, recurring lesions. They more often impair thequality of life than shorten it. When untreated, it takes an average of 15 years for healinga duodenal or gastric ulcer. With present-day therapies aimed at neutralization of gastricacid, promotion of mucus secretion, inhibition of acid secretion (H2 receptor antagonistsand parietal cell H+ ,K+ -ATPase pump inhibitors), and eradication of H. pylori infection,most ulcers heal within a few weeks, and victims usually escape the surgeons knife.The complications of peptic ulcer disease are listed in Table 17-3 . Malignanttransformation does not occur with duodenal ulcers and is extremely rare with gastriculcers. When it occurs, it is always possible that a seemingly benign lesion was, from theoutset, a deceptive ulcerative gastric carcinoma.ACUTE GASTRIC ULCERATIONFocal, acutely developing gastric mucosal defects are a well-known complication oftherapy with NSAIDs. Alternatively, they may appear following severe physiologicstress, whatever its nature—hence the term stress ulcers. Generally, there are multiplelesions located mainly in the stomach and occasionally in the duodenum. They range indepth from mere shedding of the superficial epithelium (erosion) to deeper lesions thatinvolve the entire mucosal thickness (ulceration). The shallow erosions are, in essence,an extension of acute erosive gastritis. The deeper lesions comprise well-definedulcerations, but they are not precursors of chronic peptic ulcers.
Stress erosions and ulcers are most commonly encountered in patients with shock,extensive burns, sepsis, or severe trauma; in any intracranial injury that raisesintracranial pressure; and following intracranial surgery. Those occurring in theproximal duodenum and associated with severe burns or trauma are called Curling ulcers.Gastric, duodenal, and esophageal ulcers arising in patients with intracranial injury,operations, or TABLE 17-3 -- Complications of Peptic Ulcer DiseaseBleeding• Occurs in 15% to 20% of patients• Most frequent complication• May be life-threatening• Accounts for 25% of ulcer deaths• May be the first indication of an ulcerPerforation• Occurs in about 5% of patients• Accounts for two thirds of ulcer deaths• Rarely, is the first indication of an ulcerObstruction from edema or scarring• Occurs in about 2% of patients• Most often due to pyloric channel ulcers• May also occur with duodenal ulcers• Causes incapacitating, crampy abdominal pain• Rarely, may lead to total obstruction with intractable vomiting 820tumors are designated Cushing ulcers and carry a high incidence of perforation.The genesis of the acute mucosal defects in these varied clinical settings is poorlyunderstood. No doubt, many factors are shared with acute gastritis, such as impairedoxygenation. NSAID-induced ulcers are related to decreased prostaglandin productionfrom the inhibition of cyclooxygenase. In the case of lesions associated with intracranialinjury, the proposed mechanism involves the direct stimulation of vagal nuclei byincreased intracranial pressure, leading to hypersecretion of gastric acid, which is
common in these patients. Systemic acidosis, a frequent finding in these clinical settings,may contribute to mucosal injury by lowering the intracellular pH of mucosal cells. Thesecells are also hypoxic as a consequence of stress-induced splanchnic vasoconstriction.Morphology.Acute stress ulcers are usually less than 1 cm in diameter and are circular and small. Theulcer base is frequently stained a dark brown by the acid digestion of extruded blood( Fig. 17-19 ). Unlike chronic peptic ulcers, acute stress ulcers are found anywhere in thestomach, the gastric rugal pattern is essentially normal and the margins and base of theulcers are not indurated. While they may occur singly, more often there are multiplestress ulcers throughout the stomach and duodenum. Microscopically, acute stress ulcersare abrupt lesions, with essentially unremarkable adjacent mucosa. Depending on theduration of the ulceration, there may be a suffusion of blood into the mucosa andsubmucosa and some inflammatory reaction. Conspicuously absent are scarring andthickening of blood vessels, as seen in chronic peptic ulcers. Healing with completereepithelialization occurs after the causative factors are removed. The time required forcomplete healing varies from days to several weeks.Clinical Features.Most critically ill patients admitted to hospital intensive care units develop histologicevidence of gastric mucosal damage. Bleeding from superficial gastric erosions or ulcerssufficient to require transfusion develops in 1% to 4% of these patients. Althoughprophylactic H2 -receptor antagonists and proton pump inhibitors may blunt the impact ofstress ulceration, the single most important determinant ofFigure 17-19 Multiple stress ulcers of the stomach, highlighted by dark digested blood on their surfaces.clinical outcome is the ability to correct the underlying condition(s). The gastric mucosacan recover completely if the patients do not succumb to their primary disease.
Miscellaneous ConditionsGastric dilation may arise from gastric outlet obstruction (e.g., pyloric stenosis) or fromthe functional atony of the stomach and intestines (paralytic ileus) that may develop inpatients with generalized peritonitis. The stomach may contain as much as 10 to 15 L offluid; on rare occasion, gastric rupture may occur. This is a calamitous event followedrapidly by shock or death if not treated immediately. Rarely, spontaneous gastricperforation may occur in the newborn, during labor and delivery, severe vomiting, orcardiopulmonary resuscitation, and following ingestion of extreme amounts ofcarbonated beverages.The stomach has the dubious privilege of being the major site for formation of luminalconcretions of indigestible ingested material. Phytobezoars are derived from plantmaterial, including fibers, leaves, roots, and skins of almost any plant matter.Trichobezoars, better known as "hairballs," consist of ingested hair within a mucoid coatcontaining decaying foodstuff ( Fig. 17-20 ). The dysmotility following partialgastrectomy or partial gastric outlet obstruction is conducive to bezoar formation frommore conventional ingested food. Bizarre bezoars have developed among partakers ofillicit pharmaceuticals, glue swallowers, and children or patients with neuropsychiatricdisorders, who have been known to ingest pins, nails, razor blades, coins, gloves, andeven leather wallets.HYPERTROPHIC GASTROPATHYThis designation includes a group of uncommon conditions, all characterized by giantcerebriform enlargement of the rugal folds of the gastric mucosa ( Fig. 17-21 ). The rugalenlargement is caused by hyperplasia of the mucosal epithelial cells, withoutinflammation. Three variants are recognized: • Ménétrier disease, resulting from profound hyperplasia of the surface mucous cells with accompanying glandular atrophy 821 • Hypertrophic-hypersecretory gastropathy, associated with hyperplasia of the parietal and chief cells within gastric glands • Gastric gland hyperplasia secondary to excessive gastrin secretion, in the setting of a gastrinoma (Zollinger-Ellison syndrome).
Figure 17-20 Trichobezoar, showing agglomeration of hair, food, and mucus that occurred within thegastric lumen.Figure 17-21 Hypertrophic gastropathy, showing markedly thickened gastric folds.All three conditions are of clinical importance for two reasons: (1) they may mimicinfiltrative carcinoma or lymphoma of the stomach on endoscopic and radiographicexaminations; and (2) the enormous increase in acid secretions in hypertrophic-hypersecretory gastropathy and Zollinger-Ellison syndrome places patients at risk forpeptic ulceration. A pure form of parietal cell hypertrophy, without hyperacidity, may
occur in long-term takers of acid secretion inhibitors. Cessation of therapy may cause atransient rebound of excess acid secretion.Ménétrier disease is most often encountered in males (male : female ratio 3 : 1) in thefourth to sixth decade of life but occasionally is seen in children. The etiology of thisdisease is unknown, but a role has been suggested for growth factor overexpression insuperficial gastric epithelium. Transgenic mice with transforming growth factor-α (TGF-α) expressed in the stomach exhibit a disorder clinically and histologically similar tohuman Ménétrier disease. Although the disorder may be asymptomatic, it often producesepigastric discomfort, diarrhea, weight loss, and sometimes bleeding related to superficialrugal erosions. The hypertrophic change may predominantly involve the body-fundus orantrum or may affect the entire stomach. The gastric secretions contain excessive mucusand in many instances little to no hydrochloric acid due to glandular atrophy. In somepatients, there may be sufficient protein loss in the gastric secretions to producehypoalbuminemia and peripheral edema, thus constituting a form of protein-losinggastroenteropathy. Infrequently, the mucosal hyperplasia becomes metaplastic, providinga soil for the development of gastric carcinoma.GASTRIC VARICESGastric varices develop in the setting of portal hypertension but less often thanesophageal varices. Most gastric varices lie within 2 to 3 cm of the gastroesophagealjunction, arising from longitudinally placed submucosal veins. They often appear asmasslike nodular and tortuous winding elevations of the mucosa in the cardia or fundus.Due to their deep submucosal or subserosal location and the normal color of theoverlying mucosa, it may be difficult to distinguish varices from enlarged rugae or evenmalignancy. Since they rarely occur in the absence of esophageal varices, diagnosis canusually be made without resorting to a potentially disastrous biopsy.TumorsAs in the esophagus and intestines, tumors arising from the mucosa predominate overmesenchymal and stromal tumors. These can be classified as benign and malignantlesions.BENIGN TUMORSIn the alimentary tract, the term polyp is applied to any nodule or mass that projectsabove the level of the surrounding mucosa. Use of the term is generally restricted to masslesions arising in the mucosa, although occasionally a submucosal lipoma or leiomyomamay protrude, generating a polypoid lesion. The mucosal polyps are classified as non-neoplastic or neoplastic. Gastric polyps are uncommon. Although they are usually found incidentally, dyspepsia or anemia resulting from blood loss may prompt the searchfor a gastrointestinal lesion.Morphology.
The great majority of gastric polyps (up to 90%) are non-neoplastic and appear to be of ahyperplastic nature. These polyps are composed of a variable mixture of hyperplasticsurface epithelium (foveolar epithelium) and cystically dilated glandular tissue, with alamina propria containing increased inflammatory cells and smooth muscle ( Fig. 17-22 ).The surface epithelium may be regenerative in response to surface erosion andinflammation, but true dysplasia is not present. Most hyperplastic polyps are small andsessile and are commonly located in the antrum; some may approach several centimetersin diameter and have an apparent stalk. In about 20% to 25% of cases multiple polyps,sometimes more than twenty, are observed.The adenoma of the stomach constitutes 5% to 10% of the polypoid lesions in thestomach. By definition, an adenoma contains proliferative dysplastic epithelium andthereby has malignant potential. Adenomatous polyps are much more common in thecolon, and they are described in considerable detail in the discussion of the colon. Gastricadenomas may be sessile (without a stalk) or pedunculated (stalked). The most commonlocation is the antrum. These lesions are usually single, and may grow up to 3 to 4 cm insize before detection ( Fig. 17-23 ). In contrast to the colon, adenomatous change in thestomach may cover a large region of flat gastric mucosa without forming a mass lesion.Other specific types of gastric polyps are relatively uncommon. Among these are fundicgland polyps, 822Figure 17-22 Gastric hyperplastic polyp. Low-power microscopic view of the polyp showing hyperplasticfoveolar epithelium and inflammation.
hamartomatous Peutz-Jeghers polyps, and juvenile polyps. The fundic gland polyp isan innocuous cystic dilation of glands in the oxyntic mucosa. These polyps usually occursporadically, but they can occur in the syndrome of familial adenomatous polyposis(FAP, described later). Curiously, sporadic fundic gland polyps also exhibit mutations inβ-catenin with high frequency. The hamartomatous polyps may occur in isolation, but gastric Peutz-Jeghers polyps are most commonly seen as part of the Peutz-Jegherssyndrome, and gastric juvenile polyps as part of the juvenile polyposis syndrome. All ofthese conditions will be discussed later.The inflammatory fibroid polyp (eosinophilic granuloma) is a striking lesion in that itis a bulky submucosal growth composed of inflamed vascularized fibromuscular tissuewith a prominent eosinophilic infiltrate and a tenuous mucosa stretched over the surface (Fig. 17-24 ). These polyps may occur anywhereFigure 17-23 Gastric adenoma. Gross photograph showing a large polyp in the stomach.in the alimentary tract but are found most frequently in the distal stomach. As theyprotrude into the lumen, they may occlude the pyloric channel and present abruptly asacute gastric outlet obstruction. Their origin is unknown. Whether these are inflammatoryor neoplastic lesions is still debatable.Clinical Features.Hyperplastic polyps are seen most frequently in the setting of chronic gastritis. They areregarded as having no malignant potential as such but are nevertheless found in about20% of stomachs resected for carcinoma. This is attributed to the tendency of chronicallyinflamed gastric mucosa both to form hyperplastic polyps and to develop intomalignancy.As with the colonic counterpart, the incidence of gastric adenomas increases with age,particularly into and beyond the seventh decade of life. The male-to-female ratio is 2:1.
Up to 40% of gastric adenomas contain a focus of carcinoma at the time of diagnosis,particularly the larger lesions. The risk of cancer in the adjacent gastric mucosa may be ashigh as 30%. Unlike colonic adenomas, which usually arise from apparently normalmucosa, the usual substratum for gastric adenomas is chronic gastritis with intestinalmetaplasia. Autoimmune gastritis can also lead to gastric adenoma formation.Otherwise innocuous hyperplastic polyps may occasionally harbor foci of adenomatousepithelium. As non-neoplastic and adenomatous polyps cannot reliably be distinguishedendoscopically, histologic examination of gastric polyps is mandatory.GASTRIC CARCINOMACarcinoma is the most important and the most common (90% to 95%) of malignanttumors of the stomach. Next in order of frequency are lymphomas (4%), carcinoids (3%),and mesenchymal tumors (2%), which include gastrointestinal stromal tumors,leiomyosarcoma, and schwannoma.Epidemiology.Gastric carcinoma is the second most common tumor in the world. Its incidence,however, varies widely, being particularly high in countries such as Japan, Chile, CostaRica, Colombia, China, Portugal, Russia, and Bulgaria,Figure 17-24 Inflammatory fibroid polyp; microscopic photograph showing submucosal growth ofinflamed vascularized fibromuscular tissue with prominent eosinophilic infiltrate. 823and fourfold to sixfold less common in the United States, the United Kingdom, Canada,Australia, New Zealand, France, and Sweden. It is more common in lower socioeconomicgroups and exhibits a male-to-female ratio of about 2:1. In most countries, there has been
a steady decline in both the incidence and the mortality of gastric cancer over the past sixdecades. In 1930, gastric cancer was the most common cause of cancer death in theUnited States. Between 1930 and 1998, the annual mortality rate in the United Statesdropped from about 38 to 5 per 100,000 for men, and from 28 to 3 per 100,000 forwomen. Yet it causes 2.5% of all cancer deaths in the United States and is the leading cause of cancer death worldwide. Although five-year survival rates have improved sincethe advent of endoscopy in the 1960s, they remain poor (about 20% in the United States).There are several classification systems for gastric carcinoma. The most commonly usedare the Laurén and the World Health Organization (WHO) classifications. In 1965,Laurén classified gastric carcinoma into two subtypes: those exhibiting an intestinalmorphology with the formation of bulky tumors composed of glandular structures andthose with diffuse, infiltrative growth of poorly differentiated discohesive malignant cells.The intestinal and diffuse sub-types appear to have a different pathogenetic basis. Theintestinal type predominates in high-risk areas, and develops from precursor lesions. Bycontrast, the incidence of the diffuse type is relatively constant, and the tumors have noidentifiable precursor lesions. The intestinal type exhibits a mean age of incidence of 55years and a male-to-female ratio of 2:1. Diffuse gastric cancer occurs in slightly youngerpatients (mean age, 48), with an approximately equal male-to-female ratio. Although theintestinal type was far more common, the drop in incidence of gastric cancer has occurredonly for this type. As a consequence, the incidence of intestinal and diffuse cancer is nowapproximately the same. The WHO classification system has been in use since 1977, isrelatively simple, and has gained wide acceptance. It classifies the tumor based onhistologic appearance alone ( Table 17-4 ).Pathogenesis.The major factors thought to affect the genesis of gastric cancer are summarized in Table17-5 . They apply more to the intestinal type, as the risk factors for diffuse gastric cancerare not as well defined.Helicobacter pylori Infection.Chronic infection with H. pylori generally increases the risk for developing gastriccarcinoma by five- to six-fold. The bacterial infection causes chronic gastritis, followedby atrophy, intestinal metaplasia, dysplasia, and carcinoma. The sequential alterations depend on both the presence of bacterial proteins and the host immune response; thelatter is influenced by the host genetic background. In particular, long-standing mucosalinflammation reduces acid secretion (hypochlorhydria) and pepsin secretion. This favorsbacterial growth and perpetuation of chronic inflammation, sustained mucosal epithelialcell proliferation, and hence increased risk of genomic mutation. The increased oxidativestress further promotes DNA damage. However, the vast majority of individuals infectedwith H. pylori will not develop cancer and not all H. pylori infections increase the risk ofcancer. Therefore, other factors must be involved in tumorigenesis. The risk for tumordevelopment is greatly increased in patients in whom mucosal inflammation progressesto multifocal mucosal atrophy and intestinal metaplasia. Dysplasia of the gastric mucosais the final common
TABLE 17-4 -- WHO Histologic Classification of Gastric TumorsEpithelial TumorsIntraepithelial neoplasia: adenomaAdenocarcinoma *• Papillary adenocarcinoma • Tubular adenocarcinoma • Mucinous adenocarcinoma • Signet-ring cell carcinoma • Undifferentiated carcinoma • Adenosquamous carcinoma Small-cell carcinomaCarcinoid tumorNonepithelial TumorsLeiomyomaSchwannomaGranular cell tumorLeiomyosarcomaGastrointestinal stromal tumor (GIST) (gradation from benign to malignant)Kaposi sarcomaOthersMalignant Lymphoma* The Laurén classification subdivides adenocarcinomas into intestinal and diffuse types.pathway by which intestinal-type gastric cancers develop. Adenomas containing mucosaldysplasia can also become malignant.Environment.Environmental influences may be critical in gastric carcinogenesis. When familiesmigrate from high-risk to low-risk areas (or the reverse), successive generations acquirethe level of risk that prevails in the new locales. The diet
TABLE 17-5 -- Factors Associated with Increased Incidence of Gastric CarcinomaEnvironmental FactorsInfection by H. pylori• Present in most cases of intestinal-type carcinomaDiet• Nitrites derived from nitrates (water, preserved food)• Smoked and salted foods, pickled vegetables, chili peppers• Lack of fresh fruit and vegetablesLow socioeconomic statusCigarette smokingHost FactorsChronic gastritis• Hypochlorhydria: favors colonization with H. pylori• Intestinal metaplasia is a precursor lesionPartial gastrectomy• Favors reflux of bilious, alkaline intestinal fluidGastric adenomas• 40% harbor cancer at time of diagnosis• 30% have adjacent cancer at time of diagnosisBarrett esophagus• Increased risk of gastroesophageal junction tumorsGenetic FactorsSlightly increased risk with blood group AFamily history of gastric cancerHereditary nonpolyposis colon cancer syndromeFamilial gastric carcinoma syndrome (E-cadherin mutation) 824
is suspected to be a primary factor, and adherence to certain culinary practices isassociated with a high risk of gastric carcinoma. Lack of refrigeration; consumption ofpreserved, smoked, cured, and salted foods; water contamination with nitrates; and lackof fresh fruit and vegetables are common themes in high-risk areas. The consumption ofdietary carcinogens, such as N-nitroso compounds and benzopyrene, appears to beparticularly important. Conversely, intake of green, leafy vegetables and citrus fruits,which contain antioxidants such as ascorbate (vitamin C), alpha-tocopherol (vitamin E),and beta-carotene, is negatively correlated with gastric cancer. A specific protective rolefor any one of these nutrients cannot be assumed, however, since intake of fresh foodmay simply displace consumption of preserved foods.So far there is no conclusive evidence linking alcohol intake and cigarette smoking to thedevelopment of gastric cancer. Despite initial concern, to date there appears to be noincreased risk of stomach cancer from the use of antacid drug therapies.Host.Autoimmune gastritis, like H. pylori infection, increases the risk of gastric cancer,presumably due to chronic inflammation and intestinal metaplasia. It has been noted thatblood group A patients have higher risk but it is not yet clear whether this is related to thebinding of H. pylori to Lewis B antigen, or to other mechanisms.Within the United States, blacks, Native Americans, and Hawaiians have a higher risk ofdeveloping gastric cancer. But since only about 8% to 10% of patients with gastric cancerhave a family history of this disease, genetic factors are unlikely to be a major influence.Environmental factors mentioned above, are likely to play a major role in the higherincidence of gastric cancer among these various groups. Genetic traits play a critical rolein some familial cases of gastric cancer, including gastric carcinoma occurring in thehereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Recently, E-cadheringene (CDH1) germ-line mutations have also been identified as the underlying geneticbasis for another familial gastric cancer syndrome that is characterized by earlyoccurrence of diffuse type adenocarcinoma. These patients are also at risk for developing lobular breast cancer. Other Risk Factors.Peptic ulcer disease per se does not impart increased risk for development of gastriccancer. However,
Figure 17-25 Diagram of growth patterns and spread of gastric carcinoma. In early gastric carcinoma (A),the tumor is confined to the mucosa and submucosa and may exhibit an exophytic, flat or depressed, orexcavated conformation. Advanced gastric carcinoma (B) extends into the muscularis propria and beyond.Linitis plastica is an extreme form of flat or depressed advanced gastric carcinoma.patients who have had partial gastrectomies for peptic ulcer disease have a slightlyhigher risk of gastric cancer in the residual gastric stump, attributed to thehypochlorhydria, bile reflux, and chronic gastritis that occur in the post-gastrectomystate. Ménétrier disease is also a risk factor for gastric carcinoma.Multiple genetic alterations have been described in gastric cancers, mostly in studiesinvolving intestinal-type cancers. Among these are allelic losses in various chromosomalloci, and microsatellite instability in several genes including TGFβRII, BAX and IGFRII. Moreover, p53 mutations are present in a majority of tumors, and abnormalities in  E-cadherin expression are quite frequent. Nevertheless, it has not been possible so far todefine a clear sequence of events in gastric tumorigenesis. It appears that intestinal anddiffuse gastric cancers may develop through different genetic pathways.Morphology.The location of gastric carcinomas within the stomach is as follows: pylorus and antrum,50% to 60%; cardia, 25%; with the remainder in the body and fundus. The lessercurvature is involved in about 40% and the greater curvature in 12%. Thus, a favoredlocation is the lesser curvature of the antropyloric region. Although less common, anulcerative lesion on the greater curvature is more likely to be malignant.Gastric carcinoma is classified on the basis of: (1) depth of invasion; (2) macroscopicgrowth pattern; and (3) histologic subtype. The morphologic feature having thegreatest impact on clinical outcome is the depth of invasion. Early gastric carcinomais defined as a lesion confined to the mucosa and submucosa, regardless of thepresence or absence of perigastric lymph node metastases. Some early tumors coverlarge areas of the gastric mucosa (up to 10 cm in diameter) and yet show no invasion intothe muscular wall. Early gastric carcinoma is not synonymous with carcinoma in situ, as
the latter is confined to the surface epithelial layer. Advanced gastric carcinoma is aneoplasm that has extended below the submucosa into the muscular wall and hasperhaps spread 825Figure 17-26 Gastric carcinoma. Gross photograph showing an ill-defined, excavated central ulcersurrounded by irregular, heaped-up borders.more widely. All cancers presumably begin as "early" lesions, which develop over timeinto "advanced" lesions.The three macroscopic growth patterns of gastric carcinoma, which may be evident atboth the early and advanced stages, are: (1) exophytic, with protrusion of a tumor massinto the lumen; (2) flat or depressed, in which there is no obvious tumor mass within themucosa; and (3) excavated, whereby a shallow or deeply erosive crater is present in thewall of the stomach ( Fig. 17-25 ). Exophytic tumors are readily identified byradiographic techniques and at endoscopy and may contain portions of an adenoma. Incontrast, flat or depressed malignancy may not be apparent to even the experienced eye,except as regional effacement of the normal surface mucosal pattern. Excavated cancersmay closely mimic, in size and appearance, chronic peptic ulcers. In advanced cases,cancerous craters can be identified by their heaped-up, beaded margins and shaggy,necrotic bases, as well as by the overt neoplastic tissue extending into the surroundingmucosa and wall ( Fig. 17-26 ). Uncommonly,
Figure 17-27 Gastric carcinoma. A, Intestinal type demonstrating gland formation by malignant cells,which are invading the muscular wall of the stomach. B, Diffuse type demonstrating signet-ring carcinomacells.a broad region of the gastric wall or the entire stomach is extensively infiltrated bymalignancy, creating a rigid, thickened "leather bottle," termed linitis plastica.Metastatic carcinoma, from the breast and lung, may generate a similar picture.The histologic subtypes of gastric cancer have been variously subclassified, but the twomost important types, as noted earlier, are the intestinal type and diffuse type of theLauren classification ( Fig. 17-27 ). The intestinal variant is composed of neoplasticintestinal glands resembling those of colonic adenocarcinoma (see Fig. 17-27A ), whichpermeate the gastric wall but tend to grow along broad cohesive fronts in an "expanding"growth pattern. The neoplastic cells often contain apical mucin vacuoles, and abundantmucin may be present in gland lumens. The diffuse variant is composed of gastric-typemucous cells, which generally do not form glands, but rather permeate the mucosa andwall as scattered individual cells or small clusters in an "infiltrative" growth pattern.These cells appear to arise from the middle layer of the mucosa, and the presence ofintestinal metaplasia is not a prerequisite. In this variant, mucin formation expands themalignant cells and pushes the nucleus to the periphery, creating a "signet ring"conformation (see Fig. 17-27B ). If the signet-ring cells are more than 50% of the tumor,the tumor is classified as signet-ring cell carcinoma under the WHO classification.Regardless of cell type, the amount of mucin formation varies, and in poorlydifferentiated portions of the tumor it may be absent. Conversely, excessive mucinproduction may generate large mucinous lakes that dissect tissue planes; isolated tumorcells or glands may be difficult to identify in such areas. Infiltrative tumors often evoke astrong mural desmoplastic reaction, in which the scattered cells are embedded; thefibrosis creates local rigidity of the wall, which provides a valuable clue to the presenceof an infiltrative lesion.Whatever the classification and variant, all gastric carcinomas eventually penetrate thewall to involve the serosa and spread to regional and more distant lymph nodes. For
obscure reasons, gastric carcinomas frequently metastasize to the supraclavicular sentinel(Virchow) node as the first clinical manifestation of an 826occult neoplasm. The tumor can also metastasize to the periumbilical region to form asubcutaneous nodule. This nodule is called a Sister Mary Joseph nodule, after the nunwho noted this lesion as a marker of metastatic carcinoma. Local invasion of gastriccarcinoma into the duodenum, pancreas, and retroperitoneum also is characteristic. At thetime of death, widespread peritoneal seeding and metastases to the liver and lungs arecommon. A notable site of visceral metastasis is to one or both ovaries. Althoughuncommon, metastatic adenocarcinoma to the ovaries (from stomach, breast, pancreas,and even gallbladder) is so distinctive as to be called Krukenberg tumor.Clinical Features.Gastric carcinoma is an insidious disease that is generally asymptomatic until late in itscourse. The symptoms include weight loss, abdominal pain, anorexia, vomiting, alteredbowel habits, and less frequently dysphagia, anemic symptoms, and hemorrhage. Asthese symptoms are essentially nonspecific, early detection of gastric cancer is difficult.The proportion of cancers diagnosed as early gastric carcinoma clearly depends on theintensity of the diagnostic effort to uncover asymptomatic disease. In Japan, where massendoscopy screening programs are in place, early gastric cancer constitutes about 35% ofall newly diagnosed gastric cancers. In Europe and the United States, this figure hasremained at 10% to 15% over several decades.The prognosis for gastric carcinoma depends primarily on the depth of invasion and theextent of nodal and distant metastasis at the time of diagnosis; histologic type hasminimal independent prognostic significance. The prognostic value of biomarkers such asp53 mutation and c-ERB-B2 amplification remains to be determined. Clinical prognosisof gastric cancer largely depends on the depth of tumor invasion and the presence orabsence of nodal or visceral metastasis. Surgical resection is still the standard treatmentoption, without or with adjuvant chemotherapy and radiation. The five-year survival rateof surgically treated early gastric cancer is 90% to 95%, with only a small negativeincrement if lymph node metastases are present. In contrast, the five-year survival rate foradvanced gastric cancer remains below 15%.LESS COMMON GASTRIC TUMORSGastric Lymphoma.Gastric lymphomas represent 5% of all gastric malignancies. However, the stomach is themost common site for extranodal lymphoma (20% of such cases). Nearly all gastriclymphomas are B-cell lymphomas of mucosa-associated lymphoid tissue (MALTlymphomas). Nodal-type lymphomas that may develop in the stomach are unrelated toMALT lymphomas and similar to lymphomas originating in lymph nodes (discussed inChapter 14 ). While some gastric lymphomas appear to arise de novo, the majority
(>80%) are associated with chronic gastritis and H. pylori infection. The role of H. pyloriinfection as an important etiologic factor for gastric lymphoma is supported by theelimination of about 50% of gastric lymphomas with antibiotic treatment for H. pylori.Tumors that do not regress with this type of treatment usually contain geneticabnormalities, particularly Trisomy 3 and t(11;18) translocation. This translocation bringstogether the API2 (apoptosis-inhibitor 2) gene on chromosome 11 with the MLT (mutatedin MALT lymphoma) gene on chromosome 18. The protein encoded by the fused genesis thought to inhibit apoptosis, but its precise contribution to the development of MALTlymphoma remains to be established.Morphology.Gastric lymphoma commonly occurs in the mucosa or superficial submucosa. In theMALT lymphoma, a monomorphic lymphocytic infiltrate of the lamina propria surroundsgastric glands massively infiltrated with atypical lymphocytes and undergoing destruction(the "lymphoid epithelioid" lesion; Fig. 17-28 ). These gut-type lymphomas are usuallyCD5, CD10, and CD23 negative. In contrast, nodal-type lymphomas exhibit featurescharacteristic of lymphomas arising de novo in lymph nodes, with frequently positiveimmunoreactivity for CD5, GYCLIN D1, CD10, or BCL-2. Rarely, Burkitt lymphoma,AIDS-associated lymphoma, and Hodgkin lymphoma may occur in the stomach.Gastrointestinal Stromal Tumor.A wide variety of mesenchymal neoplasms may arise in the stomach. Those originatingin nerve sheaths are known as schwannomas. All of these tumors are rare. Much morecommon are gastrointestinal stromal tumors, also called GISTs. It is thought that GISTsoriginate from the interstitial cells of Cajal, which control gastrointestinal peristalsis.These tumors have a special phenotype in that 95% of them stain with antibodies againstc-KIT, and approximately 70% stain for CD34. Despite these phenotypic similarities,GISTs show different histological patterns, and can be sub-classified into spindle andepithelioid types. Tumors that show features of enteric plexus differentiation (calledgastrointestinal autonomic nerve tumors or GANTs) are often classified among GISTs.On rare occasions, gastric GISTs occur as part of a tumor syndrome, such as Carneystriad (gastric GIST, paraganglioma and pulmonary chondroma), or neurofibromatosistype 1.Morphology.GISTs can be solitary or multiple. The tumor can protrude into the lumen with anoverlying attenuated mucosa or extrude on the serosal side of
Figure 17-28 Gastric MALT lymphoma. Note the lymphoepithelial lesions (arrows). (Courtesy of Dr.Melissa Li, University of Florida, Gainesville, FL.) 827Figure 17-29 Gastrointestinal stromal tumor. A, Gross photograph of the tumor arising from the muscularispropria of the gastric wall. B, Microscopic view of the tumor showing spindle cell feature. C,
Immunohistochemical stain showing the tumor cell c-KIT positivity.the gastric wall ( Fig. 17-29A ). The cut surface of the tumor is tan and usually lacks thewhirling smooth muscle pattern of leiomyomas or leiomyosarcomas. It varies fromslightly firm to soft, and hemorrhagic changes are common. Necrosis or cystic changescan be seen in a large tumor. Microscopically, the tumor can exhibit spindle cells ( Fig.17-29B ), plump "epithelioid" cells, or a mixture of both. Most of the tumors are quitecellular, and mitotic activity is variable. The majority of the tumor cells are positivefor c-KIT (CD117), as demonstrated by positive immunohistochemical staining ( Fig.17-29C ).Pathogenesis.The identification of c-KIT mutations and platelet-derived growth factor receptor-α(PDGFRA) mutations in these tumors constitute significant progress in understanding thepathogenesis of GISTs. c-KIT is the receptor for stem cell factor, and PDGFRA is a  receptor for platelet-derived growth factor (PDGF). It is known that 85% of GISTs havec-KIT mutations and 35% of GISTs with normal c-KIT contain PDGFRA mutations. Both c-KIT and PDGFRA have cytoplasmic tyrosine kinases that activate similarintracellular pathways. The mutations lead to constitutive activation of the tyrosine kinasesignaling pathway, promoting cell proliferation and inhibiting apoptosis. c-KIT mutationsand PDGFRA mutations appear to be mutually exclusive.Based on these pathogenic insights, a newly designed tyrosine kinase inhibitor (STI571)has been shown to be effective against this tumor. Recall that this drug is used to treat chronic myeloid leukemia, also associated with abnormal tyrosine kinase activity( Chapter 14 ). Currently, STI571 is widely used as an agent to treat GISTs; thisdemonstrates the application of a targeted therapeutic approach to the treatment of humanmalignancies.Gastric Neuroendocrine Cell (Carcinoid) Tumors.Most gastric carcinoid tumors originate from the ECL cells in the oxyntic mucosa. Thetumor can arise in the setting of chronic atrophic gastritis or multiple endocrine neoplasiatype 1 (MEN1) and Zollinger-Ellison syndrome. The underlying pathogenesis is probablyrelated to the hypergastrinemic state, resulting in ECL cell hyperplasia, a presumedpretumorous condition. Less common is the sporadic gastric carcinoid without ahypergastrinemic state, for which the pathogenesis is not known. Gastric carcinoidtumors exhibit similar histologic features to other carcinoid tumors. The clinical course isquite variable. To date, there are no reliable pathologic markers to predict the tumorbehavior.Lipomas.Lipomas are a benign neoplasm of adipose tissue, usually present in the submucosa.Metastatic Cancer.
Metastatic involvement of the stomach is unusual. The most common sources of gastricmetastases are systemic lymphomas. Metastases of malignant melanoma and carcinomastend to be multiple and may develop central ulceration. Breast and lung carcinoma maymimic diffuse gastric carcinoma by diffusely infiltrating the gastric wall to generatelinitis plastica, as described earlier for primary gastric carcinoma. 828Small and Large IntestinesNormalAnatomyThe small intestine in the human adult is approximately 6 meters in length, and the colon(large intestine) approximately 1.5 meters. The first 25 cm of the small intestine, theduodenum, are retroperitoneal; the jejunum marks the entry of the small intestine into theperitoneal cavity, terminating where the ileum enters the colon at the ileocecal valve. Thedemarcation between jejunum and ileum is not clearly defined; the jejunum arbitrarilyconstitutes the proximal third of the intraperitoneal portion and the ileum the remainder.The colon is subdivided into the cecum and the ascending, transverse, and descendingcolon. The sigmoid colon begins at the pelvic brim and loops within the peritoneal cavity,becoming the rectum at about the level of the third sacral vertebra. Halfway along its 15-cm length, the rectum passes between the crura of the peroneal muscles to becomeextraperitoneal. The reflection of the peritoneum from the rectum over the pelvic floorcreates a cul de sac known as the pouch of Douglas.VasculatureThe arterial supply of the intestine, from the proximal jejunum to the hepatic flexure ofthe colon, is derived from the superior mesenteric artery. The inferior mesenteric arteryfeeds the remainder of the colon to the level of the rectum. Each artery progressivelydivides as it approaches the gut, with rich arterial interconnections via arching mesentericarcades. Numerous
Figure 17-30 A, Normal small-bowel histology, showing mucosal villi and crypts, lined by columnar cells.B, Normal colon histology, showing flat mucosal surface and abundant vertically oriented crypts.collaterals connect the mesenteric circulation with the celiac arterial axis proximally andthe pudendal circulation distally. The lymphatic drainage essentially parallels thevascular supply but does not have the intricate patterns of arcades.The upper rectum is supplied by the superior hemorrhoidal branch of the inferiormesenteric artery. The lower portion receives its blood supply from the hemorrhoidalbranches of the internal iliac or internal pudendal artery. The venous drainage followsessentially the same distribution and is connected by an anastomotic capillary bedbetween the superior and inferior hemorrhoidal veins, providing a connection betweenthe portal and systemic venous systems. Since the colon is a retroperitoneal organ in theascending and descending portions, it derives considerable accessory arterial bloodsupply and lymphatic drainage from a wide area of the posterior abdominal wall.Small Intestinal MucosaThe most distinctive feature of the small intestine is its mucosal lining, which is studdedwith innumerable villi ( Fig. 17-30A ). These extend into the lumen as finger-likeprojections covered by epithelial lining cells. The central core of lamina propria containsblood vessels, lymphatics, a minimal population of lymphocytes, eosinophils and mastcells, and scattered fibroblasts and vertically oriented smooth muscle cells. Between thebases of the villi are the pitlike crypts of Lieberkühn, which contain stem cells thatreplenish and regenerate the epithelium. The crypts extend down to the muscularismucosa. The muscularis mucosa is a smooth, continuous sheet, serving to anchor theconfiguration of villi and
829crypts alike. In normal individuals, the villus-to-crypt height ratio is about 4 to 5:1.Within the duodenum are abundant submucosal mucous glands, termed Brunner glands.These glands secrete bicarbonate ions, glycoproteins, and pepsinogen II and are virtuallyindistinguishable from the pyloric mucous glands.The surface epithelium of the villi contains three cell types. Columnar absorptive cellsare recognized by the dense array of microvilli on their luminal surface (the brush border)and the underlying mat of microfilaments (the terminal web). Interspersed regularlybetween the absorptive cells are mucin-secreting goblet cells and a few endocrine cells,described below. Within the crypts reside stem cells, goblet cells, more abundantendocrine cells, and scattered Paneth cells. Paneth cells have apically oriented brighteosinophilic granules containing a variety of antimicrobial proteins (such as defensins),which play a role in mucosal innate immunity against bacterial infection. The villi of the small intestinal mucosa are the site for terminal digestion and absorptionof foodstuffs through the action of the columnar absorptive cells. The crypts secrete ionsand water, deliver immunoglobulin A (IgA) and antimicrobial peptides to the lumen, andserve as the site for cell division and renewal. The mucous cells of both crypts and villigenerate an adherent mucous coat, which both protects the surface epithelium andprovides an ideal local milieu for uptake of nutrients. Specific receptors for uptake ofmacromolecules are also present on the surface epithelial cells, such as those in the ileumfor intrinsic factor-vitamin B12 complexes.Colonic MucosaThe small intestine accomplishes its absorptive function with a highly liquid luminalstream. The function of the colon is to reclaim luminal water and electrolytes. Unlike themucosa of the small intestine, the colonic mucosa has no villi and is flat. The mucosa ispunctuated by numerous straight tubular crypts that extend down to the muscularismucosa ( Fig. 17-30B ). The surface epithelium is composed of columnar absorptivecells, which have shorter and less abundant microvilli than found in the small intestine,and goblet mucous cells. The crypts contain abundant goblet cells, endocrine cells, andstem cells. Paneth cells are occasionally present at the base of crypts in the cecum andascending colon. The intestinal mucosa, particularly in the ileum, is colonized byendogenous bacteria, particularly non-pathogenic strains of E. coli and organisms such asProteus, Enterobacter, Serratia and Klebsiella. The components of the endogenous floramay be displaced by exogenous bacteria, such as pathogenic strains of E. coli that causedamage to the mucosa.The regenerative capacity of the intestinal epithelium is remarkable. Cellular proliferationis confined to the crypts; differentiation and luminal migration serve to replenishsuperficial cells lost to senescence and surface abrasion. Within the small intestine, cellsmigrate out of the crypts and upward to the tips of the villi, where they are shed into thelumen. This journey normally takes between 96 and 144 hours, leading to normal renewalof the epithelial lining every 4 to 6 days. Turnover of the colonic surface epithelium takes
3 to 8 days. The rapid renewal of intestinal epithelium provides a remarkable capacity forrepair but also renders the intestine particularly vulnerable to agents that interfere withcell replication, such as radiation and chemotherapy for cancer.Endocrine CellsA diverse population of endocrine cells is scattered among the epithelial cells lining thegastric glands, small intestinal villi, and small and large intestinal crypts. Comparablecells are present in the epithelia lining the pancreas, biliary tree, lung, thyroid, andurethra. As a population, gut endocrine cells exhibit characteristic morphologic features.In most cells, the cytoplasm contains abundant fine eosinophilic granules, which harborsecretory products. The main portion of the cell is at the base of the epithelium, and thenuclei reside on the luminal side of the cytoplasmic granules.These cells exhibit a marked diversity of secretory peptides and distribution of cellsubtypes. Secretory granules are released at the basal surface of the endocrine cell oralong the basal part of its lateral surface; apical secretion (into the lumen) has not beenobserved. The various secretory products, some of which are also present in the muralautonomic neural plexus, act as chemical messengers and modulate normal digestivefunctions by a combination of endocrine, paracrine, and neurocrine mechanisms. Eachendocrine cell type, therefore, exhibits a distribution tailored to meet the physiologicneeds pertinent to a gut segment.Intestinal Immune SystemHumans are exposed to an enormous load of environmental antigens through thegastrointestinal tract. The surface area of the gastrointestinal tract through which ingestedantigens may enter far exceeds that of the skin and pulmonary tract. The immune systemmust balance tolerance of harmless ingested substances against active defense reactionsto potential microbial invaders. Dysfunction of this regulatory machinery may causesmoldering chronic disease and, occasionally, life-threatening acute conditions.Throughout the small intestine and colon are nodules of lymphoid tissue, which lie eitherwithin the mucosa or span the mucosa and a portion of the submucosa. The lymphoid nodules distort the surface epithelium to produce broad domes rather than villi; within theileum confluent lymphoid tissue becomes macroscopically visible as Peyer patches. Thesurface epithelium over lymphoid nodules contains both columnar absorptive cells and M(membranous) cells, the latter found only in small and large intestinal lymphoid sites. M
cells are able to transcytose antigenic macromolecules intact from the lumen to antigen-presenting cells under the surface epithelium. Antigen-presenting cells includemacrophages and dendritic cells. Throughout the intestines, T lymphocytes are scatteredwithin the surface epithelium, usually at the basolateral aspects of the cell. These T cellsare referred to as intraepithelial lymphocytes and include cytotoxic CD8+ cells. Thelamina propria contains helper T cells (CD4+), activated B cells, and plasma cells. Thelamina propria plasma cells secrete dimeric IgA, IgG, and IgM, which enter into thesplanchnic circulation. IgA is transcytosed directly across enterocytes or acrosshepatocytes for secretion into bile; both are mechanisms for delivering IgA to 830the intestinal lumen. The intestinal lymphoid nodules, mucosal lymphocytes, and isolatedlymphoid follicles in the appendix and mesenteric lymph nodes constitute the MALT,mentioned in the discussion of gastric tumors.Neuromuscular FunctionSmall intestinal peristalsis, both anterograde and retrograde, mixes the food stream andpromotes maximal contact of nutrients with the mucosa. Colonic peristalsis prolongscontact of the luminal contents with the mucosa. Although intestinal smooth muscle cellsare capable of initiating contractions, both small and large intestinal peristalsis ismediated by intrinsic (myenteric plexus) and extrinsic (autonomic innervation) neuralcontrol. The myenteric plexus consists of two neural networks: Meissner plexus resides atthe base of the submucosa, and Auerbach plexus lies between the inner circumferentialand outer longitudinal muscle layers of the muscle wall; lesser neural twigs extendbetween smooth muscle cells and ramify within the submucosa.PathologyMany conditions, such as infections, inflammatory diseases, motility disorders, andtumors, affect both the small and large intestines. These two organs will therefore beconsidered together. Collectively, disorders of the intestines account for a large portion ofhuman disease.Congenital AnomaliesRare anomalies of gut formation may occur. • Duplication of the small intestine or colon, usually in the form of saccular to long, cystic structures
• Malrotation of the entire bowel, resulting from improper embryologic rotation of the gut • Omphalocele, in which the abdominal musculature fails to form, leading to birth of an infant with herniation of abdominal contents into a ventral membranous sac • Gastroschisis, in which a portion of the abdominal wall fails to form altogether, causing extrusion of the intestines.The above lesions may be silent (malrotation) or catastrophic (gastroschisis). A far morecommon and innocuous lesion is heterotopia of normal pancreatic tissue but occasionallyof gastric mucosa. Both heterotopias may occur anywhere in the intestine and usually aresmall, 1- to 2-cm nodules in the mucosa or intestinal wall.ATRESIA AND STENOSISCongenital intestinal obstruction is an uncommon but dramatic lesion that may affect anylevel of the intestines. Duodenal atresia is most common; the jejunum and ileum areequally involved, but the colon is not involved. The obstruction may be complete(atresia) or incomplete (stenosis). Atresia may take the form of an imperforate mucosaldiaphragm or a stringlike segment of bowel connecting intact proximal and distalintestine. Stenosis is less common and is due to a narrowed intestinal segment or adiaphragm with a narrow central opening. Single or multiple lesions appear to arise fromdevelopmental failure, intrauterine vascular accidents, or intussusceptions (telescoping ofone intestinal segment within another) occurring after the intestine has developed. Failureof the cloacal diaphragm to rupture leads to an imperforate anus.MECKEL DIVERTICULUMFailure of involution of the vitelline duct, which connects the lumen of the developinggut to the yolk sac, produces a Meckel diverticulum. This solitary diverticulum lies on theantimesenteric side of the bowel, usually within 2 feet (85 cm) of the ileocecal valve( Fig. 17-31 ). This is a true diverticulum, in that it contains all three layers of the normalbowel wall: mucosa, submucosa, and muscularis propria. Meckel diverticula may takethe form of only a small pouch, or of a blind segment having a lumen greater in diameterthan that of the ileum and a length of up to 6 cm. Although the mucosal lining may bethat of normal small intestine, heterotopic rests of gastric mucosa or pancreatic tissueare found in about one half of these anomalies. Meckel diverticula are present in anestimated 2% of the normal population, but most remain asymptomatic or are discoveredincidentally. When peptic ulceration occurs in the small intestinal mucosa adjacent to thegastric mucosa, intestinal bleeding or symptoms resembling those of an acuteappendicitis may result. Alternatively, presenting symptoms may be related tointussusception, incarceration, or perforation.CONGENITAL AGANGLIONIC MEGACOLON—HIRSCHSPRUNG DISEASEHirschsprung disease is a congenital disorder characterized by aganglionosis of a portionof the intestinal tract. The enteric neuronal plexus develops from neural crest cells, which
migrate into the bowel wall during development, mostly in a cephalad to caudaddirection. Congenital megacolon, orFigure 17-31 Meckel diverticulum. The blind pouch is located on the antimesenteric side of the smallbowel. 831Hirschsprung disease, results when the migration of neural crest cells arrests at somepoint before reaching the anus or when the ganglion cells undergo inappropriatepremature death. This produces an intestinal segment that lacks both Meissner submucosal and Auerbach myenteric plexuses. Depending on the severity of migrationarrest, a variable length of the distal gut is not innervated. Loss of enteric neuralcoordination leads to functional obstruction and intestinal dilation proximal to theaffected segment. Note that the dilated segment may contain normal ganglia; ganglia areabsent or nearly so in the contracted region.The cause of the developmental failure is unclear, but at least eight susceptibility geneshave been identified. Mutations in these genes are associated with varying degrees ofintestinal aganglionosis and other congenital anomalies. The phenotypic expression(penetrance) among these gene mutations varies. The long-segment and short-segmentdisease (see explanation under "Morphology") appear to have different modes ofinheritance. About 50% of familial cases and approximately 15% of sporadic cases   are a consequence of mutations in the RET gene ( Chapter 7 ) that inactivate the kinaseactivity of this receptor. A much smaller proportion of cases (3%–5%) may be caused bymutations in the endothelin/endothelin-receptor system. RET and its ligands (members ofthe Glial-Derived Neurotrophic Factor family) promote survival and growth of neurites,and provide direction to migrating neural crest cells. The endothelin system participatesin the regulation of morphogenesis during embryonic development. Despite theidentification of the involvement of these and other genes in Hirschprung diseasepathogenesis, the genetic defect is unknown in a large number of cases.
Morphology.Hirschsprung disease is characterized by the absence of ganglion cells and ganglia inthe muscle wall and submucosa of the affected segment. The rectum is alwaysaffected, with involvement of more proximal colon to variable extent. Most cases involvethe rectum and sigmoid only (short-segment disease), with longer segments in a fifth ofcases, and rarely the entire colon (long-segment disease). Absence of mural ganglioncells is sometimes accompanied by thickening and hypertrophy of nonmyelinated nervefibers, representing ramifications of the lumbosacral preganglionic fibers. Proximal tothe aganglionic segment, the colon undergoes progressive dilation and hypertrophy,beginning with the descending colon. With time, the proximal innervated colon maybecome massively distended, sometimes achieving a diameter of 15 to 20 cm(megacolon). When distention outruns the hypertrophy, the colonic wall becomesmarkedly thinned and may rupture, usually near the cecum. Mucosal inflammation orshallow, so-called stercoral ulcers may appear. Unequivocal diagnosis of Hirschsprungdisease can be made histologically by the failure to detect ganglion cells in intestinalsubmucosa samples stained for acetylcholinesterase.Clinical Features.Hirschsprung disease occurs in approximately 1 out of 5,000 live births and is presentwith increased frequency (3.6%) in siblings of index cases. Males predominate 4:1.Short-segment aganglionosis with megacolon is more common in males, whereas femalespredominate among patients with long affected segments. Ten percent of all cases ofHirschsprung disease occur in children with Down syndrome, and serious neurologicabnormalities are present in another 5%, raising the possibility that this disease is onlyone feature of more generalized abnormal development of the neural crest.  Hirschsprung disease usually manifests itself in the immediate neonatal period by failureto pass meconium, followed by obstructive constipation. In those instances when only afew centimeters of the rectum are affected, the build-up of pressure may permitoccasional passage of stools or even intermittent bouts of diarrhea. Abdominal distentiondevelops if a sufficiently large segment of colon is involved. The major threats to life inthis disorder are superimposed enterocolitis with fluid and electrolyte disturbances andperforation of the colon or appendix with peritonitis.Acquired megacolon is a condition that may occur at any age and may result from: (1)Chagas disease (see Chapter 8 ), in which the trypanosomes directly invade the bowelwall to destroy the enteric plexuses; (2) organic obstruction of the bowel, by a neoplasmor inflammatory stricture; (3) toxic megacolon complicating ulcerative colitis or Crohndisease (see later); or (4) a functional psychosomatic disorder. Save for Chagas disease,where inflammatory involvement of the ganglia is evident, the remaining forms ofmegacolon are not associated with any deficiency of mural ganglia.Enterocolitis
Diarrheal diseases of the bowel make up a veritable Augean stable of entities (a messysituation cleaned by the fifth task of Hercules). Many are caused by microbiologic agents;others arise in the setting of malabsorptive disorders and idiopathic inflammatory boweldisease. Consideration should first be given to the conditions known as diarrhea anddysentery.DIARRHEA AND DYSENTERYA healthy adult drinks 2 L of fluid per day, to which is added 1 L of saliva, 2 L of gastricjuice, 1 L of bile, 2 L of pancreatic juice, and 1 L of intestinal secretions. Of these 9 L offluid presented to the intestine, less than 200 gm of stool are excreted per day, of which65% to 85% is water. Jejunal absorption of water amounts to 3 to 5 L/day, ilealabsorption 2 to 4 L/day. The colon normally absorbs 1 to 2 L/day, but is capable ofabsorbing almost 6 L/day.A precise definition of diarrhea is elusive, given the considerable variation in normalbowel habits. An increase in stool mass, stool frequency, and/or stool fluidity areperceived as diarrhea by most patients. For many individuals, this consists of daily stoolproduction in excess of 250 gm, containing 70% to 95% water. However, over 14 L offluid may be lost per day in severe cases of diarrhea (i.e., the equivalent of the circulatingblood volume). Diarrhea is often accompanied by pain, urgency, perianal discomfort, andincontinence. Low-volume, painful, bloody diarrhea is known as dysentery.The major causes of diarrhea are presented in Table 17-6 . The principal mechanisms ofdiarrhea, one or more of which may be operative in any one patient, are as follows: 832 TABLE 17-6 -- Major Causes of Diarrheal IllnessesSecretory DiarrheaInfectious: viral damage to mucosal epithelium• Rotavirus• Caliciviruses• Enteric adenoviruses• AstrovirusesInfectious: enterotoxin mediated• Vibrio cholerae• Escherichia coli• Bacillus cereus
• Clostridium perfringensNeoplastic• Tumor elaboration of peptides, serotonin, prostaglandins• Villous adenoma in distal colon (nonhormone mediated)Excess laxative useOsmotic DiarrheaDisaccharidase (lactase) deficienciesLactulose therapy (for hepatic encephalopathy, constipation)Prescribed gut lavage for diagnostic proceduresAntacids (MgSO4 and other magnesium salts)Primary bile acid malabsorptionExudative DiseasesInfectious: bacterial damage to mucosal epithelium• Shigella• Salmonella• Campylobacter• Entamoeba histolyticaIdiopathic inflammatory bowel diseaseTyphlitis (neutropenic colitis in the immunosuppressed)MalabsorptionDefective intraluminal digestionPrimary mucosal cell abnormalitiesReduced small intestinal surface areaLymphatic obstructionInfectious: impaired mucosal cell absorption• Giardia lamblia infectionDeranged MotilityDecreased intestinal transit time• Surgical reduction of gut length• Neural dysfunction, including irritable bowel syndrome
• Hyperthyroidism• Diabetic neuropathy• Carcinoid syndromeDecreased motility (increased intestinal transit time)• Small intestinal diverticula• Surgical creation of a "blind" intestinal loop• Bacterial overgrowth in the small intestine • Secretory diarrhea: Net intestinal fluid secretion leads to the output of more than 500 mL of fluid stool per day, which is isotonic with plasma and persists during fasting. • Osmotic diarrhea: Excessive osmotic forces exerted by luminal solutes lead to output of more than 500 mL of stool per day, which abates upon fasting. Stool exhibits an osmotic gap (stool osmolality exceeds plasma electrolyte concentration by ≥50 mOsm). • Exudative diseases: Mucosal destruction leads to output of purulent, bloody stools that persist on fasting; stools are frequent but may be small or large volume. • Deranged motility: Improper gut neuromuscular function may produce highly variable patterns of increased stool volume; other forms of diarrhea must be excluded. • Malabsorption: Improper absorption of gut nutrients produces voluminous, bulky stools with increased osmolarity combined with excess stool fat (steatorrhea). The diarrhea usually abates on fasting.INFECTIOUS ENTEROCOLITISIntestinal diseases of microbial origin are marked principally by diarrhea and sometimesulcerative and inflammatory changes in the small and/or large intestine. Infectiousenterocolitis is a global problem of staggering proportions, causing more than 12,000deaths per day among children in developing countries, and constituting one half of alldeaths before age 5 worldwide. Although far less prevalent in industrialized nations, these infections still have attack rates of one to two illnesses per person per year, secondonly to the common cold in frequency. This results in an estimated 99 million acute casesof either vomiting or diarrhea per year in the United States, equivalent to 40% of thepopulation. The infections are mainly associated with contaminated food and water.Acute, self-limited infectious diarrhea, which is a major cause of morbidity amongchildren, is most frequently caused by enteric viruses. In infants, infectious diarrhea maycause severe dehydration and metabolic acidosis, which may result in hospitalization indeveloped countries and death in developing countries. Bacterial infections, such asenterotoxigenic Escherichia coli, are also common offenders. However, many pathogenscan cause diarrhea; the major offenders vary with the age, nutrition, immune status of
the host, environment (living conditions, public health measures), and special predispositions, such as hospitalization, wartime dislocation, or foreign travel. In 40% to 50% of cases, the specific agent cannot be isolated. Viral Gastroenteritis Symptomatic human infection is caused by several distinct groups of viruses ( Table 17-7 ). Rotavirus accounts for an estimated 140 million cases and 1 million deaths worldwide per year. The target population is children age 6 to 24 months, but young infants and debilitated adults are susceptible to symptomatic infection. This virus accounts for 25% to 65% of severe diarrhea in infants and young children. Rotavirus is an encapsulated  virus with a segmented double-stranded RNA genome. Rotavirus selectively infects and destroys mature enterocytes in the small intestine, without infecting crypt cells. The surface epithelium of the villus is repopulated by immature secretory cells. With the loss of absorptive function and excess of secretory cells, there is net secretion of water and electrolytes, compounded by an osmotic diarrhea from incompletely absorbed nutrients. The minimal infective inoculum is approximately 10 viral particles, whereas an individual with rotavirus gastroenteritis typically sheds up to 1012 particles/mL stool. Thus, outbreaks among pediatric populations in hospitals and day-care centers are very common. The clinical syndrome has an incubation period of approximately 2 days, which is followed by vomiting and watery diarrhea for several days. Viral infection can induce protective immunity, but the protection for reinfection is often short-lived. Antirotavirus 833 TABLE 17-7 -- Common Gastrointestinal Viruses % of U.S. Childhood Size Viral Host Mode of Prodrome/DurationVirus Genome (nm) Enterocolitis Age Transmission of IllnessRotavirus dsRNA 70 60 6–24 Person-to- 2 days/3–5 days(Group A) months person, food, waterCaliciviruses ssRNA 35– 20 Child Person-to- 1–3 days/4 days 40 or person, water, adult cold foods, raw shellfishNorwalk-likeviruses Sapporo-likeviruses
TABLE 17-7 -- Common Gastrointestinal Viruses % of U.S. Childhood Size Viral Host Mode of Prodrome/DurationVirus Genome (nm) Enterocolitis Age Transmission of IllnessEnteric dsDNA 80 8 Child Person-to- 3–10 days/7+ daysadenoviruses <2 person yearsAstroviruses ssRNA 28 4 Child Person-to- 24–36 hours/1–4 days person, water, raw shellfishData from Goodgame RW: Viral causes of diarrhea. Gastroenterol Clin North Am30:779,2001.ds, double-stranded; ss, single stranded. antibodies are present in mothers milk, so rotavirus infection is most frequent at the time of weaning. Among the numerous types of adenovirus, the subtypes (enteric serotypes) Ad40, Ad41, and Ad31 appear to be responsible for enteric infections and are a common cause of diarrhea among infants. They can be distinguished from adenoviruses that cause respiratory disease by their failure to grow easily in culture. Adenoviruses cause a moderate gastroenteritis with diarrhea and vomiting, lasting for a week to 10 days after an incubation period of approximately 1 week. In the small intestine, adenoviral infection causes atrophy of the villi and compensatory hyperplasia of the crypts similar to rotavirus, resulting in malabsorption and fluid loss. The virus can also cause colitis. Immunohistochemical stain of nuclear inclusions facilitates the diagnosis. Caliciviruses include two major groups: the classic Caliciviruses (Sapporo-like viruses) and the Norwalk-like viruses (small round structured viruses). Sapporo-like viral infection is rare, while Norwalk virus, the prototype of Norwalk-like viruses, is responsible for the majority of cases of nonbacterial food-borne epidemic gastroenteritis in all age groups. Norwalk-like viruses are small icosahedral viruses containing a single- stranded RNA genome. They cause epidemic gastroenteritis with diarrhea, nausea, and vomiting among children. Outbreaks occur following exposure of multiple individuals to a common source. The clinical syndrome has an incubation period of 1 to 2 days, which is followed by 12 to 60 hours of nausea, vomiting, watery diarrhea, and abdominal pain. Astrovirus is named after its starlike appearance. It primarily affects children, (it accounts for 4% of acute gastroenteritis in young children), and has a worldwide distribution. Those infected develop anorexia, headache, and fever. Other viruses such as enterotrophic coronaviruses and toroviruses are occasionally implicated in human diarrheal disease.
Despite the high incidence of viral gastroenteritis, insights into disease pathogenesis havebeen slow in coming.Morphology.Although the enteric viruses are genetically and morphologically different from eachother, the lesions they cause in the intestinal tract are similar. The small intestinal mucosausually exhibits modestly shortened villi and infiltration of the lamina propria bylymphocytes. Vacuolization and loss of the microvillus brush border in surface epithelialcells may be evident, and the crypts become hypertrophied. Viral particles may bevisualized by electron microscopy within surface epithelial cells. In infants, rotavirus canproduce a flat mucosa resembling celiac sprue (discussed later).Bacterial EnterocolitisDiarrheal illness may be caused by numerous bacteria ( Table 17-8 ). There are severalpathogenic mechanisms for bacterial enterocolitis (also termed food poisoning): • Ingestion of preformed toxin, present in contaminated food. Major offenders are Staphylococcus aureus, Vibrio, and Clostridium perfringens. Symptoms develop within a matter of hours; explosive diarrhea and acute abdominal distress herald an illness that passes within a day or so. Ingested systemic neurotoxins, as from Clostridium botulinum, may produce rapid, and fatal, respiratory failure. • Infection by toxigenic organisms, which proliferate within the gut lumen and elaborate an enterotoxin. An incubation period of several hours to days is followed by diarrhea and dehydration if the primary pathogenic mechanism is a secretory enterotoxin, or dysentery if the primary mechanism is a cytotoxin. Travelers diarrhea (Montezumas revenge, turista) usually occurs following ingestion of fecally contaminated food or water; it begins abruptly and subsides within 2 to 3 days. It affects 20% to 50% of the 35 million people who travel worldwide from industrialized countries to developing countries each year. • Infection by enteroinvasive organisms, which proliferate, invade, and destroy mucosal epithelial cells, also leading to dysentery. As with ingestion of toxigenic organisms, the incubation period is several hours to days.The main properties of bacteria that contribute to the pathogenesis of enterocolitis are:(1) the ability to adhere to the mucosal epithelial cells and replicate, (2) the ability toelaborate enterotoxins, and (3) the capacity to invade.Bacterial Adhesion and Replication.In order to produce disease, ingested organisms must adhere to the mucosa; otherwisethey will be swept away by the fluid stream. Adherence of enterotoxigenic organismssuch as E. coli and Vibrio cholerae is mediated by plasmid-encoded adhesins. Theseproteins are expressed on the surface of the organism, sometimes in the form of fimbriaeor pili, which are rigid or wiry surface
834 TABLE 17-8 -- Major Causes of Bacterial Enterocolitis PathogenicOrganism Mechanism Source Clinical FeaturesEscherichia Travelers diarrhea, including:coli• ETEC Cholera-like toxin, Food, water Watery diarrhea no invasion• EHEC Shiga-like toxin, no Undercooked Hemorrhagic colitis, hemolytic- invasion beef products uremic syndrome• EPEC Attachment, Weaning foods, Watery diarrhea, infants and enterocyte water toddlers effacement, no invasion• EIEC Invasion, local Cheese, water, Fever, pain, diarrhea, dysentery spread person-to- personSalmonella Invasion, Milk, beef, Fever, pain, diarrhea or dysentery, translocation, eggs, poultry bacteremia, extraintestinal lymphoid infection, common source inflammation, outbreaks disseminationShigella Invasion, local Person-to- Fever, pain, diarrhea, dysentery, spread person, low- epidemic spread inoculumCampylobacter Toxins, invasion Milk, poultry, Fever, pain, diarrhea, dysentery, animal contact food sources, animal reservoirsYersinia Invasion, Milk, pork Fever, pain, diarrhea, mesentericenterocolitica translocation, adenitis, extraintestinal infection, lymphoid food sources inflammation, disseminationVibrio Enterotoxin, no Water, shellfish, Watery diarrhea, cholera,cholerae, other invasion person-to- pandemic spreadVibrios person spreadClostridium Cytotoxin, local Nosocomial Fever, pain, bloody diarrhea,difficile invasion environmental following antibiotic use, spread nosocomial acquisition
TABLE 17-8 -- Major Causes of Bacterial Enterocolitis PathogenicOrganism Mechanism Source Clinical FeaturesClostridium Enterotoxin, no Meat, poultry, Watery diarrhea, food sources,perfringens invasion fish "pigbel"Mycobacterium Invasion, mural Contaminated Chronic abdominal pain;tuberculosis inflammatory foci milk, complications of malabsorption, with necrosis and swallowing of stricture, perforation, fistulae, scarring coughed-up hemorrhage organismsETEC, enterotoxigenic E. coli; EHEC, enterohemorrhagic E. coli; EPEC,enteropathogenic E. coli; EIEC, enteroinvasive E. coli.projections. Adherence of enteropathogenic and enterohemorrhagic organisms, includingE. coli and Shigella, is also dependent on plasmid-encoded proteins, but the nature ofthese proteins is not known. Adherence causes effacement of the apical enterocytemembrane, with destruction of the microvillus brush border and changes in theunderlying cell cytoplasm. The factors regulating bacterial replication are not well understood, particularly since pathogenic organisms must compete with the normalbacterial flora to achieve a critical population density.Bacterial Enterotoxins.Bacterial enterotoxins are polypeptides that cause diarrhea. Some enterotoxins causeintestinal secretion of fluid and electrolytes without causing tissue damage; this isaccomplished by binding of the toxin to the epithelial cell membrane, entry of a portionof the toxin into the cell, and massive activation of electrolyte secretion accompanied bywater. Cholera toxin, elaborated by Vibrio cholerae, is the prototype secretagogue toxin.The toxin causes increased levels of intracellular calcium, resulting in dysfunction of thefluid and electrolyte transport, as discussed below under Cholera. Strains of E. coli(enterotoxigenic E. coli) that produce heat-labile (LT) and heat-stable (ST) secretagoguetoxins are the major cause of travelers diarrhea. The LT toxin is similar to cholera toxin,and the ST toxin induces cyclic guanosine monophosphate, resulting in increased fluidexcretion. Leukocytes are absent from the stool of patients with travelers diarrhea. Asecond group of enterotoxins are cytotoxins, exemplified by Shiga toxin produced byShigella dysenteriae and Shiga-like toxins produced by enterohemorrhagic E. coli (e.g.,E. coli O157:H7). These toxins cause direct tissue damage through epithelial cellnecrosis. Staphylococcal enterotoxins, which are major causes of food poisoning,represent yet another group of enterotoxins; are proteins that bind to the antigen receptorsof large numbers of T cells and activate the lymphocytes to secrete cytokines. Thecytokines stimulate intestinal motility and fluid secretion.Bacterial Invasion.
Both enteroinvasive E. coli and Shigella possess a large virulence plasmid that confersthe capacity for epithelial cell invasion, apparently by microbe-stimulated endocytosis.This is followed by intracellular proliferation, cell lysis, and cell-to-cell spread.Salmonella quickly pass through intestinal epithelial cells via transcytosis with minimalepithelial damage; entry into the lamina propria leads to a 5% to 10% incidence ofbacteremia, which can sometimes cause typhoid fever, meningitis, endocarditis, andosteomyelitis (commonly in the setting of sickle cell disease). Yersinia enterocoliticapenetrates the ileal mucosa and multiplies within Peyer patches and regional lymphnodes. Bacteremia is rare and usually occurs in the setting of iron-overload disease, sinceiron is a growth factor for Yersinia.Bacterial cytotoxins and invasion give rise to bacillary dysentery, which generates itsown unique misery for its victims: abdominal cramping and tenesmus with loose stoolscontaining blood, pus, and mucus. Bacillary dysentery, which results in as many as500,000 deaths among children in developing countries each year, is caused by Shigelladysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei as well as certain Otype enterotoxic E. coli. (Amebic dysentery is caused by the protozoan parasiteEntamoeba histolytica, discussed later in this chapter).Shigella Bacillary DysenteryShigella species are gram-negative facultative anaerobes that infect only humans. S.flexneri is the major cause of endemic bacillary dysentery in locations of poor hygiene,including large regions of the developing world and institutions in the 835developed world. Epidemic shigellosis can occur when individuals consume uncookedfoods at picnics or other events.Pathogenesis.Transmission is fecal-oral and is remarkable for the small number of organisms that maycause disease (10 ingested organisms cause illness in 10% of volunteers, and 500organisms cause disease in 50% of volunteers). Shigella bacteria invade the intestinalmucosal cells but do not usually go beyond the lamina propria. Dysentery is caused whenthe bacteria escape the epithelial cell phagolysosome, multiply within the cytoplasm, anddestroy host cells. Shiga toxin causes hemorrhagic colitis and hemolytic-uremicsyndrome by damaging endothelial cells in the microvasculature of the colon and theglomeruli, respectively ( Chapter 20 ). In addition, chronic arthritis secondary to S.flexneri infection, called Reiter syndrome, may be caused by a bacterial antigen; theoccurrence of this syndrome is strongly linked to HLA-B27 genotype, but theimmunologic basis of this reaction is not understood. Salmonellosis and Typhoid Fever
Salmonellae are flagellated, gram-negative bacteria that cause a self-limited food-borneand water-borne gastroenteritis (S. enteritidis, S. typhimurium, and others) or a life-threatening systemic illness, typhoid fever, marked by fever and systemic symptoms (S.typhi). In the United States, Salmonella species cause approximately 500,000 reportedcases of food poisoning, and many cases go unreported. Because Salmonella speciesother than S. typhi infect most commercially raised chickens and many cows, the majorsources of Salmonella in the United States are feces-contaminated beef and chicken thatare insufficiently washed and cooked. Stringent hygiene in the production plants and thehome kitchen helps minimize risk of contamination. In contrast, humans are the only hostof S. typhi, which is shed in the feces, urine, vomitus, and oral secretions by acutely illpersons and in the feces by chronic carriers without overt disease. Therefore, typhoidfever from S. typhi is a disease largely of developing countries, where sanitary conditionsare insufficient to stop its spread. Typhoid fever is a protracted disease that is associatedwith bacteremia, fever, and chills during the first week; widespread mononuclearphagocyte involvement with rash, abdominal pain, and prostration in the second week;and ulceration of Peyer patches with intestinal bleeding and shock during the third week.Pathogenesis.Salmonella invades intestinal epithelial cells as well as tissue macrophages. Invasion ofintestinal epithelial cells is controlled by invasion genes that are induced by the lowoxygen tension found in the gut. These genes encode proteins involved in adhesion and inrecruitment of host cytoskeletal proteins that internalize the bacterium. Similarly,intramacrophage growth is important in pathogenicity, and this seems to be mediated bybacterial genes that are induced by the acid pH within the macrophage phagolysosome.The enteric nervous system also is a critical regulator of fluid secretion in the normal gut.Neural reflex pathways increase epithelial fluid secretion in response to enteric pathogenssuch as Salmonella and Clostridium difficile. Campylobacter EnterocolitisThis comma-shaped, flagellated, gram-negative organism was once classified with thevibrios. When special culture conditions permitted its isolation in the 1970s, it becameapparent that Campylobacter was an important cause of enterocolitis and septicemia inhumans. In the United States, Campylobacter jejuni is responsible for twice the entericdisease of Salmonella and four times that of Shigella. Most infections withCampylobacter are sporadic and are associated with ingestion of improperly cookedchicken, which may be contaminated with Campylobacter and/or Salmonella. Sporadicinfections may also be associated with contact with infected dogs. Outbreaks ofCampylobacter are usually associated with unpasteurized milk or contaminated water.Pathogenesis.Invasiveness is strain dependent. Flagella of Campylobacter, which give the organism itscomma shape and motility, are necessary for the bacterium to penetrate mucus coveringepithelial surfaces. Three clinical outcomes of Campylobacter infection are possible: (1)diarrhea, which is independent of bacterial invasion; (2) dysentery with blood and mucusin the stool; and (3) enteric fever when bacteria proliferate within the lamina propria and
mesenteric lymph nodes. Postinfectious complications of Campylobacter infectionsinclude reactive arthritis in HLA-B27 carriers (as with Shigella infection) and Guillain-Barré syndrome, a demyelinating disease of peripheral nerves due to autoantibodiesagainst gangliosides GM1 and GQ1b, described in Chapter 27 . Recently, C. jejuni wasfound to be associated with the development of immunoproliferative small intestinaldisease (discussed later).CholeraVibrio cholerae are comma-shaped, gram-negative bacteria that have been the cause ofseven great long-lasting epidemics (pandemics) of diarrheal disease. Many of thesepandemics began in the Ganges Valley of India and Bangladesh, which is never free fromcholera, and then moved east. Although there are 140 serotypes of V. cholerae, untilrecently only the 01 serotype was associated with severe diarrhea. Beginning in 1992, anew V. cholerae serotype (0139, also known as Bengal) has been associated with severe,watery diarrhea. Pathogenesis.The vibrios never invade the epithelium but instead remain within the lumen and secretean enterotoxin, which is encoded by a virulence phage. Flagellar proteins involved inmotility and attachment are necessary for efficient bacterial colonization, as has beendescribed for Campylobacter. (This is in contrast to Shigella species and certain E. colistrains, which are nonmotile and yet invasive.) The Vibrio hemagglutinin, which is ametalloprotease, is important for detachment of Vibrio from epithelial cells.The secretory diarrhea characteristic of the disease is caused by release of cholera toxin( Fig. 17-32 ). Cholera toxin is composed of five binding peptides B and a catalyticpeptide A. The B peptides, serving as a "landing pad," bind to carbohydrates on GM1ganglioside on the surface of epithelial cells of the small intestine, enabling calveolar-mediated endosomal entry of toxin subunit A into the cell. Reverse transport of thesubunit A from the endosome into the cell cytoplasm is followed by cleavage of thedisulfide bond linking the two fragments of peptide A (A1 and A2). Catalytic peptide A1is generated, leading to the following sequence: • A1 interacts with 20-kD cytosolic proteins called ADP-ribosylation factors (ARF). • The ARF-A1 complex catalyzes ADP-ribosylation of a 49-kD G-protein (called Gsα ). • Binding of NAD and GTP generates an activated Gsα , which in turn binds to and stimulates adenylate cyclase. ADP-ribosylated Gsα is permanently in an active GTP-bound 836 state, resulting in persistent activation of adenylate cyclase.
• The activated adenylate cyclase generates high levels of intracellular cAMP from ATP. • Cyclic AMP stimulates secretion of chloride and bicarbonate, with associated sodium and water secretion. Chloride and sodium resorption are also inhibited.Figure 17-32 Mechanisms of cholera toxin action.The reabsorptive function of the colon is overwhelmed, and liters of dilute "rice water"diarrhea containing flecks of mucus—up to 14 L/day, equivalent to the circulating bloodvolume, causing dehydration and electrolyte imbalances. Because overall absorption inthe gut remains intact, oral formulas can replace the massive sodium, chloride,bicarbonate, and fluid losses and reduce the mortality rate from 50% to less than 1%.Antibiotic-Associated Colitis (Pseudomembranous Colitis)This entity is an acute colitis characterized by formation of an adherent layer ofinflammatory cells and debris overlying sites of mucosal injury, a so-calledpseudomembrane. It is usually caused by toxins of Clostridium difficile, a normal gutcommensal. The two major toxins produced by C. difficile are toxin A and toxin B, whichmodulate cellular signaling pathways, induce cytokine production, and cause host cellapoptosis. The disease occurs most often in patients without a background of chronic enteric disease, following a course of broad-spectrum antibiotic therapy. Nearly allantibacterial agents have been implicated. Presumably toxin-forming strains flourishfollowing alteration of the normal intestinal flora; factors favoring the initiation of toxinproduction are not understood. Rarely, the condition may appear in the absence ofantibiotic therapy, typically after surgery or superimposed on a chronic debilitatingillness. Infrequently, the small intestine is involved.Antibiotic-associated colitis occurs primarily in adults as an acute or chronic diarrhealillness, although it has been recorded as a spontaneous infection in young adults withoutpredisposing influences. Diagnosis is confirmed by the detection of the C. difficilecytotoxin in stool. Response to treatment is usually prompt, but relapse occurs in up to25% of patients.Morphology.Given the variety of bacterial pathogens, the pathologic manifestations of entericbacterial disease are quite variable. Dramatic, even lethal, diarrhea may occur without asignificant pathologic lesion, as in cholera resulting from V. cholerae. Alternatively,characteristic histology may enable diagnosis with reasonable certainty, as with C.difficile-induced pseudomembranous colitis. Most bacterial infections exhibit a non-specific pattern of damage to the surface epithelium, decreased epithelial cellmaturation and an increased mitotic rate ("regenerative change"), hyperemia andedema of the lamina propria, and variable neutrophilic infiltration into the laminapropria and epithelial layer. In the small intestine, modest villus blunting may occur; in
the colon, mucosal architecture is usually preserved. With recovery, epithelial damageand neutrophilic inflammation subside, leaving the residua of regenerative change andlymphoplasmacytic infiltration of the lamina propria. Alternatively, progressivedestruction of the mucosa leads to erosion, ulceration, and severe submucosalinflammation. Notable features of particular infections are summarized below: • Shigella primarily affects the distal colon, first with hyperemia and edema and enlargement of mucosal lymphoid nodules, creating small, projecting nodules. Within 24 hours, the acute mucosal inflammation and erosion generate a patchy and then confluent purulent exudate ( Fig. 17-33 ). The mucosa then becomes soft and friable, and irregular ulcerations appear; severe infection generates large denuded tracts of mucosa. The recovery phase is marked by formation of mucosal granulation tissue and eventual regeneration of the mucosal epithelium. • Salmonella (multiple species, including S. typhimurium and S. paratyphi) primarily affects the ileum and colon, generating blunted villi, vascular congestion, and mononuclear inflammation. Peyer patch involvement produces swelling, congestion, and eventual ulceration with linear ulcers. With S. typhi, bacteremia and systemic dissemination 837 cause proliferation of phagocytes with enlargement of reticuloendothelial and lymphoid tissues throughout the body. Peyer patches in the terminal ileum become sharply delineated, plateau-like elevations up to 8 cm in diameter, with enlargement of draining mesenteric lymph nodes. Shedding of the mucosa and swollen lymphoid tissue creates oval ulcers with their long axes along the axis of the ileum. Microscopic examination reveals macrophages containing bacteria, red blood cells, and nuclear debris. Intermingled with the phagocytes are lymphocytes and plasma cells, whereas neutrophils are present near the ulcerated surface. The spleen is enlarged, soft, and bulging, with uniformly pale red pulp, obliterated follicular markings, and prominent sinus histiocytosis and reticuloendothelial proliferation. The liver shows small, randomly scattered foci of parenchymal necrosis in which the hepatocytes are replaced by a phagocytic mononuclear aggregate, called a typhoid nodule. These distinctive nodules also occur in the bone marrow and lymph nodes. Gallbladder colonization, which may be associated with gallstones, causes a chronic carrier state. • Campylobacter jejuni and other species may involve the entire intestine from the jejunum to the anus. The small intestine exhibits a decrease in the villus-to-crypt ratio. In invasive colonic infection, the colonic mucosa appears friable and superficially eroded on proctoscopy. Histology reveals multiple superficial ulcers, mucosal inflammation, and a purulent exudate. The formation of colonic crypt abscesses and mucosal ulceration may be confused with those of ulcerative colitis (discussed later). • Yersinia enterocolitica and Y. pseudotuberculosis involve ileum, appendix, and colon. They cause mucosal hemorrhage and ulceration, bowel wall thickening, Peyer patch and mesenteric lymph node hypertrophy with necrotizing granulomas, and systemic spread with peritonitis, pharyngitis, and pericarditis.
• Vibrio cholerae affects the small intestine, especially the more proximalsegment. The mucosa essentially remains intact, with mucus-depleted crypts.• Clostridium perfringens and Clostridium difficile. C. perfringens infection isusually similar to V. cholerae, but with some epithelial damage; some strainsproduce severe necrotizing enterocolitis (NEC) with perforation ("pigbel"). C.difficile-induced pseudomembranous colitis derives its name from theplaquelike adhesion of fibrinopurulent-necrotic debris and mucus to damagedcolonic mucosa ( Fig. 17-34A )—these are not true "membranes" since thecoagulum is not an epithelial layer. Pseudomembrane formation is not restrictedto C. difficile-induced colitis: It also may occur following any severe mucosalinjury, as in ischemic colitis, volvulus, and with necrotizing infections(staphylococci, shigella, candida, NEC). What is striking about C. difficile toxin-induced colitis is the microscopic lesion ( Fig. 17-34B ). The surface epithelium isdenuded, and the superficial lamina propria contains a dense infiltrate ofneutrophils and occasional capillary fibrin thrombi. Superficially damaged cryptsare distended by a mucopurulent 838exudate, which erupts out of the crypt to form a mushrooming cloud that adheresto the damaged surface—the coalescence of this "cloud" forms thepseudomembrane.• Enteropathogenic E. coli: At least four distinct types of pathogenic E. coli areknown to cause significant diseases—the enterotoxigenic (ETEC),enterohemorrhagic (EHEC), enteroinvasive (EIEC), and enteroadherent (mainly,enteropathogenic, EPEC). In North America, the most important one is EHECserotype E. coli O 157:H7. EHEC are intestinal commensals in many animals. Humans are usually infected by contaminated meat. These bacteria produceShiga-like toxins, which damage enterocytes and vascular endothelial cells. Inaddition to abdominal pain and diarrhea, some patients, particularly children, maydevelop life-threatening hemolytic-uremic syndrome characterized by the clinicaltriad of hemolytic anemia, renal failure, and thrombocytopenia.
Figure 17-33 Shigella enterocolitis. Segment of colon showing pale, granular, inflamed mucosa withpatches of coagulated exudate.Figure 17-34 Pseudomembranous colitis from C. difficile infection. A, Gross photograph showing plaquesof yellow fibrin and inflammatory debris adherent to a reddened colonic mucosa. B, Low-powermicrograph showing superficial erosion of the mucosa and an adherent pseudomembrane of fibrin, mucus,and inflammatory debris.The complications of severe bacterial enterocolitis are the expected consequences ofmassive fluid loss or destruction of the intestinal mucosal barrier and includedehydration, sepsis, and perforation. Without quick intervention, death ensues rapidly,particularly in the very young. Alternatively, an infection may produce extremediscomfort without being life threatening. All enteroinvasive organisms can mimic acuteonset of idiopathic inflammatory bowel disease.Yersinia and Mycobacterium tuberculosis may also present as subacute diarrhealillnesses. Tuberculosis is covered in detail in Chapter 8 .Bacterial Overgrowth SyndromeA key mechanism for clearing bacteria from the small intestine is the normal motility,which ensures that bacteria entering into the small intestine are propelled downstreambefore they can adhere to the mucosa and proliferate. Gastric hypoacidity, immunologicdeficiencies, and intestinal dysmotility with intestinal stasis may enable bacteria toproliferate within the small bowel, so-called bacterial overgrowth syndrome. Surgicalprocedures in particular may set the stage for bacterial overgrowth. These includeBillroth procedures, in which the gastric antrum is resected, thereby decreasing the timefor exposure of ingested bacteria to gastric acid. Surgical creation of Roux-en-Y loops, asin the Billroth II procedure or in a pancreatoduodenectomy (Whipple) procedure, createsa blind intestinal loop that is a site for bacterial overgrowth. The bacterial populations aremixed enteric populations, without specific dominant species.Patients usually present with chronic diarrhea, abdominal pain, malabsorption, andweight loss. The clinical diagnosis largely depends on the clinical history anddemonstration of the presence of bacteria in the proximal segment of the small intestine
by direct culture of an aspirate. Breath tests for volatile bacterial byproducts may be anoninvasive option for a presumptive diagnosis of bacterial overgrowth syndrome.Parasitic EnterocolitisAlthough viruses and bacteria are the predominant enteric pathogens in the United States,parasitic disease and protozoal infection collectively affect over one half of the worldspopulation on a chronic or recurrent basis. The small intestine can harbor as many as 20species of parasites, including nematodes (the roundworms Ascaris and Strongyloides,hookworms, pinworms), cestodes (flatworms, tapeworms), trematodes (flukes), andprotozoa. Some of the parasitic infections are covered in Chapter 8 . Here we will brieflydiscuss the common parasitic infections of the intestinal tract.NematodesAscaris lumbricoides is the most common nematode, infecting over a billion individualsworldwide. Infection occurs by ingestion of eggs as a result of human fecal-oralcontamination. The ingested ova hatch in the intestine, and larvae penetrate the intestinalmucosa. The disease associated with this parasitic infection is related to larval migrationfrom the splanchnic circulation to the systemic circulation (jejunum-to-liver-to-lung),with formation of hepatic abscess or Ascaris pneumonitis. Larvae migrate up the trachea,are swallowed, and arrive again in the intestine to mature into adult worms. Adult wormmasses can physically obstruct the intestine or the biliary tree. Diagnosis is usually madeby detection of the eggs in the feces.Strongyloides larvae live in fecally contaminated ground soil and penetrate throughunbroken skin. They migrate through the lungs, generating pulmonary infiltrates witheosinophilia, and arrive in the intestine to mature into adult worms. Unlike otherintestinal worms, which require an ova or larval stage outside the human, the eggs ofStrongyloides can hatch within the intestine and larvae can penetrate the mucosa, causingautoinfection. Hence, Strongyloides infection can persist in one individual for life;immunosuppressed individuals can have overwhelming autoinfection. Strongyloidesincites a strong tissue eosinophilic reaction, causing eosinophilia as well.Hookworm (Necator duodenale and Ancylostoma duodenale) infection affects anestimated 1 billion people worldwide and causes significant morbidity. The infectioninitiates from larva penetration through the skin. The larva develops further in the lungsand gains access to the duodenum by upward migration in the bronchial tree, followed byswallowing. The worms attach to the mucosa, suck blood, and reproduce. The smallintestinal mucosa usually exhibits multiple superficial erosions, focal hemorrhage, andinflammatory infiltrates. Long-term infection causes iron deficiency anemia. Diagnosiscan be made by detection of the eggs in fecal smear.Enterobius vermicularis (pinworms) do not invade host tissue and live their entire lifewithin the intestinal lumen. Pinworm infections occur in industrialized countries as wellas developing countries; in the United States more than 60 million people havepinworms. Because these are noninvasive worms, they rarely cause serious illness.
Enterobius vermicularis infection (enterobiasis) occurs in situations where fecal-oralcontamination is common. Adult worms living in the intestine migrate to the anal orificeat night, where the female deposits eggs on the perirectal mucosa. As the eggs are quite 839irritative, rectal and perineal pruritus ensue. Human-to-human contact is aided by digitalmanipulation of the area. Both eggs and adult pinworms remain viable external to thebody, and reinfection is common. Diagnosis is easily made by applying cellophane tapeto the perianal skin and examining the tape for eggs under the microscope.Trichuris trichiura (whipworm) is less common, occurring primarily in young children.Similar to enterobius vermicularis, these worms do not penetrate the intestinal mucosaand rarely cause serious disease. Heavy infections, however, may cause bloody diarrheaand rectal prolapse. Diagnosis is established by finding the characteristic eggs in thestool.CestodesThe intestinal cestodes reside only within the intestinal lumen and never invade beyondthe intestinal mucosa. Three species of cestodes (multisegmental flatworms, tapeworms)are Diphyllobothrium latum (fish tapeworm), Taenia solium (pork tapeworm), andHymenolepsis nana (dwarf tapeworm). Infection occurs by ingestion of raw orundercooked meat that contains encysted larvae. Release of the larvae enables attachmentto the intestinal mucosa through its head, or scolex. The worm derives its nutrients fromthe food stream and enlarges by formation of egg-filled proglottids (segments). Humansare generally infected by one worm only; since the worm does not penetrate the intestinalmucosa, eosinophilia does not generally occur. Nevertheless, the parasite burden can bestaggering, as adult worms can grow to many meters in length. Shedding of proglottids orindividual eggs produces copious fecal release of eggs. Diagnosis is established byexamination of stool for the ova.AmebiasisEntamoeba histolytica (ameba) is a dysentery-causing protozoan parasite spread by fecal-oral transmission. This protozoan infects approximately 500 million persons indeveloping countries such as India, Mexico, and Colombia, resulting in approximately 40million cases of dysentery and liver abscess.Pathogenesis.E. histolytica cysts, which have a chitin wall and four nuclei, are the infectious formbecause they are resistant to gastric acid. Ingested quadrinucleate cysts colonize thesurface of colonic mucin epithelial cells. Cysts release trophozoites, the ameboid forms,which reproduce under anaerobic conditions without harming the host. Because theparasites lack mitochondria or Krebs cycle enzymes, amebae are obligate fermenters ofglucose to ethanol. Metronidazole, the best drug to treat invasive infections with
entamoebae (as well as other parasites such as Giardia and trichomonads), targetsferridoxin-dependent pyruvate oxidoreductase, an enzyme critical in such fermentationthat is present in these organisms but is absent in humans.Amebae cause dysentery when they attach to the colonic epithelium, as they causeepithelial cell apoptosis, invade the crypts of colonic glands, and burrow into the laminapropria. The organisms then burrow laterally to create, with the accompanyinginflammation and tissue necrosis, a flask-shaped ulcer with a narrow neck and broadbase. Amebic proteins that may be involved in tissue invasion include: (1) cysteineproteinases, which are able to break down proteins of the extracellular matrix; (2) a lectinon the parasite surface that binds to carbohydrates on the surface of colonic epithelialcells and red blood cells; and (3) a channel-forming protein called the amebapore, whichmakes holes in the plasma membrane of host cells and lyses them. The presence in stoolof trophozoites containing ingested red blood cells is indicative of tissue invasion byvirulent organisms.Morphology.Amebiasis most frequently involves the cecum and ascending colon, followed in order bythe sigmoid, rectum, and appendix. In severe fullblown cases, however, the entire colonis involved. Amebae can mimic the appearance of macrophages because of theircomparable size and large number of vacuoles; the parasites, however, have a smallernucleus, which contains a large karyosome ( Fig. 17-35 ). Amebae invade through thecrypt epithelium and burrow into the mucosa and submucosa, eliciting a neutrophilicreaction. They are stopped by the muscularis propria and fan out laterally to create aflask-shaped ulcer with a narrow neck and broad base. These maturing ulcers contain fewhost inflammatory cells and exhibit extensive liquefactive necrosis. As the lesionprogresses, the overlying surface mucosa is deprived of its blood supply and sloughs. Themucosa between ulcers is often normal or mildly inflamed. On occasion, the formation ofprofuse circumferential granulation tissue can create colonic stricture.In about 40% of patients with amebic dysentery, parasites penetrate splanchnic vesselsand embolize to the liver to produce solitary, or less often multiple, discrete abscesses,sometimes exceeding 10 cm in diameter. Amebic liver abscesses have a scantinflammatory reaction at their margins and a shaggy fibrin lining. Because of hemorrhageinto the cavities, the abscesses are sometimes filled with a chocolatecolored, odorless,pasty material. Secondary bacterial infection may make these abscesses purulent.
Figure 17-35 Entamoeba histolytica in colon. High-power view of the organisms. Note some of theorganisms ingesting red blood cells. 840Clinical Features.Clinically, the patient may present with abdominal pain, bloody diarrhea, or weight loss.Occasionally, acute necrotizing colitis and megacolon can occur, which carry significantmortality. Rarely, amebic abscesses reach the lung and the heart by direct extension fromthe liver or spread from the liver through the blood into the kidneys and brain. Suchabscesses remain long after the acute intestinal illness has passed.GiardiasisGiardia lamblia is the most common pathogenic parasitic infection in humans. It is an intestinal protozoan spread by fecally contaminated water or food. Infection may besubclinical or may cause acute or chronic diarrhea, steatorrhea, or constipation. BecauseGiardia cysts are not killed by chlorine, Giardia is endemic in public water supplies thatare not filtered through sand and in contaminated streams accessed by campers.Pathogenesis.In the United States, Giardia infections are especially frequent in institutions for thementally ill and in day-care centers. Giardia, like Entamoeba, ferments glucose, lacksmitochondria, and exists in two forms: (1) a dormant but infectious cyst spread by thefecal-oral route from person to person (as well as from beavers to persons); and (2)trophozoites that multiply in the intestinal lumen. Transition from trophozoites to cysts isinduced by decreases in availability of cholesterol as Giardia moves from duodenum tojejunum. In contrast to Entamoeba, Giardia trophozoites have two nuclei rather than one,
are flagellated, reside in the duodenum rather than the colon, adhere to but do not invadethe intestinal epithelial cells, and so cause diarrhea rather than dysentery.Infection can occur by ingestion of as few as 10 cysts. Giardia trophozoites adhere tosugars on intestinal epithelial cells through a parasite lectin that is activated when it iscleaved by proteases, which are plentiful in the lumen of the duodenum. Tight contactbetween the parasite and the epithelial cell is made by a sucker-like disc, composed ofcytoplasmic tubulin and unique intermediate filaments called giardins. Although Giardiadoes not secrete toxin, it contains a cystein-rich surface protein that resembles diarrhea-causing toxins secreted by certain snakes. The physical presence of rapidly proliferatingtrophozoites and their toxic proteins damages the microvillus brush border, causing amalabsorptive state. Immunity mediated by antibodies, including secretory IgA is important in resistance toGiardia, because agammaglobulinemic individuals are severely affected by the parasite.Immunity to Giardia, however, is limited by the parasites ability to vary its majorsurface proteins into antigenically distinct forms, encoded by more than 50 differentgenes.Morphology.In stool smears, G. Iamblia trophozoites are pear shaped and binucleate. Duodenal biopsyspecimens are often teeming with sickle-shaped trophozoites, which are tightly bound bythe concave attachment disc to the villus surface of the intestinal epithelial cells ( Fig.17-36 ). As Giardia does not actually invade the mucosa, small intestinal morphologyFigure 17-36 Giardia lamblia. Trophozoite (arrow) of the organism immediately adjacent to the duodenalsurface epithelium.may be virtually normal. However, many patients exhibit marked blunting of the smallintestinal villi with a mixed inflammatory infiltrate in the lamina propria. The brush
borders of the surface absorptive epithelial cells are irregular, and sometimes there isvirtual absence of villi, resembling the atrophic stage of celiac disease.Clinical Features.Infected patients exhibit a malabsorptive diarrhea, owing to mucosal epithelial cell injury.Functional lactase deficiency also occurs in 20% to 40% of chronically infected patientsby mechanisms that are not understood. The infection can last for months or years. Thesymptoms may be severe in immunocompromised patients. Diagnosis is readily made byexamination of stool for cysts; small intestinal biopsy or examination of a small intestinalaspirate also permits identification of the organisms. While giardiasis is responsive tooral antimicrobial therapy, recurrence is common following cessation of treatment.Necrotizing EnterocolitisNecrotizing enterocolitis (NEC) is an acute, necrotizing inflammation of the small andlarge intestines with the severe consequence of transmural necrosis of intestinalsegments. While it can occur at any age, NEC is particularly devastating in the neonate. It is the most common acquired gastrointestinal emergency of neonates, particularly thosewho are premature or of low birth weight. It may occur at any time in the first 3 monthsof life, but its peak incidence is around the time when infants are started on oral foods (2to 4 days old). This condition is described in Chapter 10 .Collagenous and Lymphocytic ColitisCollagenous colitis is a distinctive disorder of the colon characterized by chronic waterydiarrhea and patches of bandlike collagen deposits directly under the surface epithelium.Lymphocytic colitis is characterized by chronic watery diarrhea and a prominentintraepithelial infiltrate of lymphocytes. Collagenous 841colitis occurs primarily in middle-aged and older women; lymphocytic colitis affectsmales and females equally. Both sets of patients can have between 3 to 20 nonbloody,watery bowel movements per day, accompanied by cramping abdominal pain.Radiographic studies are unremarkable, and endoscopy characteristically reveals normalmucosa. The pathogenesis of both these conditions remains unclear; they do appear to beseparate conditions. Lymphocytic colitis shows a strong association with autoimmune diseases, including celiac sprue, thyroiditis, arthritis, and autoimmune gastritis. Bothdiseases are benign in nature, with neither debilitating weight loss nor malignancy aspotential outcomes. While collagenous colitis and lymphocytic colitis are uncommon,they must be considered in every adult patient who presents with a noninflammatory,watery diarrhea.MISCELLANEOUS INTESTINAL INFLAMMATORY DISORDERSAcquired Immunodeficiency Syndrome (AIDS)
Diarrheal illness occurs in 50% of AIDS patients in North America and may approach100% in developing countries. Some patients exhibit a malabsorptive syndrome with small intestinal villus atrophy or a colitic syndrome resembling ulcerative colitis in theabsence of demonstrable pathogens. Although most cases are probably due to coexistentinfections in these immunocompromised patients, the concept of AIDS enteropathy,attributable to direct mucosal damage by human immunodeficiency virus infection, hasbeen proposed but remains unproven. The spectrum of infections occurring in AIDS isdiscussed in Chapter 6 .TransplantationDiarrhea is a significant complication of bone marrow transplantation. Pretransplantconditioning may cause direct toxic injury to the small intestinal mucosa, evident as villusblunting, degeneration and flattening of crypt epithelial cells, decreased mitoses, andatypia of cell nuclei. Abrupt onset of severe watery diarrhea is a major feature of acuteGVHD. A distinctive histologic lesion is focal crypt cell necrosis, in which debris fromnecrotic cells occupies lacunae within the epithelial layer, with minimal to absentinflammatory cell response in the lamina propria ( Fig. 17-37 ). In more advanced GVHD, necrosis may become so severe as to lead to total sloughing of the mucosa. Inaddition to fluid and electrolyte derangements, the life-threatening complications ofsepsis and intestinal hemorrhage may ensue. Alimentary tract symptoms are less evidentin chronic GVHD but may include dysphagia secondary to esophageal involvement andoccasionally malabsorption due to chronic intestinal injury. Small intestinaltransplantation also carries with it a spectrum of complications, including rejection andCMV infection.Drug-Induced Intestinal InjuryWhen one considers the vast quantities of drugs ingested by humans, with or without theblessings of the medical profession, it is remarkable that the gastrointestinal tract escapesrelatively unscathed. Focal ulceration can occur when a pill adheres to the mucosa andreleases all of its contents locally, as may occur in the esophagus with "dry swallows."Drug-induced
Figure 17-37 Graft-versus-host disease of the colon. Note the apoptotic cell in the crypt (arrow).acute erosive gastritis has been mentioned earlier. The small intestine and colon aresusceptible to drug-induced enterocolitis, most commonly associated with the use ofNSAIDs. A nonspecific pattern of small intestinal inflammation may lead to malabsorption. Colonic inflammation may produce an acute or chronic diarrheal illness;ulceration and stricture formation also occur. Drug-induced gastrointestinal injury mustbe considered whenever abdominal illness is encountered. Considering this possibilitymay, on occasion, spare patients from erroneous diagnosis of a chronic intestinal illness.Radiation EnterocolitisAbdominal irradiation may severely impair the normal proliferative activity of the smallintestinal and colonic mucosal epithelia. Acute radiation enteritis manifests as anorexia,abdominal cramps, and a malabsorptive diarrhea, attributable to acute mucosal injury.Chronic radiation enteritis or colitis may exhibit more indolent symptoms than the acuteform or may present as an inflammatory colitis. The mucosal damage may be perpetuatedby radiation-induced vascular injury and may be accompanied by ischemic fibrosis andstricture.Neutropenic Colitis (Typhlitis)Typhlitis was a nineteenth-century term for severe acute and chronic inflammation of thececal and appendiceal region, which in retrospect was probably the outcome of untreatedacute appendicitis. The term is now used to describe a life-threatening acuteinflammatory destruction of the mucosa of the cecal region occurring in neutropenicindividuals. The presumed pathogenesis is impaired mucosal immunity in combinationwith compromised blood flow in the cecal region.Diversion Colitis
Diversion colitis is an inflammatory mucosal lesion occurring in segments of the colonthat have been surgically isolated. Colonic enterocytes derive a significant portion oftheir 842caloric supply from short-chain fatty acids present in the luminal stream. Surgicaldiversion of the stream, as through an ileostomy, renders the colonic mucosa susceptibleto nutritional deprivation. The changes may range from very mild with increased laminapropria lymphocytes, to a severe exudative diarrheal disease that resembles ulcerativecolitis. Restoration of fecal flow through the colon, or enemas containing short-chainfatty acids, permits mucosal recovery.Solitary Rectal Ulcer SyndromeSolitary rectal ulcer syndrome is an inflammatory condition of the rectum resulting frommotor dysfunction of the anorectal musculature. Dysregulation of the anorectal sphincter,in particular impaired relaxation of the anorectal sling, may create sharp angulation of theanterior rectal shelf. Abrasion of the overlying rectal mucosa creates an oval ulcer andsurrounding mucosal inflammation, frequently with the formation of an inflammatorypolyp. Associated partial prolapse of the rectal mucosa is common. Patients experience acharacteristic triad: rectal bleeding, mucus discharge from the anus, and superficialulceration of the anterior rectal wall.Malabsorption SyndromesMalabsorption is characterized by defective absorption of fats, fat-soluble and othervitamins, proteins, carbohydrates, electrolytes and minerals, and water. The mostcommon clinical presentation is chronic diarrhea, and the hallmark of malabsorption issteatorrhea (excessive fecal fat content). At the most basic level, malabsorption is theresult of disturbance of at least one of these normal digestive functions: 1. Intraluminal digestion, in which proteins, carbohydrates and fats are broken down into assimilable forms. The process begins in the mouth with saliva, receives a major boost from gastric peptic digestion, and continues in the small intestine, assisted by the emulsive action of bile salts (see Chapter 18 ). 2. Terminal digestion, which involves the hydrolysis of carbohydrates and peptides by disaccharidases and peptidases, respectively, in the brush border of the small intestinal mucosa. 3. Transepithelial transport, in which nutrients, fluid, and electrolytes are transported across the epithelium of the small intestine for delivery to the intestinal vasculature. Absorbed fatty acids are converted to triglycerides and, with cholesterol, are assembled into chylomicrons for delivery to the intestinal lymphatic system.
The major diseases and disorders causing malabsorption are listed in Table 17-9 . Thisclassification is most helpful for diseases in which there is a single, clear-cut abnormality.In many malabsorptive disorders a defect in one pathophysiologic process predominates,but others may contribute or may be secondary outcomes of the primary cause. Althoughmany causes of malabsorption can be established clinically, small intestinal mucosalbiopsy may be required to satisfactorily identify or exclude celiac disease.Clinically, the malabsorption syndromes resemble each other more than they differ. Theconsequences of malabsorption affect many organ systems: TABLE 17-9 -- Major Malabsorption SyndromesDefective Intraluminal DigestionDigestion of fats and proteins• Pancreatic insufficiency, owing to pancreatitis or cystic fibrosis• Zollinger-Ellison syndrome, with inactivation of pancreatic enzymes by excess gastricacid secretionSolubilization of fat, owing to defective bile secretion• Ileal dysfunction or resection, with decreased bile salt uptake• Cessation of bile flow from obstruction, hepatic dysfunctionNutrient preabsorption or modification by bacterial overgrowthPrimary Mucosal Cell AbnormalitiesDefective terminal digestion• Disaccharidase deficiency (lactose intolerance)• Bacterial overgrowth, with brush border damageDefective epithelial transport• Abetalipoproteinemia• Primary bile acid malabsorption owing to mutations in the ileal bile acid transporterReduced Small Intestinal Surface AreaGluten-sensitive enteropathy (celiac disease)Crohn diseaseLymphatic ObstructionLymphomaTuberculosis and tuberculous lymphadenitisInfection
Acute infectious enteritisParasitic infestationTropical sprueWhipple disease (Tropheryma whippelii)IatrogenicSubtotal or total gastrectomyShort-gut syndrome, following extensive surgical resectionDistal ileal resection or bypass • Alimentary tract: diarrhea, both from nutrient malabsorption and excessive intestinal secretions, flatus, abdominal pain, weight loss, and mucositis resulting from vitamin deficiencies • Hematopoietic system: anemia from iron, pyridoxine, folate, and/or vitamin B12 deficiency and bleeding from vitamin K deficiency • Musculoskeletal system: osteopenia and tetany from calcium, magnesium, and vitamin D deficiency • Endocrine system: amenorrhea, impotence, and infertility from generalized malnutrition; hyperparathyroidism from protracted calcium and vitamin D deficiency • Epidermis: purpura and petechiae from vitamin K deficiency, edema from protein deficiency, dermatitis and hyperkeratosis from deficiencies of vitamin A, zinc, essential fatty acids and niacin • Nervous system: peripheral neuropathy from vitamin A and B12 deficiencies.The passage of abnormally bulky, frothy, greasy, yellow, or gray stools (steatorrhea) is aprominent feature of malabsorption, accompanied by weight loss, anorexia, abdominaldistention, borborygmi, and muscle wasting. The malabsorptive disorders mostcommonly encountered in the United States are celiac disease, pancreatic insufficiency,and Crohn disease. 843Pancreatic insufficiency, primarily from chronic pancreatitis or cystic fibrosis, is a majorcause of defective intraluminal digestion. Typical features of defective intraluminaldigestion are an osmotic diarrhea from undigested nutrients and steatorrhea. Excessivegrowth of normal bacteria within the proximal small intestine (bacterial overgrowth,discussed earlier) also impairs intraluminal digestion and can damage mucosal epithelialcells, causing impaired terminal digestion and epithelial absorption.CELIAC DISEASE
Celiac disease (also referred to as celiac sprue, gluten-sensitive enteropathy) is achronic disease, in which there is a characteristic mucosal lesion of the small intestineand impaired nutrient absorption, which improves on withdrawal of wheat gliadins andrelated grain proteins from the diet. Celiac disease occurs largely in Caucasians and is rare or nonexistent among native Africans, Japanese, and Chinese. Its prevalence in theUnited States is somewhat difficult to define; in Europe the prevalence is in the range of1:100 to 1:200. The disease was first described more than a century ago, but its connection to gluten was not known until the 1940s, changing its clinical management.Pathogenesis.The fundamental disorder in celiac disease is a sensitivity to gluten, which is the alcohol-soluble, water-insoluble protein component (gliadin) of wheat and closely related grains(oat, barley, and rye). The hallmark of this disease is a T-cell mediated chronicinflammatory reaction with an autoimmune component, which most likely develops as aconsequence of a loss of tolerance to gluten. Interplay between genetic predisposingfactors, the host immune response, and environmental factors is central to diseasepathogenesis. The small intestinal mucosa, when exposed to gluten, accumulatesintraepithelial CD8+ T cells and large numbers of lamina propria CD4+ T cells, whichare sensitized to gliadin. The recognized epitopes are confined to residues 57–75 ofgliadin. It has been long known that family history is important in celiac disease. Almost allindividuals with celiac disease share the major histocompatibility complex class II HLA-DQ2 orFigure 17-38 Celiac disease (gluten-sensitive enteropathy). A, A peroral jejunal biopsy specimen ofdiseased mucosa shows diffuse severe atrophy and blunting of villi, with a chronic inflammatory infiltrateof the lamina propria. B, A normal mucosal biopsy.HLA-DQ8 haplotype. It has been proposed that gliadin is deamidated by the enzymetransglutaminase and that deamidated gliadin peptides bind to DQ2 and DQ8.Recognition of these peptides by CD4+ T cells leads to secretion of interferon γ, whichdamages the intestinal wall. Although this is an attractive hypothesis, its key elements
remain to be proven. It is also unclear how CD8+ T cells accumulate in the epithelium.They do not recognize gliadin, but seem to respond to stress-induced molecules onepithelial cells. The epithelial cells secrete large amounts of IL-15 that activates CD8+ Tcells and increases the risk of lymphoma development.Morphology.By endoscopy, the small intestinal mucosa appears flat or scalloped, or may be visuallynormal. Biopsies demonstrate diffuse enteritis, with marked atrophy or total loss ofvilli. The surface epithelium shows vacuolar degeneration, loss of the microvillus brushborder, and an increased number of intraepithelial lymphocytes ( Fig. 17-38 ). The crypts,on the other hand, exhibit increased mitotic activity and are elongated, hyperplastic, andtortuous, so that the overall mucosal thickness remains the same. The lamina propria hasan overall increase in plasma cells, lymphocytes, macrophages, eosinophils, and mastcells. All these changes are usually more marked in the proximal small intestine than inthe distal, since it is the duodenum and proximal jejunum that are exposed to the highestconcentration of dietary gluten. Although these changes are characteristic of celiacdisease, they can be mimicked by other diseases, most notably tropical sprue. Mucosalhistology usually reverts to normal or near-normal following a period of gluten exclusionfrom the diet.Clinical Features.The symptoms of celiac disease vary tremendously from patient to patient. Symptomaticdiarrhea and failure to thrive may be evident during infancy, yet adults may seekattention only in their fifth decade of life. The classic presentation includes diarrhea,flatulence, weight loss, and fatigue. However, extraintestinal manifestations ofmalabsorption may overshadow the intestinal symptoms. A characteristic 844skin blistering lesion, dermatitis herpetiformis, can occur in patients with celiac disease.Neurologic disorders are occasionally seen. Detection of circulating anti-gliadin or "anti-endomysial" antibodies strongly favors the diagnosis; antibodies against tissuetransglutaminase also may be detected, as this is the autoantigen recognized by anti-endomysial antibody. Definitive diagnosis rests on (1) clinical documentation ofmalabsorption; (2) demonstration of the intestinal lesion by small bowel biopsy; and (3)unequivocal improvement in both symptoms and mucosal histology on gluten withdrawalfrom the diet. If there is doubt about the diagnosis, gluten challenge followed by rebiopsyhas been advocated. Serologic tests used for screening or treatment follow-up include thedetection of antibodies against tissue transglutaminase and gliadin.Most patients with celiac disease who adhere to a gluten-free diet remain wellindefinitely and ultimately die of unrelated causes. However, there is a long-term risk ofmalignant disease, which includes non-Hodgkin lymphoma (moderate risk), small
intestinal adenocarcinoma, and esophageal squamous cell carcinoma (50- to 100-foldhigher risk than the general population).TROPICAL SPRUE (POSTINFECTIOUS SPRUE)This condition is so named because it is a celiac-like disease that occurs almostexclusively in people living in or visiting the tropics. The distribution of the disease iscurious: It is common in the Caribbean (but not in Jamaica), central and southern Africa,the Indian subcontinent and Southeast Asia, and portions of Central and South America.The disease may occur in endemic form, and epidemic outbreaks have occurred. Nospecific causal agent has been clearly associated with tropical sprue, but bacterialovergrowth by enterotoxigenic organisms (e.g., E. coli and Hemophilus) has beenimplicated.Morphology.Intestinal changes are extremely variable, ranging from near normal to severe diffuseenteritis. Unlike celiac sprue, injury is seen at all levels of the small intestine. Patientsfrequently have folate and/or vitamin B12 deficiency, leading to markedly atypicalenlargement of the nuclei of epithelial cells (megaloblastic change), reminiscent of thechanges seen in pernicious anemia.Malabsorption usually becomes apparent within days or a few weeks of an acutediarrheal enteric infection in visitors to endemic locales and may persist if untreated. Themainstay of treatment is broad-spectrum antibiotics, supporting an infectious etiology.Intestinal lymphoma does not appear to be associated with this disorder.WHIPPLE DISEASEWhipple disease is a rare disease caused by the bacterium Tropheryma whippelii. It is asystemic condition that may involve any organ of the body, but principally affects theintestine, central nervous system, and joints. The disease was first described as intestinal lipodystrophy by George Whipple in 1907. The bacterial etiology wasdiscovered in the 1960s on the basis of ultrastructural observations. The pathogenesis ofWhipple disease is still not clear. The causal organism T. whippelii is a gram-positiveactinomycete, named on the basis of molecular phylogenetic analysis. The bacteriaproliferate preferentially within macrophages and invoke no significant host immunereaction.Morphology.The hallmark of Whipple disease is a small-intestinal mucosa laden with distendedmacrophages in the lamina propria. The macrophages contain PAS-positive, diastase-resistant granules (which are lysosomes stuffed with partially digested microorganisms)and rod-shaped bacilli on electron microscopy ( Fig. 17-39 ). The PAS stain is notspecific for this bacterium. In untreated cases, bacilli can be seen as well in neutrophils,the extracellular space of the lamina propria, and even in epithelial cells. Expansion ofthe villi by the dense infiltrate of macrophages imparts a shaggy gross appearance to the
intestinal mucosal surface; edema of the mucosa thickens the intestinal wall.Accompanying these changes is involvement of mesenteric lymph nodes by the sameprocess and lymphatic dilation, suggesting lymphatic obstruction. The lymphaticblockade is believed to be responsible for lipid deposition in the villi, thus the originalimpression of intestinal lipodystrophy. Bacilli-laden macrophages also can be found inthe synovial membranes of affected joints, the brain, cardiac valves, and elsewhere. Ateach of these sites, inflammation is essentially absent. Functional impairmentnevertheless can be considerable at each affected site.Clinical Features.Whipple disease is principally encountered in Caucasians in the fourth to fifth decades oflife, with a strong male predominance of 10:1. Many of the published cases came fromrural regions, suggesting an environmental influence. It usually presents as a form ofmalabsorption with diarrhea and weight loss, sometimes of years duration. Arthropathyis often the initial presentation. Atypical presentations, with polyarthritis, obscurepsychiatric complaints, cardiac abnormalities, and other symptom complexes, arecommon. Lymphadenopathy and hyperpigmentation are present in over half of patients.Currently, the diagnosis still rests on demonstration of small intestinal PAS-positivemacrophages that contain rod-shaped organisms on electron microscopy. The culture ofthis bacterium in 1997 and the completion of its whole genome sequence in 2003 willmost likely give rise to more specific molecular diagnosis of this disease. Response to antibiotic therapy is usually prompt, although some patients have a protracted, refractorycourse.DISACCHARIDASE (LACTASE) DEFICIENCYThe disaccharidases, of which the most important is lactase, are located in the apical cellmembrane of the villous absorptive epithelial cells. Congenital lactase deficiency is avery rare condition, but acquired lactase deficiency is common, particularly amongNative Americans and African Americans. Incomplete breakdown of the disaccharidelactose into its monosaccharides glucose and galactose leads to osmotic diarrhea from theunabsorbed lactose. Bacterial fermentation of 845
Figure 17-39 Whipple disease. A, Note foamy macrophages in the lamina propria. B, PAS stain showingthe positive granules in the foamy macrophages. C, Electron micrograph of a lamina propria macrophageshowing many bacilli within the cell (arrow) and in the extracellular space (arrowhead). Inset, Highermagnification of macrophage cytoplasm showing cross-sectional profiles of bacilli and their cell walls(small arrows). (C, courtesy of George Kasnic and Dr. William Clapp, University of Florida, Gainesville,FL.)the unabsorbed sugars leads to increased hydrogen production, which is readily measuredin exhaled air by gas chromatography.When caused by an inherited enzyme deficiency, malabsorption becomes evident withthe initiation of milk feeding. The infants develop explosive, watery, frothy stools andabdominal distention. Malabsorption is promptly corrected when exposure to milk andmilk products is terminated. In the adult, lactase insufficiency apparently develops as an
acquired disorder, sometimes in association with viral and bacterial enteric infections orother disorders of the gut. Neither light nor electron microscopy has disclosedabnormalities of the mucosal cells of the bowel in either the hereditary or acquired formof the disease. 846ABETALIPOPROTEINEMIAInability to synthesize apolipoprotein B is a rare inborn error of metabolism transmittedby autosomal recessive inheritance. It is characterized by a defect in the synthesis andexport of lipoproteins from intestinal mucosal cells. Free fatty acids and monoglyceridesthat are produced by hydrolysis of dietary fat enter the absorptive epithelial cells and arere-esterified in the normal fashion but cannot be assembled into chylomicrons. As aconsequence, triglycerides are stored within the cells, creating lipid vacuolation that isreadily evident under the light microscope, particularly with special fat stains.Concomitantly, there is complete absence in plasma of all lipoproteins containingapolipoprotein B (chylomicrons, very-low-density lipoproteins, and low-densitylipoproteins). The failure to absorb certain essential fatty acids leads to lipid membranedefects, readily evident in the characteristic acanthocytic erythrocytes (burr cells). Thedisease becomes manifest in infancy and is dominated by failure to thrive, diarrhea, andsteatorrhea.Idiopathic Inflammatory Bowel DiseaseIdiopathic inflammatory bowel disease is a set of chronic inflammatory conditionsresulting from inappropriate and persistent activation of the mucosal immune system,driven by the presence of normal intraluminal flora. The two disorders known as inflammatory bowel disease (IBD) are Crohn disease (CD) and ulcerative colitis (UC).These diseases share many common features but have distinctly different clinicalmanifestations. IBD is common in developed countries, with up to 1 in 200 of individualsof Northern European descent affected by these diseases. The annual incidence of IBD inthe United States is approximately 3 to 10 new cases per 100,000 people.Both CD and UC are chronic, relapsing inflammatory disorders of obscure origin. CD isan autoimmune disease that may affect any portion of the gastrointestinal tract fromesophagus to anus, but most often involves the distal small intestine and colon. UC is achronic inflammatory disease limited to the colon and rectum. Both exhibitextraintestinal inflammatory manifestations. Before considering these diseasesseparately, the pathogenesis of IBD is considered.ETIOLOGY AND PATHOGENESIS
A remarkable attribute of the normal gastrointestinal tract is that the mucosal immunesystem is always poised to respond against ingested pathogens but is unresponsive tonormal intestinal microflora. In IBD, this state of homeostasis is disrupted, leading to two key pathogenic abnormalities—strong immune responses against normal flora, anddefects in epithelial barrier function. The basis of these abnormalities is still notestablished, which is why both CD and UC are considered idiopathic diseases. However,recently, extensive investigations of animal models, and more limited analyses of lesionsfrom patients, have led to some important conclusions about the pathogenesis of IBD. It is postulated that IBD results from unregulated and exaggerated local immune responsesto commensal microbes in the gut, in genetically susceptible individuals. Thus, as inmany other autoimmune disorders ( Chapter 6 ), the pathogenesis of IBD involves failureof immune regulation, genetic susceptibility, and environmental triggers, specificallymicrobial flora. Below we summarize some salient points about each of the factors thatcontribute to IBD.Genetic Susceptibility.Fifteen percent of IBD patients have affected first-degree relatives, and the lifetime risk ifeither a parent or sibling is affected is 9%. Dizygotic twins have the concordance ratesexpected for siblings; monozygotic twins exhibit a 30% to 50% concordance rate for CD.These associations clearly indicate that genetic susceptibility plays an important role inthe development of IBD. The disease is a complex multigenic trait, and is not inherited inMendelian fashion. Many candidate genes are known to be associated with, and likelycontribute to, the development of IBD. These include HLA associations; an HLA-DR1/DR1/DQw5 allelic combination has been observed in 27% of North American whitepatients with CD, whereas HLA-DR2 is increased in patients with UC. A gene calledNOD2 (so named because the encoded protein has a nucleotide-binding oligomerizationdomain) has recently been shown to be associated with CD. The NOD2 protein is expressed in many types of leukocytes as well as epithelial cells, and is thought tofunction as an intracellular receptor for microbes. Upon binding microbial components, itmay trigger the NF-κB pathway; recall that NF-κB is a transcription factor that triggersthe production of cytokines and other proteins involved in innate immune defense againstinfectious pathogens ( Chapter 6 ). The NOD2 mutations that are associated with Crohndisease may reduce the activity of the protein, resulting in the persistence of intracellularmicrobes and uncontrolled, prolonged immune responses. There is, however, no directproof in support of this hypothesis. Other gene(s) associated with CD have been localizedto chromosome 5q31; although a candidate gene in this locus has not been identified, thisregion is rich in genes encoding several cytokines that may contribute to IBD. Finally, itis worth mentioning that in inbred mice, the knockout of many different genes,individually, leads to the common pathologic manifestation of chronic inflammation inthe intestine. It is, therefore, likely that immune dysregulations arising by multiplemechanisms may contribute to IBD in humans.Role of Intestinal Flora.Animal studies have definitively established the importance of gut flora in IBD. If gene- knockout mice that normally develop IBD are made germfree, the disease disappears.
However, the hunt for a specific microbe as the underlying cause has been largelyfruitless. There is also no clear evidence that reducing intestinal flora has a beneficialeffect on the course of IBD in humans. Microbes could exacerbate immune reactions byproviding antigens and inducing costimulators and cytokines, all of which contribute toT-cell activation ( Chapter 6 ). Defects in the barrier function of the intestinal epitheliumcould allow luminal flora to gain access to the mucosal lymphoid tissue, and thus triggerimmune responses.Abnormal T-Cell Responses.It is believed that the exaggerated local immune response in IBD is a consequence of toomuch T-cell activation and/or too little control by regulatory T lymphocytes. Both aspectshave been clearly illustrated in animal models of the disease, and the lesions in humansshow clear evidence of T-cell reactions (see below). 847Thus, susceptibility genes, intestinal flora, and defective control of immune reactions allseem to play a role in the initiation and progression of IBD. One interesting, and largelyunanswered question is, are these diseases caused by "true" autoimmunity, i.e. are theimmune responses directed against self-antigens in the intestinal epithelium or onlyagainst the antigens of intestinal microbes. Regardless of the specificity of the pathogenicimmune response, several features of the response and its role in the disease are known. • In both CD and UC, the prime culprits appear to be T-cells, particularly CD4+ T-cells, and the lesions are likely caused by T-cells and their products. Although antibodies against certain self-antigens, such as tropomyosin, have been detected in some patients with UC, it is not clear that these autoantibodies play a pathogenic role. • Crohn disease appears to be the result of a chronic delayed-type hypersensitivity reaction induced by IFN-γ-producing TH 1 cells. The nature of the inflammatory infiltrate, especially the presence of granulomas, is consistent with a TH 1 response. • Although animal models suggest that ulcerative colitis is caused by excessive activation of TH 2 cells, in the human disease the signature TH 2 cytokine, IL-4, has not been found in the lesions. It may be that the lesions are caused by an atypical TH 2 response, or that there is no consistent pattern of T cell activation or dominant cytokine production.Diagnosis of IBD.Since the exact etiology of IBD is not known, the diagnosis of IBD and the distinctionbetween CD and UC are dependent on clinical history, radiographic examination,laboratory findings, and pathologic examination of tissue. There is no single test uponwhich a diagnosis is made. Even with the best efforts, the distinction between the twodiseases still cannot be made in some cases. As discussed later, pathologic appearance,
both macroscopic and microscopic, plays a central role in establishing a definitivediagnosis. In recent years, considerable effort has been given to developing accuratenoninvasive laboratory tests. The pANCA (perinuclear antineutrophilic cytoplasmic antibody) is positive in 75% of patients with UC and in only 11% with CD. Another test detects an antibody against the cell wall mannan polysaccharide of Saccharomycescerevisiae (ASCA). This antibody appears to be elevated in CD patients. The clinicalutility of these tests remains to be proven.CROHN DISEASEWhen first described by Crohn, Ginsburg, and Oppenheimer in 1932, this idiopathicdisorder was thought to be limited to the terminal ileum, hence the designation terminalileitis. Recognition that sharply delineated bowel segments might be affected, withintervening unaffected ("skip") areas, led to the alternative name regional enteritis.Predominant involvement of the colon gave rise to the term granulomatous colitis. It isnow clear that any level of the alimentary tract may be involved and that there aresystemic manifestations; thus, the eponymic name Crohn disease is preferred. When fullydeveloped, Crohn disease is characterized pathologically by (1) sharply delimited andtypically transmural involvement of the bowel by an inflammatory process with mucosaldamage, (2) the presence of noncaseating granulomas, and (3) fissuring with formationof fistulae.Epidemiology.Crohn disease occurs throughout the world, but primarily in Western developedpopulations. Its annual incidence in the United States is around 3 per 100,000, with ratesbetween 4 and 10 per 100,000 reported in Great Britain and Scandinavia. The incidenceand prevalence of CD has been steadily rising in the United States and Northern Europe.It occurs at any age, from young childhood to advanced age, but peak ages of detectionare the second and third decades of life with a minor peak in the sixth and seventhdecades. Females are affected slightly more often than males. Whites appear to developthe disease two to five times more often than do nonwhites. In the United States, CDoccurs three to five times more often among Jews than among non-Jews. Smoking is astrong exogenous risk factor.Morphology.In CD, there is gross involvement of the small intestine alone in about 40% of cases, ofsmall intestine and colon in 30%, and of the colon alone in about 30%. CD may involvethe duodenum, stomach, esophagus, and even mouth, but these sites are distinctlyuncommon. In diseased bowel segments, the serosa is granular and dull gray, and oftenthe mesenteric fat wraps around the bowel surface (creeping fat). The mesentery of theinvolved segment is also thickened, edematous, and sometimes fibrotic. The intestinalwall is rubbery and thick, as a consequence of edema, inflammation, fibrosis, andhypertrophy of the muscularis propria. As a result, the lumen is almost alwaysnarrowed; in the small intestine this is evidenced on x-ray as the "string sign," a thinstream of barium passing through the diseased segment. Strictures may occur in the colonbut are usually less severe. A classic feature of CD is the sharp demarcation of
diseased bowel segments from adjacent uninvolved bowel. When multiple bowelsegments are involved, the intervening bowel is essentially normal ("skip" lesions).A characteristic sign of early disease is focal mucosal ulcers resembling canker sores(aphthous ulcers), edema, and loss of the normal mucosal texture. With progressivedisease, mucosal ulcers coalesce into long, serpentine linear ulcers, which tend to beoriented along the axis of the bowel ( Fig. 17-40 ). As the intervening mucosa tends to berelatively spared, the mucosa acquires a coarsely textured,Figure 17-40 Crohn disease of ileum, showing narrowing of the lumen, bowel wall thickening, serosalextension of mesenteric fat ("creeping fat"), and linear ulceration of the mucosal surface (arrowheads). 848cobblestone appearance. Narrow fissures develop between the folds of the mucosa,often penetrating deeply through the bowel wall ( Fig. 17-41 ) and leading to boweladhesions and serositis. Further extension of fissures leads to fistula or sinus tractformation, either to an adherent viscus, to the outside skin, or into a blind cavity. Freeperforation or localized abscesses may also develop.The characteristic histologic features of CD are: • Mucosal inflammation. The earliest lesion in CD appears to be focal neutrophilic infiltration into the epithelial layer, particularly overlying mucosal lymphoid aggregates. As the disease becomes more established, neutrophils infiltrate isolated crypts; when a sufficient number of neutrophils have traversed the epithelium of a crypt (both in the small and large intestines), a crypt abscess is formed, usually with ultimate destruction of the crypt. • Chronic mucosal damage. The hallmark of inflammatory bowel disease, both CD and UC, is chronic mucosal damage. Architectural distortion is manifested in the small intestine as variable villus blunting; in the colon, crypts exhibit irregularity and branching. The degree of the glandular architectural distortion in CD is usually less severe than in UC. Crypt destruction leads to
progressive atrophy, particularly in the colon. The mucosa may undergometaplasia: This may take the form of gastric antraltype glands (pyloricmetaplasia) or the development of Paneth cells in the distal colon, where they arenormally absent (Paneth cell metaplasia).• Ulceration. Ulceration is the usual outcome of severe active disease. Ulcerationmay be superficial, may undermine adjacent mucosa in a lateral fashion, or maypenetrate deeply into underlying tissue layers. There is often an abrupt transitionbetween ulcerated and adjacent normal mucosa.• Transmural inflammation affecting all layers. Chronic inflammatory cellssuffuse the affected mucosa and, to a lesser extent, all underlying tissue layers.Lymphoid aggregates are usually scattered throughout the bowel wall.• Noncaseating granulomas. In about half of the cases, sarcoid-like granulomasmay be present in all tissue layers, both within areas of active disease and inuninvolved regions of the bowel ( Fig. 17-42 ). Granulomas have beendocumented throughout the alimentary tract, from mouth to rectum, in patientswith CD limited to one bowel segment. Conversely, the absence of granulomasdoes not preclude the diagnosis of CD.• Other mural changes. In diseased segments, the muscularis mucosa usuallyexhibits reduplication, thickening, and irregularity. Fibrosis of the submucosa,muscularis propria, and mucosa eventually leads to stricture formation. Lesscommon findings are mucosal and submucosal lymphangiectasia, hypertrophy ofmural nerve fibers, and localized vasculitis.
Figure 17-41 Crohn disease of the colon; a deep fissure extending into the muscle wall, a second, shallowulcer (on the upper right), and relative preservation of the intervening mucosa. Abundant lymphocyteaggregates are present, evident as dense blue patches of cells at the interface between mucosa andsubmucosa.Clinical Features.The clinical manifestations of Crohn disease are extremely variable. They are generallymore subtle than those of UC. The disease usually begins with intermittent attacks ofrelatively mild diarrhea, fever, and abdominal pain, spaced by asymptomatic periodslasting for weeks to many months. Often the attacks are precipitated by periods ofphysical or emotional stress. Although emotional influences are thought not to have anydirect role in the initiation of the disease, they may contribute to flare-ups. In those withcolonic involvement, occult or overt fecal blood loss may lead toFigure 17-42 Crohn disease of the colon. A noncaseating granuloma is present in the lamina propria of anuninvolved region of colonic mucosa (arrow). 849anemia over time, but massive bleeding is uncommon. In about one-fifth of patients theonset is more abrupt, with acute right lower quadrant pain, fever, and diarrhea sometimessuggesting acute appendicitis or an acute bowel perforation. The course of the diseaseincludes bouts of diarrhea with fluid and electrolyte losses, weight loss, and weakness.During this lengthy, chronic disease, complications may arise from fibrosing strictures,particularly of the terminal ileum, and fistulas to other loops of bowel, the urinarybladder, vagina, or perianal skin, or into a peritoneal abscess. Extensive involvement ofthe small bowel, including the terminal ileum, may cause marked loss of albumin(protein-losing enteropathy), generalized malabsorption, specific malabsorption ofvitamin B12 (resulting in pernicious anemia), or malabsorption of bile salts, leading tosteatorrhea.
Extraintestinal manifestations of this disease include migratory polyarthritis, sacroiliitis,ankylosing spondylitis, erythema nodosum, and clubbing of the fingertips. Hepaticprimary sclerosing cholangitis (see Chapter 18 ) occurs, but the association is not asstrong as in UC. Any of these manifestations can develop before onset of intestinalsymptoms. Deranged systemic immunity is thought to underlie these related disorders.Uveitis, nonspecific mild hepatic pericholangitis, and renal disorders secondary totrapping of the ureters in the inflammatory process sometimes develop. Systemicamyloidosis is a rare late consequence.There is an increased incidence of cancer of the gastrointestinal tract in patients withlong-standing progressive CD, with a five- to six-fold increased risk over age-matchedpopulations. However, the risk of cancer in CD is considerably less than in patients withchronic UC.ULCERATIVE COLITISUlcerative colitis is an ulceroinflammatory disease limited to the colon and affectingonly the mucosa and submucosa except in the most severe cases. Unlike CD, UC extendsin a continuous fashion proximally from the rectum. Well-formed granulomas are absent.Like CD, UC is a systemic disorder associated in some patients with migratorypolyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, hepatic involvement(pericholangitis and primary sclerosing cholangitis; Chapter 18 ), and skin lesions.Epidemiology.UC is global in distribution and varies in incidence relative to CD, supporting the conceptthat they are separate diseases. In the United States, Great Britain, and Scandinavia theincidence is about 4 to 12 per 100,000 population, which is slightly greater than CD. Aswith CD, the incidence of this condition has risen in recent decades. In the United Statesit is more common among whites than among blacks, and females are affected more oftenthan males. The onset of disease peaks between ages 20 and 25, but the condition mayarise in both younger and considerably older individuals. Nonsmoking is associated withUC; ex-smokers are at higher risk for developing UC than never-smokers.Morphology.Ulcerative colitis involves the rectum and extends proximally in a retrogradefashion to involve the entire colon ("pancolitis") in the more severe cases. It is adisease of continuity, and "skip" lesions such as occur in Crohn disease are notfound ( Fig. 17-43 ). In 10% of patients with severe pancolitis, the distal ileum maydevelop mucosal inflammation ("backwash ileitis"). This is probably due to theincompetence of the iliocecal valve, resulting in reflux of the inflammatory material fromthe colon. In contrast to CD, the ileitis is often diffuse and limited to within 25 cm fromthe ileocecal valve. The appendix may be involved with both CD and UC.In the course of colonic involvement with UC, the mucosa may exhibit slight reddeningand granularity with friability and easy bleeding. With fully developed severe, active
inflammation, there may be extensive and broad-based ulceration of the mucosa in thedistal colon or throughout its length ( Fig. 17-44 ). Isolated islands of regeneratingmucosa bulge upward to create pseudopolyps. Often the undermined edges of adjacentulcers interconnect to create tunnels covered by tenuous mucosal bridges. As with CD,the ulcers of UC are frequently aligned along the axis of the colon, but rarely do theyreplicate the linear serpentine ulcers of CD. With indolent chronic disease or with healingof active disease, progressive mucosal atrophy leads to a flattened and attenuatedmucosal surface ( Fig. 17-45 ). Unlike CD, mural thickening does not occur in UC, andthe serosal surface is usually completely normal. Only in the most severe cases ofulcerative disease (UC, CD, and other severe inflammatory diseases) does toxic damageto the muscularis propria and neural plexus lead to complete shutdown of neuromuscularfunction. In this instance the colon progressively swells and becomes gangrenous (toxicmegacolon) ( Fig. 17-46 ).The mucosal alterations in UC are similar to those of colonic CD, with inflammation,chronic mucosalFigure 17-43 Comparison of the distribution patterns of Crohn disease and ulcerative colitis, as well as thedifferent conformations of the ulcers and wall thickenings.
850Figure 17-44 Ulcerative colitis. Ulcerated hemorrhagic surface with knobby pseudopolyps. (Courtesy ofDr. Kim Bechard, Brigham and Womens Hospital, Boston, MA.)damage, and ulceration ( Fig. 17-47 ). First, a diffuse, predominantly mononuclearinflammatory infiltrate in the lamina propria is almost universally present, even at thetime of clinical presentation. Neutrophilic infiltration of the epithelial layer may producecollections of neutrophils in crypt lumina (crypt abscesses). These are not specific forUC and may be observed in CD or any active inflammatory colitis. Unlike CD, there areno granulomas, although rupture of crypt abscesses may incite a foreign body reaction inthe lamina propria. Second, further destruction of the mucosa leads to outright ulceration,extending into the submucosa and sometimes leaving only the raw, exposed muscularispropria. Third, with remission of active disease, granulation tissue fills in the ulcercraters, followed by regeneration of the mucosal epithelium. Submucosal fibrosis andmucosal architectural disarray and atrophy remain as residua of healed disease.
Figure 17-45 Ulcerative colitis. Low-power micrograph showing marked chronic inflammation of themucosa with atrophy of colonic glands, moderate submucosal fibrosis, and a normal muscle wall.Figure 17-46 Toxic megacolon. Complete cessation of colon neuromuscular activity has led to massivedilatation of the colon and black-green discoloration signifying gangrene and impending rupture.A key feature of UC is that the mucosal damage is continuous from the rectum andextending proximally. In CD, mucosal damage in the colon may be continuous but isjust as likely to exhibit skip areas. It should be noted that quiescent UC, particularlytreated disease in which active neutrophilic inflammation is not present, may appearvirtually normal histologically. This does not preclude risk for dysplasia, as nowdescribed.Particularly significant in ulcerative colitis is the spectrum of epithelial changessignifying dysplasia and the progression to frank carcinoma. Nuclear atypia and lossof cytoplasmic differentiation may be present in inflamed or uninflamed colonic mucosa.Epithelial dysplasia is referred to as being low-grade or high-grade; cytologic features are the key to evaluating dysplasia. Distinguishing between regenerative changes and
dysplasia can be very difficult and sometimes impossible. Pathologists are allowed somelatitude in noting atypical changes that may not be definitive for a diagnosis of dysplasia. Plaque-like dysplastic lesions, overt polypoid dysplasia (adenomas),Figure 17-47 Ulcerative colitis. Microscopic view of the mucosa, showing diffuse active inflammationwith crypt abscess and glandular architectural distortion. 851or invasive carcinoma are the ultimate lesions arising from flat dysplasia. It should benoted that elderly patients with UC are also at risk for sporadic adenomas. Distinctionbetween IBD-associated dysplasia and a coexistent incidental adenoma may be difficult.Clinical Features.Ulcerative colitis typically presents as a relapsing disorder marked by attacks of bloodymucoid diarrhea that may persist for days, weeks, or months and then subside, only torecur after an asymptomatic interval of months to years or even decades. In the fortunatepatient, the first attack is the last. At the other end of the spectrum, the explosive initialattack may lead to such serious bleeding and fluid and electrolyte imbalance as toconstitute a medical emergency. In most patients, bloody diarrhea containing stringymucus, accompanied by lower abdominal pain and cramps usually relieved by defecation,is the first manifestations of the disease. In a small number of patients, constipation mayappear paradoxically, due to disruption of normal peristalsis. Often the first attack ispreceded by a stressful period in the patients life. Spontaneously, or more often afterappropriate therapy, these symptoms abate in the course of days to weeks. Flare-ups,when they do occur, may be precipitated by emotional or physical stress and rarely byconcurrent intraluminal growth of enterotoxin-forming C. difficile. Sudden cessation ofbowel function with toxic dilatation (toxic megacolon) rarely develops with severe acuteattacks; perforation is a potentially lethal event.
The outlook for patients with UC depends on two factors: (1) the severity of activedisease and (2) its duration. About 60% of patients have clinically mild disease. In theseindividuals, the bleeding and diarrhea are not severe, and systemic signs and symptomsare absent. However, almost all patients (97%) have at least one relapse during a 10-yearperiod, and about 30% of patients require colectomy within the first 3 years of onset dueto uncontrollable disease. On rare occasion, * TABLE 17-10 -- Distinctive Features of Crohn Disease and Ulcerative ColitisFeature Crohn Disease - SI Crohn Disease - C Ulcerative ColitisMacroscopicBowel region Ileum ± colon Colon ± ileum Colon onlyDistribution Skip lesions Skip lesions DiffuseStricture Early Variable Late/rareWall appearance Thickened Thin ThinDilation No Yes YesMicroscopicInflammation Transmural Transmural Limited in mucosaPseudopolyps No to slight Marked MarkedUlcers Deep, linear Deep, linear SuperficialLymphoid reaction Marked Marked MildFibrosis Marked Moderate MildSerositis Marked Variable Mild to noneGranulomas Yes (50%) Yes (50%) NoFistulae/sinuses Yes Yes NoClinicalFat/vitamin Yes Yes, if ileum NomalabsorptionMalignant potential Yes Yes YesResponse to surgery Poor Fair Good*SI, Crohn disease of the small intestine; C, Crohn disease of the colon. Features are often not all present ina single case.
the disease runs a fulminant course; unless medically or surgically controlled, this toxicform of the disease can lead to death soon after onset.The most feared long-term complication of UC is cancer. There is a tendency fordysplasia to arise in multiple sites, and the underlying inflammatory disease may maskthe symptoms and signs of carcinoma. UC is characterized by DNA damage withmicrosatellite instability in mucosal cells. More recently, genomic instability wasdetected in non-dysplastic areas of patients with UC, suggesting that these patients haveDNA repair deficiency and genomic instability throughout the intestinal tract. The associated carcinomas are often infiltrative without obvious exophytic masses, furtherunderscoring the importance of early diagnosis. Historically, the risk of cancer is highestin patients with pancolitis of 10 or more years duration, in whom it is 20- to 30-foldhigher than in a control population. However, recent screening programs of patients with UC now indicate that the rate of progression to dysplasia and carcinoma is in factquite low, provided that initial examinations were negative for dysplasia. Since great costis involved in mass screening, the debate over the cost-effectiveness of repeatedcolonoscopies in patients with long-term inactive disease continues; the modestimprovement in patient outcome may be related to better patient care, rather thanidentification of dysplasia per se.The features of CD and UC are compared in Table 17-10 .Vascular DisordersISCHEMIC BOWEL DISEASEIschemic lesions may be restricted to the small or large intestine, or may affect both,depending on the particular vessel(s) affected. Acute occlusion of one of the three majorsupply trunks of the intestines—celiac, superior mesenteric, and inferior mesentericarteries—may lead to infarction of several meters of intestine. However, insidious loss ofone 852
Figure 17-48 Acute ischemic bowel disease. Schematic of the three levels of severity, diagrammed for thesmall intestine.vessel may be without effect, due to the rich anastomotic interconnections. Lesionswithin the end arteries, which penetrate the gut wall, produce small, focal ischemiclesions. As depicted in Figure 17-48 , the severity of injury ranges from: (1) transmuralinfarction of the gut, involving all visceral layers; to (2) mural infarction of the mucosaand submucosa; to (3) mucosal infarction, if the lesion extends no deeper than themuscularis mucosae. Almost always, transmural infarction is caused by mechanicalcompromise of the major mesenteric blood vessels. Mucosal Mucosal or mural infarctionmore often results from hypoperfusion, either acute or chronic. Mesenteric venousthrombosis is a less frequent cause of vascular compromise. The predisposing conditionsfor ischemia are as follows: • Arterial thrombosis: severe atherosclerosis (usually at the origin of the mesenteric vessel), systemic vasculitis, dissecting aneurysm, angiographic procedures, aortic reconstructive surgery, surgical accidents, hypercoagulable states, and oral contraceptives • Arterial embolism: cardiac vegetations, angiographic procedures, and aortic atheroembolism • Venous thrombosis: hypercoagulable states, oral contraceptives, antithrombin III deficiency, intraperitoneal sepsis, the postoperative state, invasive neoplasms (particularly hepatocellular carcinoma), cirrhosis, and abdominal trauma • Nonocclusive ischemia: cardiac failure, shock, dehydration, and vasoconstrictive drugs (e.g., digitalis, vasopressin, propranolol) • Miscellaneous: radiation injury, volvulus, stricture, amyloidosis, diabetes mellitus, and internal or external herniation.Embolic arterial occlusion most often involves the branches of the superior mesentericartery. The origin of the inferior mesenteric artery from the artery is more oblique, andthis may contribute to the relative sparing of this arterial axis from embolism. Despite themultiplicity of possible causes, there remains a significant percentage of cases in whichno well-defined basis for the vascular insufficiency can be identified. Mesenteric vascularspasm has been invoked in some cases, without definitive proof.Ischemic injury has two phases: the initial hypoxic injury at the onset of blood supplycompromise and secondary reperfusion injury at the time of blood resupply to thehypoxic tissue. Most of the intestinal injury in ischemic bowel disease is actually causedby reperfusion. The underlying pathophysiology in reperfusion injury is a complexprocess. Among the most important factors in this process are the generation of oxygenfree radicals, neutrophil infiltration, and the production of inflammatory mediators intissue that has insufficient metabolic reserve to detoxify injurious free radicals and othermediators ( Chapter 1 ).Morphology.
The severity of vascular compromise and the time frame during which it develops aremajor determinants of the morphology of ischemic bowel diseases. The most severe,acute lesions are considered first.Transmural Infarction.Small intestinal infarction following sudden and total occlusion of mesenteric arterialblood flow may involve only a short segment, but more often involves a substantialportion. The splenic flexure of the colon is at greatest risk of ischemic injury because it isthe watershed between the distribution of the superior and inferior mesenteric arteries,but any portion of the colon may be affected. With mesenteric venous occlusion,anterograde and retrograde propagation of thrombus may lead to extensive involvementof the splanchnic bed. Regardless of whether the arterial or venous side is occluded, theinfarction appears hemorrhagic because of blood reflow into the damaged area. In theearly stages, the infarcted bowel appears intensely congested and dusky to purple-red( Fig. 17-49 ), with foci of subserosal and submucosal ecchymotic discoloration. Withtime, the wall becomes edematous, thickened, rubbery, and hemorrhagic. The lumencommonly contains sanguineous mucus or frank blood. In arterial occlusions thedemarcation from normal bowel is usually sharply defined, but in venous occlusions thearea of dusky cyanosis fades gradually into the adjacent normal bowel, having no clear-cut definition between viable and nonviable bowel. Histologically, there is obviousedema, interstitial hemorrhage, and sloughing necrosis of the mucosa. Normal features ofthe mural musculature, particularly cellular nuclei,Figure 17-49 Infarcted small bowel, secondary to acute thrombotic occlusion of the superior mesentericartery. 853become indistinct. Within 1 to 4 days, intestinal bacteria produce outright gangrene andsometimes perforation of the bowel. There may be little inflammatory response.
Mucosal and Mural Infarction.Mucosal and mural infarction may involve any level of the gut from the stomach to theanus. The lesions may be multifocal or continuous and widely distributed. Affected areasof the bowel may appear dark red or purple, owing to the accumulated luminalhemorrhage. However, hemorrhage and an inflammatory exudate are absent from theserosal surface. On opening the bowel, there is hemorrhagic, edematous thickening of themucosa, which may penetrate more deeply into the submucosa and muscle wall.Superficial ulceration may be present.In the mildest form of ischemic injury, the superficial epithelium of the colon or the tipsof small intestinal villi may be necrotic or sloughed. Inflammation is absent, and theremay only be mild vascular dilation. With complete mucosal necrosis, epithelial sloughingleaves behind only the acellular scaffolding of the lamina propria ( Fig. 17-50 ). Whensevere, there is extensive hemorrhage and necrosis of multiple tissue layers. Secondaryacute and chronic inflammation is evident along the viable margins underlying andadjacent to the affected area. Bacterial superinfection and the formation of enterotoxicbacterial products may induce superimposed pseudomembranous inflammation,particularly in the colon. Thus, the mucosal changes may mimic enterocolitis ofnonvascular origin.Chronic Ischemia.With chronic vascular insufficiency to a region of intestine, mucosal inflammation andulceration may develop, mimicking both acute enterocolitis from other causes andidiopathic IBD. Submucosal chronic inflammation and fibrosis may lead to stricture( Fig. 17-51 ). Although colonic strictures
Figure 17-50 Mucosal infarction of the small bowel. The mucosa is hemorrhagic, and there is no epitheliallayer. The remaining layers of the bowel are intact.Figure 17-51 Chronic ischemia of the colon, resulting in chronic mucosal damage and a stricture.typically occur in the watershed area of the splenic flexure, both acute and chronicmucosal ischemia are notoriously segmental and patchy.Clinical Features.Bowel infarction is an uncommon but grave disorder that imposes a 50% to 75% deathrate, largely because the window of time between onset of symptoms and perforation issmall. It tends to occur in older individuals, when cardiac and vascular diseases are mostprevalent. Preexistent abdominal disease also increases the risk of bowel infarction, dueto adhesions and torsion. Severe abdominal pain and tenderness develop suddenly in thesetting of transmural infarction, sometimes accompanied by nausea, vomiting, andbloody diarrhea or grossly melanotic stool. Patients may progress to shock and vascularcollapse within hours. Peristaltic sounds diminish or disappear, and spasm creates board-like rigidity of the abdominal wall musculature. Because there are far more commoncauses of these physical signs, such as acute appendicitis, perforated peptic ulcer, andacute cholecystitis, the diagnosis of intestinal gangrene may be delayed or missed, withdisastrous consequences.Mucosal and mural infarction, by themselves, may not be fatal, particularly if the causeof vascular compromise is corrected. A confusing array of nonspecific abdominalcomplaints, combined with intermittent bloody diarrhea, may be the only indication ofnonocclusive enteric ischemia. Nevertheless, bowel embarrassment may progress to moreextensive infarction, and sepsis or serious blood loss may set in. Chronic ischemic colitismay present as an insidious inflammatory disease, with intermittent episodes of bloodydiarrhea interspersed with periods of healing, mimicking IBD.
Several clinical conditions that cause ischemic intestinal injury merit emphasis. Ischemicbowel or infarction may occur in the setting of severe atherosclerosis of the aorta andmesenteric vasculature. Cholesterol emboli dislodged from large vessels occlude smallervessels downstream, leading to regions of localized compromise. Second, vasculitisaffecting the mesenteric vasculature may cause ischemic injury. The commonly seenvasculitides that affect the intestine are polyarteritis 854nodosum, Henoch-Schönlein disease, and Wegener granulomatosis. Third, amyloidosisoften affects mesenteric blood vessels and may actually present as chronic intestinalischemia.ANGIODYSPLASIAAngiodysplasia is a non-neoplastic intestinal lesion of vascular dilation andmalformation. Tortuous dilations of submucosal and mucosal blood vessels are seen mostoften in the cecum or right colon, usually only after the sixth decade of life. Although theprevalence of these lesions is less than 1% in the adult population, they account for 20%of significant lower intestinal bleeding; intestinal hemorrhage may be chronic andintermittent, or acute and massive. Most angiodysplasias span the mucosa andsubmucosa and contain a small amount of smooth muscle, suggesting that they are ectaticnests of preexisting veins, venules, and capillaries. The vascular channels may beseparated from the intestinal lumen by only the vascular wall and a layer of attenuatedepithelial cells, explaining the propensity toward bleeding.The pathogenesis of angiodysplasia remains speculative, but it is attributed to mechanicalfactors operative in the colonic wall, with possibly a congenital contribution. Normaldistention and contraction may intermittently occlude the submucosal veins that penetratethrough the muscle wall. This then leads to focal dilation and tortuosity of overlyingsubmucosal and mucosal vessels. According to LaPlaces Law, tension in the wall of acylinder is a function of intraluminal pressure and diameter. Because the cecum has thewidest diameter of the colon, it develops the greatest wall tension, perhaps explaining thedistribution of these lesions. Vascular degenerative changes related to aging may alsoplay some role. The evidence to support a congenital cause is the association ofangiodysplasia with other congenital abnormalities such as aortic stenosis and Meckeldiverticulum.HEMORRHOIDSHemorrhoids are variceal dilations of the anal and perianal venous plexuses. Theseextremely common lesions affect about 5% of the general population and developsecondary to persistently elevated venous pressure within the hemorrhoidal plexus. Themost frequent predisposing influences are constipation with straining at stool and thevenous stasis of pregnancy. Except for pregnant women, they are rarely encountered inpersons under age 30. More rarely, but much more importantly, hemorrhoids may reflect
collateral anastomotic channels that develop as a result of portal hypertension ( Chapter18 ).Morphology.The varicosities may develop in the inferior hemorrhoidal plexus and thus are locatedbelow the anorectal line (external hemorrhoids). Alternatively, they may develop fromdilation of the superior hemorrhoidal plexus and produce internal hemorrhoids.Commonly, both plexuses are affected, and the varicosities are referred to as combinedhemorrhoids. Histologically, these lesions consist only of thin-walled, dilated,submucosal varices that protrude beneath the anal or rectal mucosa. In their exposed,traumatized position, they tend to become thrombosed and, in the course of time,recanalized. Superficial ulceration, fissure formation, and infarction with strangulationmay develop.Diverticular DiseaseA diverticulum is a blind pouch leading off the alimentary tract, lined by mucosa thatcommunicates with the lumen of the gut. Congenital diverticula involve all three layers ofthe bowel wall. The prototype is the Meckel diverticulum, discussed earlier; congenitaldiverticula are not uncommon in the ascending colon.Virtually all other diverticula are acquired and either lack or have an attenuatedmuscularis propria. Acquired diverticula may occur in the esophagus, stomach, andduodenum, but the most common site is the left side of the colon, with the majority in thesigmoid colon. Acquired duodenal diverticula occur in over 1% of adults, possiblyreflecting defects from healed peptic ulcer disease. Multiple diverticula of the jejunumand ileum are rare, occurring in the setting of abnormalities in the muscle wall ormyenteric plexus.Unless otherwise specified, diverticular disease refers to acquired outpouchings of thecolonic mucosa and submucosa. Colonic diverticula are rare in persons under age 30,but in Western adult populations over age 60 the prevalence approaches 50%. Theygenerally occur multiply and are referred to as diverticulosis. They are much lessfrequent in nonindustrialized tropical countries and in Japan.Morphology.Most colonic diverticula are small, flask-like or spherical outpouchings, usually 0.5 to 1cm in diameter and located in the sigmoid colon ( Fig. 17-52A ). However, thedescending colon or entire colon may be affected. They tend to occur alongside thetaeniae coli and are elastic, compressible, and easily emptied of fecal contents. As thesesacs dissect into the fat-containing peritoneal pouches on the surface of the colon(epiploic appendices), they may be missed on casual inspection. Histologically, colonicdiverticula have a thin wall composed of a flattened or atrophic mucosa, compressedsubmucosa, and attenuated or totally absent muscularis propria ( Fig. 17-52B ).
Hypertrophy of the circular layer of the muscularis propria in the affected bowel segmentis usually seen; the taeniae coli are also unusually prominent.Obstruction and/or perforation of diverticula leads to inflammatory changes, producingperidiverticulitis and dissecting into the immediately adjacent pericolic fat. In time, theinflammation may lead to marked fibrotic thickening in and about the colonic wall,sometimes producing narrowing sufficient to resemble a colonic cancer. Extension ofdiverticular infection may lead to pericolic abscesses, sinus tracts, and sometimes pelvicor generalized peritonitis.Pathogenesis.The morphology of colonic diverticula strongly suggests that two factors are importantin their genesis: (1) focal weakness in the colonic wall and (2) increased intraluminalpressure. The colon is unique in that the longitudinal 855Figure 17-52 Diverticulosis. A, Section through the sigmoid colon, showing multiple sac-like diverticulaprotruding through the muscle wall into the mesentery. The muscularis propria in between the diverticularprotrusions is markedly thickened. B, Low-power photomicrograph of diverticulum of the colon, showingprotrusion of mucosa and submucosa through the muscle wall. A dilated blood vessel at the base of thediverticulum was a source of bleeding; some blood clot is present within the diverticular lumen.muscle coat is not complete, but is gathered into three equidistant bands (the taeniae coli).Where nerves and arterial vasa recta penetrate the inner circular muscle coat alongsidethe taeniae, focal defects in the muscle wall are created. The connective tissue sheathsaccompanying these perforating vessels provide points of weakness for herniations.Exaggerated peristaltic contractions, with spasmodic sequestration of bowel segments,are the likely cause of increased intraluminal pressure. It has been proposed that dietslow in fiber reduce stool bulk, which in turn leads to increased peristaltic activity,particularly in the sigmoid colon. Exaggerated contractions sequester segments of bowel
(segmentation); this deranged motility can lead to symptoms in the absence ofinflammation.Clinical Features.Most individuals with diverticular disease remain asymptomatic throughout their lives,and the lesions are most often discovered incidentally. Only about 20% of those affectedever develop manifestations. These may include intermittent cramping or continuouslower abdominal discomfort, constipation, distention, and a sensation of never being ableto completely empty the rectum. Patients sometimes experience alternating constipationand diarrhea. Occasionally there may be minimal chronic or intermittent blood loss, orrarely massive hemorrhages.Longitudinal studies have shown that diverticula can regress early in their developmentor may become more numerous and prominent with time. Whether a high-fiber dietprevents such progression or protects against superimposed diverticulitis is still unclear.Diets supplemented with high fiber may provide symptomatic improvement, but thetreatment may seem worse than the disease. Even when diverticulitis supervenes, it mostoften resolves spontaneously. Relatively few patients require surgical intervention forobstructive or inflammatory complications.Intestinal ObstructionObstruction of the gastrointestinal tract may occur at any level, but the small intestine ismost often involved due to its narrow lumen. The causes of small and large intestinalobstruction are presented in Table 17-11 . Tumors and infarction, although the mostserious, account for only about 10% to 15% of small-bowel obstructions. Four of theentities—hernias, intestinal adhesions, intussusception, and volvulus—collectivelyaccount for 80% ( Fig. 17-53 ). The clinical manifestations of intestinal obstructioninclude abdominal pain and distention, vomiting, constipation, and failure to pass flatus.If the obstruction is mechanical or vascular in origin, immediate surgical intervention isusually required.HERNIASA weakness or defect in the wall of the peritoneal cavity may permit protrusion of apouch-like, serosa-lined sac of peritoneum called a hernial sac. The usual sites of suchweakness are anterior at the inguinal and femoral canals, umbilicus, and in surgical scars.Rarely, retroperitoneal hernias may occur, chiefly about the ligament of Trietz. Herniasare of concern chiefly because segments of viscera frequently protrude and becometrapped in them (external herniation). This is particularly true with inguinal hernias,since they tend to have narrow orifices and large sacs. The most frequent intruders aresmall-bowel loops, but portions of omentum or large bowel also may TABLE 17-11 -- Major Causes of Intestinal ObstructionMechanical Obstruction
AdhesionsHernias, internal or externalVolvulusIntussusceptionTumorsInflammatory stricturesObstructive gallstones, fecaliths, foreign bodiesCongenital strictures; atresiasCongenital bandsMeconium in mucoviscoidosisImperforate anusPseudo-obstructionParalytic ileus (e.g., postoperative)Vascular—bowel infarctionMyopathies and neuropathies (e.g., Hirschsprung) 856Figure 17-53 Schematic depicting the four major causes of intestinal obstruction: (1) Herniation of asegment in the umbilical or inguinal regions; (2) adhesion between loops of intestine; (3) intussusception;(4) volvulus formation.
become trapped. Pressure at the neck of the pouch may impair venous drainage of thetrapped viscus. The resultant stasis and edema increase the bulk of the herniated loop,leading to permanent trapping, or incarceration. With time, compromise of arterialsupply and venous drainage (strangulation) leads to infarction of the trapped segment.ADHESIONSSurgical procedures, infection, and even endometriosis often cause localized or moregeneral peritoneal inflammation (peritonitis). As the peritonitis heals, adhesions maydevelop between bowel segments and/or the abdominal wall and operative site. Thesefibrous bridges can create closed loops through which other viscera may slide andeventually become trapped (internal herniation). The sequence of events followingherniation—obstruction and strangulation—is much the same as with external hernias.Quite rarely, fibrous adhesions arise as congenital defects. Intestinal herniation must beconsidered, then, even without a previous history of peritonitis or surgery.INTUSSUSCEPTIONIntussusception occurs when one segment of the intestine, constricted by a wave ofperistalsis, suddenly becomes telescoped into the immediately distal segment of bowel.Once trapped, the invaginated segment is propelled by peristalsis farther into the distalsegment, pulling its mesentery along behind it. When encountered in infants and children,there is usually no underlying anatomic lesion or defect in the bowel, and the patient isotherwise healthy. Some cases of intussusception are associated with rotavirus infection,suggesting that localized intestinal inflammation may serve as a traction point for theintussusception. However, intussusception in adults signifies an intraluminal mass ortumor as the point of traction. In both settings, intestinal obstruction ensues, and trappingof mesenteric vessels leads to infarction.VOLVULUSComplete twisting of a loop of bowel about its mesenteric base of attachment alsoproduces intestinal obstruction and infarction. This lesion occurs most often in largeredundant loops of sigmoid, followed in frequency by the cecum, small bowel (all orportions), stomach, or (rarely) transverse colon. Recognition of this seldom-encounteredlesion demands constant awareness of its possible occurrence.Tumors of the Small and Large IntestineEpithelial tumors of the intestines are a major cause of morbidity and mortalityworldwide. The colon (including the rectum) is host to more primary neoplasms than anyother organ in the body. Colorectal cancer ranks second only to bronchogenic carcinomaamong the cancer killers in North America. Adenocarcinomas constitute the vast majorityof colorectal cancers and represent 70% of all malignancies arising in the gastrointestinaltract. Curiously, the small intestine is an uncommon site for benign or malignant tumorsdespite its great length and vast pool of dividing mucosal cells.
The classification of intestinal tumors is the same for the small intestine and colon and issummarized in Table 17-12 . Although small intestinal tumors are addressed first, thebulk of our discussion is devoted to colorectal neoplasia.TUMORS OF THE SMALL INTESTINEWhile the small bowel represents 75% of the length of the alimentary tract, its tumorsaccount for only 3% to 6% of gastrointestinal tumors, with a slight preponderance ofbenign tumors. The most common benign tumors in the small intestine are adenomas andmesenchymal tumors (see later discussion on gastrointestinal stromal tumors). Lipomas, 857 TABLE 17-12 -- Tumors of the Small Intestine and ColonNon-neoplastic (Benign) PolypsHyperplastic polypsHamartomatous polyps• Juvenile polyps• Peutz-Jeghers polypsInflammatory polypsLymphoid polypsNeoplastic Epithelial LesionsBenign• Adenoma *Malignant• Adenocarcinoma *• Carcinoid tumor• Anal zone carcinomaMesenchymal LesionsGastrointestinal stromal tumor (GIST) (gradation from benign to malignant)Other benign lesions• Lipoma• Neuroma• Angioma
Kaposi sarcomaLymphoma* Benign and malignant counterparts of the most common neoplasms in the intestines; virtually all lesionsare in the colon.angiomas, and rare hamartomatous mucosal lesions comprise the remainder. One of theenigmas of medicine is the rarity of malignant tumors of the small intestine—annual U.S.death rate is under 1000, representing only about 1% of gastrointestinal malignancies.Small intestinal adenocarcinomas and carcinoids have roughly equal incidence, followedin order by lymphomas and sarcomas. As the latter three exhibit a broader distributionthan the small intestine, they are discussed later.AdenomasAdenomas account for approximately 25% of benign small intestinal tumors, with benignmesenchymal tumors (especially leiomyomas), lipomas, and neuromatous lesionsfollowing in frequency. Most adenomas occur in the region of the ampulla of Vater. Theusual presentation is that of a 30- to 60-year-old patient with occult blood loss, rarelywith obstruction or intussusception; some are discovered incidentally during radiographicinvestigation. Patients with familial polyposis coli (discussed later) are particularly proneto developing periampullary adenomas. Macroscopically, the ampulla of Vater isenlarged and exhibits a velvety surface ( Fig. 17-54 ). Microscopically, these adenomasresemble their counterparts in the colon (discussed later). Frequently, there is extensionof adenomatous tissue into the ampullary orifice, rendering surgical excision difficult,short of a pancreatoduodenectomy to remove the entire ampullary region. Like itscounterpart in the colon, the small intestinal adenoma is a premalignant lesion. Theadenoma-carcinoma sequence has been demonstrated in small intestinal tumors.Figure 17-54 Adenoma of the ampulla of Vater, showing exophytic tumor at the ampullary orifice.
AdenocarcinomaThe large majority of small intestinal adenocarcinomas occur in the duodenum, usually in40- to 70-year-old patients. These tumors grow in a napkin-ring encircling pattern or aspolypoid exophytic masses, in a manner similar to colonic cancers. Tumors in theduodenum, particularly those involving the ampulla of Vater, may cause obstructivejaundice early in their course. More typically, intestinal obstruction is the presentingevent, with symptoms of cramping pain, nausea, vomiting, and weight loss. As in patientswith adenoma, fatigue from occult blood loss may be the only sign. Rarely, the tumorousmass is a lead point for intussusception.A major risk factor for adenocarcinoma of the small intestine is the chronic inflammationassociated with CD, although most tumors are sporadic and have no identifiablepredisposing condition. Other conditions with increased risk for small intestinaladenocarcinoma are: celiac disease, familial adenomatous polyposis (FAP), hereditarynonpolyposis colorectal cancer (HNPCC) syndrome, and Peutz-Jeghers syndrome. Froma broader epidemiologic perspective, alcohol and tobacco consumption are consideredrisk factors.At the time of diagnosis, most tumors have already penetrated the bowel wall, invadedthe mesentery or other segments of the gut, spread to regional nodes, and sometimesmetastasized to the liver and even more widely. Despite these problems, wide en blocexcision of these cancers yields about a 70% five-year survival rate.TUMORS OF THE COLON AND RECTUMColorectal carcinoma is one of the most common malignancies of Western countries.Consideration must first be given to the panoply of non-neoplastic and neoplastic butbenign tumorous lesions of the colon and rectum. These are collectively known as polyps.Polyps of the colorectal mucosa are extraordinarily common in the older adultpopulation. Several concepts pertaining to terminology must be emphasized ( Fig.17-55 ): • A polyp is a tumorous mass that protrudes into the lumen of the gut. Presumably all polyps start as small, sessile lesions without a definable stalk. In many instances, traction on the mass may create a stalked, or pedunculated polyp. 858 • Polyps may be formed as the result of abnormal mucosal maturation, inflammation, or architecture. These polyps are non-neoplastic and do not have malignant potential per se. An example is the hyperplastic polyp. • Those epithelial polyps that arise as the result of proliferation and dysplasia are termed adenomatous polyps, or adenomas. They are true neoplastic lesions and are precursors of carcinoma.
• Some polypoid lesions may be caused by submucosal or mural tumors. However, as with the stomach and small intestine, unless otherwise specified the term polyp refers to lesions arising from the epithelium of the mucosa.Figure 17-55 Diagrammatic representation of two forms of sessile polyp (hyperplastic polyp and adenoma)and of two types of adenoma (pedunculated and sessile). There is only a loose association between thetubular architecture for pedunculated adenomas and the villous architecture for sessile adenomas. TABLE 17-13 -- Hereditary Syndromes Involving the Gastrointestinal TractSyndromes Altered Gene Pathology in GI TractFamilial adenomatous polyposis APC Multiple adenomatous(FAP) polyps• Classic FAP• Attenuated FAP• Gardner syndrome• Turcot syndromePeutz-Jeghers syndrome STK11 Hamartomatous polyps
TABLE 17-13 -- Hereditary Syndromes Involving the Gastrointestinal TractSyndromes Altered Gene Pathology in GI TractJuvenile polyposis syndrome SMAD4 Juvenile polyps BMPRIAHereditary nonpolyposis Defects in mismatch DNA Colon cancercolorectal carcinoma repair genesTuberous sclerosis TSC1 Inflammatory polyps TSC2Cowden disease PTEN Hamartomatous polypsNon-Neoplastic PolypsThe overwhelming majority of intestinal polyps occur on a sporadic basis, particularly inthe colon, and increase in frequency with age. Non-neoplastic polyps include thehyperplastic polyp, the hamartomatous polyp, the inflammatory polyp, and the lymphoidpolyp. Hyperplastic polyps represent about 90% of all epithelial polyps in the largeintestine. They may arise at any age but usually are discovered incidentally in the sixthand seventh decades. They are found in more than half of all persons age 60 and older. Itis believed that the hyperplastic polyp results from decreased epithelial cell turnover andaccumulation of mature cells on the surface. Harmatomatous polyps are malformations ofthe glands and the stroma. They can occur sporadically or occur in the setting of geneticsyndromes ( Table 17-13 ). Inflammatory polyps, also known as pseudopolyps, representislands of inflamed regenerating mucosa surrounded by ulceration. These are seenprimarily in patients with severe, active IBD. Lymphoid polyps are an essentially normalvariant of the mucosal bumps containing intramucosal lymphoid tissue.Morphology.Hyperplastic Polyps.These are small (usually <5 mm in diameter) epithelial polyps that appear as nipple-like,hemispheric, smooth, moist protrusions of the mucosa, usually positioned on the tops ofmucosal folds. They may occur singly but more often are multiple, and over half arefound in the rectosigmoid colon. Histologically, they are composed of well-formedglands and crypts lined by non-neoplastic epithelial cells, most of which showdifferentiation into mature goblet or absorptive cells. The delayed shedding of surfaceepithelial cells leads to infoldings of the crowded epithelial cells and fission of the crypts,creating a serrated epithelial profile and an irregular crypt architecture ( Fig. 17-56A ).Although large hyperplastic polyps may rarely coexist with foci of adenomatous change,the usual small, hyperplastic polyp is considered to have virtually no malignantpotential. However, the hyperplastic polyps occurring in the setting of the rare
hyperplastic polyposis syndrome can harbor epithelial cell dysplasia (adenoma), andhence are considered at risk for carcinoma. The 859underlying genetic basis for this syndrome is not known.Hamartomatous Polyps.Juvenile polyps represent focal hamartomatous malformations of the mucosal epitheliumand lamina propria. For the most part they are sporadic lesions, with the vast majorityoccurring in children younger than age 5. Isolated hamartomatous polyps may beidentified in the colon of adults; these incidental lesions are referred to as retentionpolyps. In both age groups, nearly 80% of the polyps occur in the rectum, but they maybe scattered throughout the colon. Juvenile polyps tend to be large (1 to 3 cm indiameter), rounded, smooth or slightly lobulated lesions with stalks up to 2 cm in length;retention polyps tend to be smaller (<1 cm diameter). Histologically, lamina propriacomprises the bulk of the polyp, enclosing abundant cystically dilated glands.Inflammation is common, and the surface may be congested or ulcerated. In general theyoccur singly and being hamartomatous lesions have no malignant potential. However, therare autosomal dominant juvenile polyposis syndrome, in which there are multiple (50to 100) juvenile polyps in the gastrointestinal tract, does carry a risk of adenomas andhence adenocarcinoma. Mutations in the SMAD4/DPC4 gene (which encodes a TGF-βsignaling intermediate) account for some cases of juvenile polyposis syndrome. Peutz-Jeghers polyps are hamartomatous polyps that involve the mucosal epithelium,lamina propria, and muscularis mucosa. These hamartomatous lesions may also occursingly or multiply in the Peutz-Jeghers syndrome. This rare autosomal dominantsyndrome is characterized by multiple hamartomatous polyps scattered throughout theentire gastrointestinal tract and melanotic mucosal and cutaneous pigmentation aroundthe lips, oral mucosa, face, genitalia, and palmar surfaces of the hands. Patients with thissyndrome are at risk for intussusception, which is a common cause of mortality. Peutz-Jeghers polyps tend to be large and pedunculated with a firm lobulated contour.Histologically, an arborizing network of connective tissue and well-developed smoothmuscle extends into the polyp and surrounds normal abundant
Figure 17-56 Non-neoplastic colonic polyps. A, Hyperplastic polyp; high-power view showing the serratedprofile of the epithelial layer. B, Peutz-Jeghers polyp; low-power view showing the splaying of smoothmuscle into the superficial portion of the pedunculated polyp.glands lined by normal intestinal epithelium rich in goblet cells ( Fig. 17-56B ). Thedistribution of polyps in patients is reported as follows: stomach, 25%; colon, 30%; andsmall bowel, 100%. While these hamartomatous polyps themselves do not havemalignant potential, patients with the syndrome have an increased risk ofdeveloping carcinomas of the pancreas, breast, lung, ovary, and uterus. The well-documented and characteristic tumors include sex cord tumors of the ovary, adenomamalignum of the uterine cervix, and Sertoli cell tumors of the testis. Whengastrointestinal adenocarcinoma occurs, it arises from concomitant adenomatous lesions.The underlying genetic basis for Peutz-Jeghers syndrome is the mutation of the geneSTK11 (LKB1) located on chromosome 19. The gene encodes a protein withserine/threonine kinase activity.Two other hamartomatous polyposis syndromes merit comment: Cowden syndrome andCronkhite-Canada syndrome.Cowden syndrome is an autosomal dominant genetic syndrome characterized by multiplehamartomas involving organs derived from all three germinal layers. The commonlyinvolved sites are gastrointestinal tract and mucocutaneous locations. Intestinalhamartomatous polyps, facial trichilemmomas, acral keratoses, and oral papillomas arecharacteristic. While these hamartomas do not have malignant potential, the syndromepredisposes the patient to develop thyroid and breast cancers. The underlying geneticabnormality is the germ line mutation of the PTEN gene located on chromosome 10( Chapter 7 ).Cronkhite-Canada syndrome is a nonhereditary disorder characterized by the presence ofgastrointestinal hamartomatous polyposis and ectodermal abnormalities (such as nailatrophy, skin pigmentation, and alopecia). The etiology of this disorder is currentlyunknown.Adenomas
Adenomas (adenomatous polyps) are intraepithelial neoplasms that range from small,often pedunculated lesions to large neoplasms that are usually sessile. The prevalence of 860colonic adenomas is about 20% to 30% before age 40, rising to 40% to 50% after age 60.Males and females are affected equally. There is a well-defined familial predisposition tosporadic adenomas, accounting for about a fourfold greater risk among first-degreerelatives and also a fourfold greater risk of colorectal carcinoma.Adenomatous polyps are segregated into three subtypes on the basis of the epithelialarchitecture: • Tubular adenomas: tubular glands • Villous adenomas: villous projections • Tubulovillous adenoma: a mixture of the above.There is considerable overlap among these categories, so by convention, tubularadenomas exhibit more than 75% tubular architecture, villous adenomas contain morethan 50% villous architecture, and tubulovillous adenomas contain 25% to 50% villousarchitecture. Tubular adenomas are by far the most common; about 5% to 10% ofadenomas are tubulovillous, and only 1% are villous.All adenomatous lesions arise as the result of epithelial proliferative dysplasia, whichmay range from low-grade to high-grade dysplasia (carcinoma in situ). Furthermore,there is strong evidence that adenomas are a precursor lesion for invasive colorectaladenocarcinomas (discussed below). The period required for an adenoma to double in size is estimated to be about 10 years. Thus, they are slow growing and must certainlyhave been present for many years before detection. The following concepts are pertinent: • Most tubular adenomas are small and pedunculated; conversely, most pedunculated polyps are tubular. • Villous adenomas tend to be large and sessile, and sessile polyps usually exhibit villous features.
Figure 17-57 A, Pedunculated adenoma showing a fibrovascular stalk lined by normal colonic mucosa anda head that contains abundant dysplastic epithelial glands, hence the blue color with the H & E stain. B, Asmall focus of adenomatous epithelium in an otherwise normal (mucin-secreting, clear) colonic mucosa,showing how the dysplastic columnar epithelium (deeply stained) can populate a colonic crypt and create atubular architecture.The malignant risk with an adenomatous polyp is correlated with three interdependentfeatures: polyp size, histologic architecture, and severity of epithelial dysplasia, asfollows: • Cancer is rare in tubular adenomas smaller than 1 cm in diameter. • The risk of cancer is high (approaching 40%) in sessile villous adenomas more than 4 cm in diameter. • Severe dysplasia, when present, is often found in villous areas.Thus, the most worrisome lesions are villous adenomas greater than 4 cm in diameter.However, since all degrees of dysplasia (low-grade and high-grade) and even invasiveadenocarcinoma may be encountered in an adenoma of any subtype, it is impossible fromgross inspection of a polyp to determine its clinical significance.It must be mentioned that not all adenomas are protuberant polyps. Some adenomas areessentially "flat" and can only be identified by histologic examination. These adenomasare referred to as flat adenoma, depressed adenoma, or microscopic adenoma.Morphology.Most tubular adenomas (90%) are found in the colon, but they can occur in the stomachand small intestine, especially in the vicinity of the ampulla of Vater. About half the time
they occur singly; in the remainder, two or more lesions are distributed at random. Thesmallest tubular adenomas are smooth-contoured and sessile; larger ones tend to becoarsely lobulated and have slender stalks ( Fig. 17-57A ). Uncommonly, they exceed 2.5cm in diameter. Histologically, the stalk is composed of fibromuscular tissue andprominent blood vessels (derived from the submucosa) and it is usually covered by 861normal, non-neoplastic mucosa. However, adenomatous epithelium may extend down thestalk and into adjacent regions of the mucosa, particularly in the stomach. Whether smallor large, adenomatous lesions are composed of neoplastic (dysplastic) epithelium, whichlines glands as a tall, hyperchromatic, somewhat disordered epithelium that may or maynot show mucin vacuoles ( Fig. 17-57B ). In the clearly benign tubular adenoma, thebranching glands are well separated by lamina propria and the degree of dysplasia islow-grade. However, high-grade dysplasia may be present and may merge withareas of overt malignant change confined to the mucosa (intramucosal carcinoma).Carcinomatous invasion into the submucosal stalk of the polyp constitutes invasiveadenocarcinoma.Villous adenomas are the larger and more ominous of the epithelial polyps. They tend tooccur in older persons, most commonly in the rectum and rectosigmoid colon, but theymay be located elsewhere. They generally are sessile, up to 10 cm in diameter, velvety orcauliflower-like masses projecting 1 to 3 cm above the surrounding normal mucosa.Their histology is that of frondlike villiform extensions of the mucosa ( Fig. 17-58A ),covered by dysplastic, sometimes very disorderly columnar epithelium ( Fig. 17-58B ).All degrees of dysplasia may be encountered. When invasive carcinoma occurs, there isno stalk as a buffer zone, and invasion is directly into the wall of the colon (submucosa ordeeper).Tubulovillous adenomas are typically intermediate between the tubular and villouslesions in terms of their frequency of having a stalk or being sessile, their size, and thegeneral level of dysplasia found in such lesions. The risk of harboring in situ or invasivecarcinoma generally correlates with the proportion of the lesion that is villous.Clinical Features.Colorectal tubular (and tubulovillous) adenomas may be asymptomatic, but many arediscovered during evaluation of anemia or occult bleeding. Villous adenomas are muchmore frequently symptomatic than the other
Figure 17-58 A, Sessile adenoma with villous architecture. Each frond is lined by dysplastic epithelium. B,Portion of a villous frond with dysplastic columnar epithelium on the left and normal colonic columnarepithelium on the right.patterns, and often are discovered because of overt rectal bleeding. Rarely, villousadenomas may hypersecrete copious amounts of mucoid material rich in protein andpotassium, leading to either hypoproteinemia or hypokalemia. Notably, screeningprograms are intended to detect asymptomatic adenomas before they progress tomalignancy.The clinical impact of malignant change in an adenoma depends on the following: • High-grade dysplasia (carcinoma in situ) has not yet acquired the ability to metastasize and is still a clinically benign lesion. • Because lymphatic channels are largely absent in the colonic mucosa, being present erratically only at the very base of the lamina propria, intramucosal carcinoma with lamina propria invasion only is regarded also as having little or no metastatic potential. • If the lesion penetrates through the muscularis mucosa into the submucosal space, the resultant invasive adenocarcinoma is a malignant tumor with metastatic potential. Nevertheless, endoscopic removal of a pedunculated adenoma is regarded as an adequate excision provided that three histologic conditions are met: (1) the adenocarcinoma is superficial and does not approach the margin of excision across the base of the stalk; (2) there is no vascular or lymphatic invasion; and (3) the carcinoma is not poorly differentiated. • Invasive adenocarcinoma arising in a sessile polyp cannot be adequately resected by polypectomy, and further surgery may be required.
• Regardless of whether carcinoma is present, the only adequate treatment for a pedunculated or sessile adenoma is complete resection. If adenomatous epithelium remains behind the patient still has a premalignant lesion or may even be harboring invasive carcinoma in the residual lesion.Familial SyndromesFamilial polyposis syndromes are uncommon autosomal dominant disorders. Theirimportance lies in the propensity for malignant transformation and in the insights thatthey have provided in unraveling the molecular basis of colorectal 862cancer. Peutz-Jeghers syndrome, described earlier, is characterized by hamartomatouspolyps and a modestly increased risk of cancer, frequently in extragastrointestinal sites.Juvenile polyposis syndrome and Cowden syndrome have also been mentioned earlier.FAP exhibits innumerable adenomatous polyps and has a frequency of progression tocolon adenocarcinoma approaching 100%. Hereditary nonpolyposis colorectal cancersyndrome (HNPCC or Lynch syndrome) is characterized by the development ofcolorectal carcinoma, endometrial carcinoma, and carcinoma of the small intestine,ureter, or renal pelvis. As we discuss later, many of the molecular events underlying thesesyndromes have been identified.Familial Adenomatous Polyposis (FAP) Syndrome.FAP is the archetype of the adenomatous polyposis syndromes. It is caused by mutationsof the adenomatous polyposis coli (APC) gene on chromosome 5q21 ( Chapter 7 ). The same gene mutations cause a broad spectrum of clinical manifestations. Based on theclinical presentation, FAP can be further classified as classic FAP, attenuated FAP,Gardner syndrome, and Turcot syndrome.In the classic FAP syndrome, patients typically develop 500 to 2500 colonic adenomasthat carpet the mucosal surface ( Fig. 17-59 ). Occasionally as few as 150 polyps arepresent; a minimum of 100 polyps is necessary for a diagnosis of classic FAP. Multipleadenomas may also be present elsewhere in the alimentary tract, including the region ofthe ampulla of Vater. Histologically, the vast majority of polyps are tubular adenomas;occasional polyps may have villous features. Some patients already have cancer of thecolon or rectum at the time of diagnosis. Cancer-prevention measures include earlydetection and prophylactic colectomy in siblings and first-degree relatives at risk. Inaddition to colonic polyps, FAP patients can have polyps in the stomach (adenomas orfundic gland polyps) and small intestine (especially around the ampulla of Vater).In attenuated FAP, patients tend to develop fewer polyps (average, 30), and most of thepolyps are located in the proximal
Figure 17-59 Familial adenomatous polyposis in an 18-year-old woman. The mucosal surface is carpetedby innumerable polypoid adenomas.colon. The lifetime risk of cancer development is usually around 50%.Patients with Gardner syndrome exhibit intestinal polyps identical to those in classicFAP, combined with multiple osteomas (particularly of the mandible, skull, and longbones), epidermal cysts, and fibromatosis. Less frequent are abnormalities of dentition,such as unerupted and supernumerary teeth, and a higher frequency of duodenal andthyroid cancer.Turcot syndrome is a rare clinical syndrome marked by the combination of adenomatouscolonic polyposis and tumors of the central nervous system. Two thirds of patients withTurcot syndrome have APC gene mutations and develop brain medulloblastomas. Theremaining one third have mutations in one of the genes associated with HNPCC anddevelop brain glioblastomas.Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome.HNPCC is an autosomal dominant familial syndrome (extensively described by HenryLynch, hence the alternative name of Lynch syndrome). It is characterized by an increased risk of colorectal cancer and extraintestinal cancer, particularly of theendometrium. Adenomas occur in low numbers and considerably earlier than in thegeneral adult population. However, the colonic malignancies that develop in thissyndrome often are multiple and are not usually associated with pre-existing adenomas.The hallmark of HNPCC is mutations in DNA repair genes, leading to microsatelliteinstability, as discussed in Chapter 7 .Colorectal Carcinogenesis
Most colorectal carcinomas occur sporadically in the absence of well-defined familialsyndromes. Like the majority of cancers in other organs, there are conditions associatedwith risk of tumor development. Regardless of the inciting event, a well-described set ofgenetic alterations occurs that ultimately leads to colorectal malignancy. The modelproposed by Fearon and Vogelstein is widely accepted as the prototypical sequence forcolorectal cancer development. The pathologic basis for this model is the adenoma- carcinoma sequence, which has been documented by these observations: • Populations that have a high prevalence of adenomas have a high prevalence of colorectal cancer, and vice versa. • The distribution of adenomas within the colorectum is more or less comparable to that of colorectal cancer. • The peak incidence of adenomatous polyps antedates by some years the peak for colorectal cancer. • When invasive carcinoma is identified at an early stage, surrounding adenomatous tissue is often present • The risk of cancer is directly related to the number of adenomas, and hence the virtual certainty of cancer in patients with familial polyposis syndromes. • Programs that assiduously follow patients for the development of adenomas and remove all that are suspicious reduce the incidence of colorectal cancer.The occurrence of colorectal carcinoma without evidence of adenomatous precursorssuggests that some dysplastic lesions can degenerate into malignancy without passingthrough a polypoid stage.Molecular Carcinogenesis.Study of colorectal carcinogenesis has provided fundamental insights into the general 863mechanisms of cancer evolution. Many of these principles were discussed in Chapter 7 .Here we will discuss concepts specifically pertinent to carcinogenesis in the colon.It is now believed that there are two pathogenetically distinct pathways for thedevelopment of colon cancer, both of which involve the stepwise accumulation of multiple mutations. However, the genes involved and the mechanisms by which themutations accumulate are different.The first pathway, sometimes called the APC/β-caterin pathway, is characterized bychromosomal instability that results in stepwise accumulation of mutations in a series ofoncogenes and tumor suppressor genes. The molecular evolution of colon cancer alongthis pathway occurs through a series of morphologically identifiable stages. Initially,there is localized colon epithelial proliferation. This is followed by the formation of smalladenomas that progressively enlarge, become more dysplastic, and ultimately develop
into invasive cancers. This is referred to as the adenoma-carcinoma sequence ( Fig. 17-60). The genetic correlates of this pathway are as follows:Loss of Adenomatous Polyposis Coli (APC) Gene.The APC gene has been mapped to 5q21. Its mutation is the genetic basis for FAPsyndrome and fulfills the "first hit" concept advanced by Knudson in the 1970s. Loss of this gene is believed to be the earliest event in the formation of adenomas. This dual-function tumor suppressor gene encodes a protein that binds to microtubule bundles andpromotes cell migration and adhesion. APC also acts as a gatekeeper protein, as itregulates levels of β-catenin, an important mediator of the Wnt/β-catenin signalingpathway (see Fig. 7-38 , Chapter 7). This signaling pathway plays a critical role in thenormal intestinal epithelial development. It is also involved in development of colorectalcarcinomas. More than 80% of colorectal carcinomas have inactivated APC, and 50% ofcancersFigure 17-60 Schematic of the morphologic and molecular changes in the adenoma-carcinoma sequence. Itis postulated that loss of one normal copy of the tumor suppressor gatekeeper gene APC occurs early.Indeed, individuals may be born with one mutant allele of APC, rendering them extremely likely to developcolon cancer. This is the "first hit," according to Knudsons hypothesis. The loss of the normal copy of theAPC gene follows ("second hit"). Mutations of the oncogene K-RAS seem to occur next. Additionalmutations or losses of heterozygosity inactivate the tumor suppressor gene p53 (on chromosome 17p) andSMAD2 and SMAD4 on chromosome 18q, leading finally to the emergence of carcinoma, in whichadditional mutations occur. It is important to note that while there seems to be a temporal sequence ofchanges, as shown, the accumulation of mutations, rather than their occurrence in a specific order, is moreimportant.without APC mutations have β-catenin mutations. β-catenin is a member of the cadherin-based cell adhesive complex, which also acts as a transcription factor if the protein istranslocated to the nucleus. When it is not bound to E-cadherin and participating in cell-to-cell adhesion, a cytoplasmic degradation complex (consisting of APC, Axin, GSK-3β,and β-catenin) leads to β-catenin phosphorylation and degradation. In the setting of APC
mutations (loss of normal function), β-catenin accumulates in the cytoplasm and istranslocated to the nucleus to bind to a family of transcription factors called T-cell factoror lymphoid enhancer factor (TCF or LEF) proteins. The TCF contributes a DNA-binding domain and β-catenin contributes a transactivation domain. Genes activated bythe β-catenin-TCF complex are thought to include those regulating cell proliferation andapoptosis, such as c-MYC and CYCLIN D1. Hence, normal APC function promotes celladhesion and regulates cell proliferation; absence of APC function leads to decreasedcell adhesion and increased cellular proliferation.Reported mutations in the APC gene include missense mutations and deletions, resultingin synthesis of truncated APC proteins. Mutant β-catenin loses binding affinity toGSK-3β, the kinase that phosphorylates and degrades β-catenin, in normal cells. APCmutations are present in 80% of sporadic carcinomas.Mutation of K-RAS.The K-RAS gene ( Chapter 7 ) is the most frequently observed activated oncogene inadenomas and colon cancers. K-RAS plays a role in intracellular signal transduction andis mutated in fewer than 10% of adenomas less than 1 cm in size, in about 50% ofadenomas larger than 1 cm, and in approximately 50% of carcinomas.Loss of SMADs.A common allelic loss in colon cancer is on 18q21. Initially, DCC (deleted in coloncancer), was thought to be the suppressor gene involved in colorectal 864cancer, which was located in this region. However, the role of DCC in colorectalcarcinogenesis has been questioned, since mutant mice lacking both alleles of DCC showno abnormalities. SMAD2 and SMAD4 ( Chapter 7 ), involved in TGF-β signaling, are located on 18q21. Lack of SMAD4 increases gastrointestinal tumorigenesis. Loss of p53.Losses at chromosome 17p have been found in 70% to 80% of colon cancers, yetcomparable losses are infrequent in adenomas. These chromosomal deletions affect thep53 gene, suggesting that mutations in p53 occur late in colon carcinogenesis. Thecritical role of p53 in cell-cycle regulation is discussed in Chapter 7 .Activation of Telomerase.Telomeres plays a role in stabilizing the chromosome. They shorten with each celldivision until cell senescence develops ( Chapter 1 ). Telomerase is a ribonucleoproteincomplex with telomeric reverse transcriptase (TERT) as the catalytic subunit. Telomeraseactivity is required to maintain telomere stability and hence cell immortality, aprerequisite for all cancer cells ( Chapter 7 ). Most adenomas lack telomerase activity, but
a majority of cancers in humans, including colorectal carcinoma, have increasedtelomerase activity. Although the sequence of events outlined above is common, it should be emphasized thatthe accumulation of mutations is more important than their occurrence in a specificorder.Microsatellite Instability Pathway.The second pathway is characterized by genetic lesions in DNA mismatch repair genes( Chapter 7 ). It is involved in 10% to 15% of sporadic cases and in the HNPCCsyndrome. As in the APC/β-catenin schema, there is accumulation of mutations, but theinvolved genes are different, and, unlike in the adenoma-carcinoma sequence, there areno clearly identifiable morphologic correlates. Defective DNA repair caused byinactivation of DNA mismatch repair genes is the fundamental and the most likelyinitiating event in colorectal cancers that travel this road. Inherited mutations (germ-linemutations) in any of five genes that are involved in DNA repair are responsible for thefamilial syndrome of HNPCC. These human mismatch repair genes, hMSH2(chromosome 2p22), hMLH1 (chromosome 3p21), MSH6 (chromosome 2p21), hPMS1(chromosome 2q31-33), and hPMS2 (chromosome 7p22), are involved in genetic"proofreading" during DNA replication and have earned the moniker of caretaker genes( Chapter 7 ). The majority of the mutations (90%) involve MSH2 and MLH1. Mutations in the mismatch repair genes cause alteration of microsatellites, leading tomicrosatellite instability. Microsatellites are fragments of repeat sequences in the humangenome, which contains approximately 50,000 to 100,000 microsatellites. Thesesequences are prone to misalignment during DNA replication. In normal cells, themisalignment is repaired by the caretaker genes. Patients with HNPCC inherit one mutantDNA repair gene ("the first hit") and one normal allele. For unclear reasons, cells in someorgans (colon, stomach, endometrium) are susceptible to a second, somatic mutation("the second hit" of the Knudson hypothesis), which inactivates the normal allele (loss ofheterozygosity or LOH). With homozygous loss of mismatch repair genes, mutation ratesare up to 1000 times higher than normal, and most of the HNPCC tumors showmicrosatellite instability. About 10% to 15% of sporadic colon cancers have mutations insimilar DNA repair genes, Most microsatellite sequences are in noncoding regions of thegenes, and, hence, mutations in these genes are probably harmless. However, somemicrosatellite sequences are located in the coding or promoter region of genes involvedin regulation of cell growth. Such genes include type II TGF-β receptor and BAX. TGF-βsignaling inhibits the growth of colonic epithelial cells, and the BAX gene causesapoptosis. Loss of mismatch repair leads to the accumulation of mutations in these andother growth-regulating genes, culminating in the emergence of colorectal carcinomas.Although there is no readily identifiable adenoma-carcinoma sequence that typifiestumors arising from defects in mismatch repair, it has been noted that some of the so-called hyperplastic polyps seen on the right side of the colon display microsatelliteinstability and may well be precancerous. Fully developed tumors that arise via the mismatch repair pathway do show some distinctive morphologic features, includingproximal colonic location, mucinous histology, and infiltration by lymphocytes. In
general, these tumors have better prognosis than stage-matched tumors that arise by theAPC pathway.Colorectal CarcinomaVirtually 98% of all cancers in the large intestine are adenocarcinomas. They representone of the prime challenges to the medical profession, because they usually arise inpolyps and produce symptoms relatively early and at a stage generally curable byresection. Yet, there are an estimated 148,300 new cases per year and about 56,600deaths, accounting for 10% of all cancer-related deaths in the United States. Epidemiology, Etiology, and Pathogenesis.The peak incidence for colorectal carcinoma is between ages 60 and 79. Fewer than 20%of cases occur before age 50. When colorectal carcinoma is found in a young person, pre-existing ulcerative colitis or one of the polyposis syndromes must be suspected. Withlesions in the rectum, the male-to-female ratio is 1.2:1; for more proximal tumors there isno gender difference. Colorectal carcinoma has a worldwide distribution, with the highestdeath rates in the United States, Australia, New Zealand, and Eastern European countries.Its incidence is substantially lower—up to 10-fold—in Mexico, South America, andAfrica. Environmental factors, particularly dietary practices, are implicated in thesestriking geographic contrasts in incidence. Japanese and Polish families that havemigrated from their low-risk areas to the United States have acquired, over the course of20 years, the rate prevailing in the new environment. Both groups, for the most part,adopted the common dietary practices of the U.S. population. Other studies implicateobesity and physical inactivity as risk factors for colon cancer.  The dietary factors receiving the most attention as predisposing to a higher incidence ofcancer are (1) excess dietary caloric intake relative to requirements, (2) a low content ofunabsorbable vegetable fiber, (3) a corresponding high content of refined carbohydrates,(4) intake of red meat, and (5) decreased intake of protective micronutrients. It istheorized that reduced fiber content leads to decreased stool bulk, increased fecal transittime in the bowel, and an altered bacterial flora of the intestine. Potentially toxicoxidative byproducts of carbohydrate degradation by bacteria are therefore present inhigher concentrations in the stools and are held in contact with the colonic mucosa forlonger periods of time. Moreover, high cholesterol intake in red meat enhances the 865synthesis of bile acids by the liver, which in turn may be converted into potentialcarcinogens by intestinal bacteria. Refined diets also contain less of vitamins A, C, and E,which may act as oxygen-radical scavengers ( Chapter 1 ). Intriguing as thesespeculations may be, the putative mechanisms of dietary effects remain unproven.Indeed, recent studies have challenged the notion that low-fat, high-fiber diets protectagainst recurrence of colorectal adenomas, the precursors of colon cancer.
Several epidemiological studies suggest that use of aspirin and other NSAIDs exerts aprotective effect against colon cancer. In the Nurses Health Study, women who used fourto six tablets of aspirin/day for 10 years or more had a decreased incidence of coloncancer. Two recent studies have revealed that aspirin reduces the risk of recurrentadenomas in patients with previous colorectal carcinomas or adenomas. The mechanism of such chemoprevention is not fully understood, but it is likely mediated by inhibition ofcyclooxygenase-2 ( Chapter 2 ). This enzyme is overexpressed in neoplastic epitheliumand seems to regulate angiogenesis and apoptosis. On the basis of these findings, the U.S.Food and Drug Administration has approved the use of COX-2 inhibitors aschemopreventive agents in patients with the familial adenomatous polyposis syndrome.Morphology.The distribution of the cancers in the colorectum is as follows: cecum/ascending colon,22%; transverse colon, 11%; descending colon, 6%; rectosigmoid colon, 55%; and othersites, 6%. The right-sided colon cancers tend to have greater microsatellite instability.Ninety-nine per cent of carcinomas occur singly, but when multiple carcinomas arepresent, they are often at widely disparate sites in the colon. While most cases occursporadically, about 1% to 3% of colorectal carcinomas occur in patients with familialsyndromes (i.e., FAP or HNPCC) or IBD.Although all colorectal carcinomas begin as in situ lesions, they evolve into differentmorphologic patterns. Tumors in the proximal colon tend to grow as polypoid,exophytic masses that extend along one wall of the capacious cecum and ascending colon( Fig. 17-61 ). Obstruction is uncommon. When carcinomas in the distal colon arediscovered, they tend to be annular, encircling lesions that produce so-called napkin-ringconstrictions of the bowel ( Fig. 17-62 ). The margins of the napkin ring are classicallyheaped up, beaded, and firm, and the midregion is ulcerated. The lumen is markedlynarrowed, and the proximal bowel may be distended. Both forms of neoplasm directlypenetrate the bowel wall over the course of time (probably years) and may appear assubserosal and serosal white, firm masses, frequently causing puckering of the serosalsurface. Uncommonly, but particularly in association with ulcerative colitis, colorectalcancers are insidiously infiltrative and difficult to identify radiographically andmacroscopically. Such lesions tend to be exceedingly aggressive, and spread at an earlystage in their evolution.Unlike the gross pathology, the microscopic characteristics of right- and left-sidedcolonic adenocarcinomas are similar. Differentiation may range from tall, columnar cellsresembling their counterparts in adenomatous lesions, which now invade the submucosaand muscularis propria ( Fig. 17-63 ), to undifferentiated,
Figure 17-61 Carcinoma of the cecum. The fungating carcinoma projects into the lumen but has not causedobstruction.frankly anaplastic masses. Invasive tumor incites a strong desmoplastic stromalresponse, leading to the characteristic firm, hard consistency of most colonic carcinomas.Many tumors produce mucin, which is secreted into the gland lumina or into theinterstitium of the gut wall. Because this secretion
Figure 17-62 Carcinoma of the descending colon. This circumferential tumor has heaped-up edges and anulcerated central portion. The arrows identify separate mucosal polyps. 866Figure 17-63 Invasive adenocarcinoma of colon, showing malignant glands infiltrating the muscle wall.
dissects through the gut wall, it aids the extension of the malignancy and worsens theprognosis.Certain specific features should be noted. Foci of endocrine differentiation may be foundin about 10% of colorectal carcinomas. Alternatively, in some cancers the cells take on asignet-ring appearance. The small-cell undifferentiated carcinoma appears to arise fromendocrine cells per se and elaborates a variety of bioactive secretory products. Somecancers, particularly in the distal colon, have foci of squamous cell differentiation and aretherefore referred to as adenosquamous carcinomas. In contrast, carcinomas arising inthe anorectal canal constitute a distinct subgroup of tumors, dominated by squamouscell carcinoma. Tumors associated with HNPCC tend to be poorly differentiated and richin mucin.Clinical Features.Colorectal cancers remain asymptomatic for years; symptoms develop insidiously andfrequently have been present for months, sometimes years, before diagnosis. Cecal andright colonic cancers are most often called to clinical attention by the appearance offatigue, weakness, and iron-deficiency anemia. These bulky lesions bleed readily andmay be discovered at an early stage, provided the colon is examined thoroughlyradiographically and during colonoscopy. Left-sided lesions come to attention byproducing occult bleeding, changes in bowel habit, or crampy left lower quadrantdiscomfort. In theory, the chance for early discovery and successful removal should begreater for patients with lesions on the left side, because these patients usually haveprominent disturbances in bowel function such as melena, diarrhea, and constipation.However, cancers of the rectum and sigmoid tend to be more infiltrative at the time ofdiagnosis than proximal lesions, and therefore have a somewhat poorer prognosis. It is aclinical maxim that iron-deficiency anemia in an older male means gastrointestinalcancer until proven otherwise. In females the situation is less clear, since menstruallosses, multiple pregnancies, or abnormal uterine bleeding may underlie such an anemia.Systemic manifestations such as weakness, malaise, and weight loss are ominous, in thatthey usually signify more extensive disease.All colorectal tumors spread by direct extension into adjacent structures and bymetastasis through the lymphatics and blood vessels. In order of preference, the favoredsites of metastatic spread are the regional lymph nodes, liver, lungs, and bones, followedby many other sites, including the serosal membrane of the peritoneal cavity, brain, andothers. In general, the disease has spread beyond the range of curative surgery in 25% to30% of patients. Anal region carcinomas are locally invasive and metastasize to regionallymph nodes and distant sites.The single most important prognostic indicator of colorectal carcinoma is the extent ofthe tumor at the time of diagnosis, the so-called stage. A staging system formerly widelyused is that described by Aster and Coller in 1954, which represents a modification ofclassifications proposed by Dukes and Kirklin. Currently, the system most widely used isthe tumor-nodes-metastasis (TNM) classification and staging system from the AmericanJoint Commission on Cancer ( Table 17-14 ). The criteria for pathologic staging are
shown in Figure 17-64 . Regardless of the system used, survival at 1, 5, and 10 years isstrongly correlated with the stage of disease at the time of surgical resection. Staging canbe accurately applied only after the extent of spread is determined by surgical explorationand anatomic examination.The overriding challenge is to discover these neoplasms when curative resection ispossible, preferably when they are still adenomatous polyps. Indeed, each death fromcolonic cancer in the United States must be viewed as a preventable tragedy, but progresshas been relatively slow in coming.Carcinoid TumorsThe first carcinoid tumor was identified in the ileum by Lubarsch more than 100 yearsago. The term carcinoid was used by Oberndorfer in 1907 because the tumor wasdescribed as a carcinoma-like lesion but with a much more indolent clinical course.Carcinoid tumor is derived from resident endocrine cells, with the gastrointestinal tractand lung as the predominant sites of occurrence. TABLE 17-14 -- TNM Classification of Carcinoma of the Colon and RectumTumor Stage Histologic Features of the NeoplasmTis Carcinoma in situ (high-grade dysplasia) or intramucosal carcinoma (lamina propria invasion)T1 Tumor invades submucosaT2 Extending into the muscularis propria but not penetrating through itT3 Penetrating through the muscularis propria into subserosaT4 Tumor directly invades other organs or structuresNx Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in 1 to 3 lymph nodesN2 Metastasis in 4 or more lymph nodesMx Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis 867
Figure 17-64 Pathologic staging of colorectal cancer. Staging is based on the depth of tumor invasion.Mucosal endocrine cells generate bioactive compounds, particularly peptide andnonpeptide hormones, and play a major role in coordinated gut function. Although theyare derived from epithelial stem cells in the mucosal crypts, they are designatedendocrine cells because of their endocrine and paracrine function and their resemblanceto endocrine cells elsewhere, as in the pancreas. Mucosal endocrine cells are abundant inother organs, including the lungs, but the great preponderance of carcinoid tumors arisingfrom these cells are in the gut. A scattering of carcinoid tumors arises in the pancreas orperipancreatic tissue, lungs, biliary tree, and even liver. The peak incidence of theseneoplasms is in the sixth decade, but they may appear at any age. They comprise less than2% of colorectal malignancies but almost half of small intestinal malignant tumors.The classification of carcinoid tumors is still controversial. The prevailing view is thatcarcinoid tumor may represent a well-differentiated end of the spectrum is the small cellcarcinoma. Carcinoid tumors may be confined to the mucosa and submucosa or may bemalignant in behavior with deep invasion and metastatic spread to regional lymph nodesand the liver. Intriguingly, there is no reliable histologic difference between seeminglybenign and obviously malignant carcinoid tumors. While there are no reliable molecularmarkers to
Figure 17-65 Carcinoid tumor. A, Multiple protruding tumors are present at the ileocecal junction. B, Thetumor cells exhibit a monotonous morphology, with a delicate intervening fibrovascular stroma. C,Electron micrograph showing dense core bodies in the cytoplasm.predict tumor behavior, the tendency for aggressive behavior correlates with the site oforigin, the depth of local penetration, the size of the tumor, and the histologic features ofnecrosis and mitosis. Hence, it is possible to establish a reasonable clinical assessment ofthese tumors. Appendiceal and rectal carcinoids infrequently metastasize, even thoughthey may show extensive local spread. By contrast, 90% of ileal, gastric, and coloniccarcinoids that have penetrated halfway through the muscle wall have spread to lymphnodes and distant sites such as the liver at the time of diagnosis. This is especially true fortumors greater than 2 cm in diameter.Morphology.The appendix is the most common site of gut carcinoid tumors, followed by the smallintestine (primarily ileum), rectum, stomach, and colon. However, the rectal tumors mayrepresent up to half of tumors that come to clinical attention. Those that arise in thestomach and ileum are frequently multicentric, but the remainder tend to be solitarylesions. In the appendix they appear as bulbous swellings of the tip, which frequentlyobliterate the lumen. Elsewhere in the gut, they appear as intramural or submucosalmasses that create small, polypoid or plateau-like elevations rarely more than 3 cm indiameter ( Fig. 17-65A ). The overlying mucosa may be intact or ulcerated, and thetumors may permeate the bowel wall to invade the mesentery. A characteristic feature isa solid, yellow-tan appearance on transection. The tumors are exceedingly firm owing tostriking desmoplasia, and when these fibrosing lesions penetrate the mesentery of thesmall bowel they may cause angulation or kinking sufficient to cause obstruction. Whenpresent, visceral metastases are usually small, dispersed nodules and rarely achieve thesize seen with the primary lesions. Notably, rectal and appendiceal carcinoids almostnever metastasize.Histologically, the neoplastic cells may form discrete islands, trabeculae, stands, glands,or undifferentiated sheets. Whatever their organization the tumor cells are monotonouslysimilar, having a scant, pink granular cytoplasm and a round to oval stippled nucleus. Inmost tumors there is minimal variation in cell and nuclear size and mitoses are infrequent
or absent ( Fig. 17-65B ). In unusual cases there may be more significant anaplasia andsometimes mucin 868secretion within the cells and gland formations. Rarely, tumors arise resembling small-cell carcinomas of the lung ( Chapter 15 ) or contain abundant psammoma bodies similarto those seen in thyroid carcinomas ( Chapter 24 ). By electron microscopy ( Fig.17-65C ), the cells in most tumors contain membrane-bound secretory granules withosmophilic centers (dense-core granules) in the cytoplasm. Most carcinoids containchromogranin A, synaptophysin, and neuron-specific enolase. Specific hormonal peptidesmay occasionally be identified by immunocytochemical techniques.Clinical Features.Gastrointestinal carcinoids only rarely produce local symptoms, which are caused byangulation or obstruction of the small intestine. Many (especially rectal and appendiceal)are asymptomatic and are found incidentally. However, the secretory products of somecarcinoids may produce a variety of syndromes or endocrinopathies, depending on theiranatomic site ( Chapter 7 ). Gastric, peripancreatic, and pancreatic carcinoids can releasetheir products directly into the systemic circulation, and can produce, for example, theZollinger-Ellison syndrome related to excess elaboration of gastrin, Cushing syndromeassociated with corticotropin secretion, and hyperinsulinism. In some instances, thesetumors may be smaller than 1 cm and extremely difficult to find, even during surgicalexploration.Some neoplasms are associated with a distinctive carcinoid syndrome ( Table 17-15 ).The syndrome occurs in about 1% of all patients with carcinoids and in 20% of thosewith widespread metastases. Uncertainties remain about the precise origin of thecarcinoid syndrome, but most manifestations are thought to arise from excess elaborationof serotonin (5-hydroxytryptamine, 5-HT). Elevated levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), are present in the blood and urine of most patientswith the classic syndrome. 5-HT produced by gastrointestinal carcinoid tumors isdegraded to functionally inactive 5-HIAA in the liver. Thus, hepatic metastases areusually present for the development of the syndrome from gastrointestinal carcinoids,because under these conditions, a sufficient amount of substances produced by the tumorscan reach the systemic circulation without metabolic degradation by the liver. Notsurprisingly, hepatic TABLE 17-15 -- Clinical Features of the Carcinoid Syndrome• Vasomotor distubancesCutaneous flushes and apparent cyanosis (most patients)• Intestinal hypermotility
Diarrhea, Cramps, nausea, vomiting (most patients)• Asthmatic bronchoconstrictive attacksCouth, wheezing, dyspnea (about one third of patients)• HepatomegalyNodular liver owing to hepatic metastases (some patients)• Systemic fibrosis (some patients)Cardiac involvement Pulmonic and tricuspid valve thickening and stenosisEndocardial fibrosis, principally in the right ventricle(Bronchial carcinoids affect the left side)Retroperitoneal and pelvic fibrosisCollagenous pleural and intimal aortic plaquesmetastases are usually not required for the production of a carcinoid syndrome byextraintestinal carcinoids (such as those arising in the lungs or ovaries), because activesubstances produced by the tumors are directly released into the systemic circulation.Other secretory products of carcinoids such as histamine, bradykinin, kallikrein, andprostaglandins may also contribute to the manifestations of the carcinoid syndrome.The overall five-year survival rate for carcinoids (excluding appendiceal) isapproximately 90%. Even with small-bowel tumors with hepatic metastases, it is betterthan 50%. However, widespread disease will usually cause death.GASTROINTESTINAL LYMPHOMAAny segment of the gastrointestinal tract may be secondarily involved by systemicdissemination of non-Hodgkin lymphomas. However, up to 40% of lymphomas arise insites other than lymph nodes, and the gut is the most common location. Conversely, about1% to 4% of all gastrointestinal malignancies are lymphomas. By definition, primarygastrointestinal lymphomas exhibit no evidence of liver, spleen, mediastinal lymph node,or bone marrow involvement at the time of diagnosis—regional lymph node involvementmay be present. Primary gastrointestinal lymphomas usually arise as sporadicneoplasms but also occur more frequently in certain patient populations: (1) Chronicgastritis caused by H. pylori, (2) chronic spruelike syndromes, (3) natives of theMediterranean region, (4) congenital immunodeficiency states, (5) infection with humanimmunodeficiency virus, and (6) following organ transplantation withimmunosuppression.
Intestinal tract lymphomas can be classified into B-cell and T-cell lymphomas. The B-cell lymphoma can be subdivided into MALT lymphoma, immunoproliferative small-intestinal disease (IPSID), and Burkitt lymphoma. 1. MALT lymphoma is a sporadic lymphoma, which arises from the B cells of MALT (mucosa-associated lymphoid tissue, described under gastric lymphoma). This type of lymphoma is the most common form in the Western hemisphere. The biologic features of these lymphomas are different from node-based lymphomas in that (1) many behave as focal tumors in their early stages and are amenable to surgical resection; (2) relapse may occur exclusively in the gastrointestinal tract; (3) genotypic changes are different than those observed in nodal lymphomas: the t(11;18) translocation is relatively common in MALT lymphoma; and (4) the cells are usually CD5- and CD10-negative. This type of gastrointestinal lymphoma usually affects adults, has no gender predilection, and may arise anywhere in the gut: stomach (55% to 60% of cases); small intestine (25% to 30%), proximal colon (10% to 15%), and distal colon (up to 10%). The appendix and esophagus are only rarely involved. The pathogenesis of these lymphomas is under intense scrutiny. The concept has been advanced that lymphomas of MALT origin arise in the setting of mucosal lymphoid activation and that these lymphomas are the malignant counterparts of hypermutated, postgerminal-center memory B cells. As discussed earlier, Helicobacter-associated chronic gastritis, in particular, has been proposed as a driving force for the development of gastric MALT lymphoma, the result of antigen-driven somatic mutation of 869 gastric lymphoid tissue. However, the etiologic factors for intestinal lymphoma are still unknown, although history of IBD appears to increase the risk. 2. IPSID is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-cell lymphoma arising in patients with Mediterranean ancestry, having a background of chronic diffuse mucosal plasmacytosis. The plasma cells synthesize an abnormal Igα heavy chain, in which the variable portion has been deleted. A high proportion of patients have malabsorption and weight loss preceding the development of the lymphoma. The diagnosis is made most commonly in children and young adults, and both sexes appear to be affected equally. The exact etiology of this type of lymphoma is not known, although infection appears to play a role.  3. The intestinal T-cell lymphoma is usually associated with a long-standing malabsorption syndrome (such as celiac disease) that may not constitute a true gluten-sensitive enteropathy. This lymphoma occurs in relatively young individuals (age 30 to 40), often following a 10- to 20-year history of symptomatic malabsorption. Alternatively, a diffuse enteropathy with malabsorption may accompany the development of a lymphoma. Intestinal T-cell
lymphoma arises most often in the proximal small bowel, and its overall prognosis is poor (reported 11% five-year survival rate).Morphology.Gastrointestinal lymphomas can assume a variety of gross appearances. Since all the gutlymphoid tissue is mucosal and submucosal, early lesions appear as plaque-likeexpansions of the mucosa and submucosa. Diffusely infiltrating lesions may produce full-thickness mural thickening, with effacement of the overlying mucosal folds and focalulceration. Others may be polypoid, protruding into the lumen, or form large, fungating,ulcerated masses. Tumor infiltration into the muscularis propria splays the muscle fibers,gradually destroying them. Because of this feature, advanced lesions frequently causemotility problems with secondary obstruction. Large tumors sometimes perforate becauseof lack of stromal support; reduction in tumor bulk during chemotherapy also may lead toperforation.In the earliest histologic lesions, atypical lymphoid cells may be seen infiltrating themucosa, with effacement and loss of glands and massive expansion of lymphoid tissue.Extreme numbers of atypical lymphoid cells may populate the superficial or glandularepithelium (lymphoepithelial lesion). With established lymphomas, the mucosa,submucosa, and even muscle wall are replaced by a monotonous infiltrate of malignantcells, consisting of a mixture of small lymphocytes and immunoblasts in varyingproportions. Lymphoid follicles are occasionally formed. Most gut lymphomas are of B-cell type (over 95%) and are evenly split between low- and high-grade tumors. The smallfraction of T-cell lymphomas occurring in the intestine are commonly high-grade lesions.Clinical Features.With the exception of T-cell lymphomas, primary gastrointestinal lymphomas generallyhave a better prognosis than do those arising in other sites. Ten-year survival for patientswith localized mucosal or submucosal disease approaches 85%. Early discovery is key tosurvival; thus, gastric lymphomas generally have a better outcome than those of the smallor large bowel. In general, the depth of local invasion, size of the tumor, the histologicgrade of the tumor, and extension into adjacent viscera are important determinants ofprognosis.MESENCHYMAL TUMORSMesenchymal tumors may occur anywhere in the alimentary tract. The nomenclature forthese tumors is largely based on the tumor cell phenotypes. Lipomas show a propensityfor the submucosa of the small and large intestines, and lipomatous hypertrophy mayoccur in the ileocecal valve. A variety of spindle-cell lesions may arise in the muscle wallof any gut segment. The great majority of these tumors are of smooth muscle origin, andhence can be termed leiomyomas and leiomyosarcomas. Gastrointestinal stromal tumors(GISTs), are now considered to be a distinctive tumor type, characterized by c-KITimmunoreactivity, as discussed earlier (see "Gastric Tumors"). The small intestine is thesecond most common location for this tumor, (the stomach being the most common).
Both benign and malignant versions of GIST may occur at any age and in either sex.Vascular tumors such as Kaposi sarcomas are considered elsewhere (see Chapter 11 ).Morphology.Lipomas are usually well-demarcated, firm nodules (almost always less than 4 cm indiameter) arising within the submucosa or muscularis propria. The overlying mucosa isstretched and attenuated. Rarely, they grow to larger size and produce hemisphericelevation of the mucosa with ulceration over the dome of the tumor. Malignant stromaltumors (primarily leiomyosarcoma) tend to produce large, bulky, intramural masses thateventually fungate and ulcerate into the lumen or project subserosally into the abdominalspace. Histologically, lipomas, leiomyomas, and leiomyosarcomas resemble theircounterparts encountered elsewhere ( Chapter 26 ). In the case of the stromal tumors(e.g., leiomyomas and leiomyosarcomas), large size and a high mitotic rate are correlatedwith an aggressive course.Clinical Features.Most mesenchymal tumors are asymptomatic. In the stomach, larger lesions (benign ormalignant) may produce symptoms resembling those of peptic ulcer, particularlybleeding that is sometimes massive. Intestinal lesions may present with bleeding, and forthe small intestine, rare obstruction or intussusception. Benign lesions are easilyresectable. Surgical removal is usually possible for the malignant lesions as well, sincethey tend to grow as cohesive masses. Five-year survival rate for leiomyosarcoma, forexample, is 50% to 60%. Metastases, however, are present in about one third of cases.TUMORS OF THE ANAL CANALThe anal canal is the terminal portion of the large intestine. It is divided into three zones:the upper (covered with rectal mucosa), the middle (partially covered with a transitionalmucosa), and the lower (covered by stratified squamous mucosa). The tumors located inthis anatomic location are designated as carcinoma of the anal canal. Patterns ofdifferentiation 870include a basaloid pattern, squamous cell carcinoma, and adenocarcinoma.Anal canal carcinoma with basaloid differentiation is a tumor populated by immatureproliferative cells derived from the basal layer of a stratified squamous epithelium. Thesetumors may occur sporadically and be uniform in their histologic features. Alternatively,basaloid differentiation may be a component of a tumor that exhibits more genuinesquamous cell differentiation and/or the mucin vacuole-containing features ofadenocarcinoma. All such tumors remain classified as anal canal carcinoma.Pure squamous cell carcinomas of the anal canal are closely associated with chronic HPVinfection. Some rare cases are also related to immunosuppression, as encountered in 
renal transplantation and in AIDS patients. As with the genital tract, chronic HPVinfection of the anal canal often causes precursor lesions such as condyloma acuminatum,squamous epithelium dysplasia, and carcinoma in situ.Pure adenocarcinoma of the anal canal is often the extension of rectal adenocarcinoma.Rarely, other tumors may arise from the anal canal, notably Paget disease, small-cellcarcinoma, and melanoma.AppendixNormalThe appendix is an underdeveloped residuum of the otherwise voluminous cecum. Theadult appendix averages 6 to 7 cm in length, is partially anchored by a mesentericextension from the adjacent ileum, and has no known function. The appendix has thesame four layers as the remainder of the gut and possesses a colonic-type mucosa. Adistinguishing feature of this organ is the extremely rich lymphoid tissue of the mucosaand submucosa, which in young individuals forms an entire layer of germinal folliclesand lymphoid pulp. This lymphoid tissue undergoes progressive atrophy during life to thepoint of complete disappearance in advanced age. In the elderly the appendix, particularlythe distal portion, sometimes undergoes fibrous obliteration.PathologyDiseases of the appendix loom large in surgical practice; appendicitis is the mostcommon acute abdominal condition the surgeon is called on to treat. Appendicitis is oneof the best-known medical entities and yet may be one of the most difficult diagnosticproblems to confront the emergency physician. A differential diagnosis must includevirtually every acute process that can occur within the abdominal cavity, as well as someemergent conditions affecting organs of the thorax.Acute AppendicitisInflammation in the right lower quadrant was considered a nonsurgical disease of thececum (typhlitis or perityphlitis) until Fitz recognized acute appendicitis as a distinctentity in 1886. Appendiceal inflammation is associated with obstruction in 50% to 80%of cases, usually in the form of a fecalith and, less commonly, a gallstone, tumor, or ballof worms (oxyuriasis vermicularis). Continued secretion of mucinous fluid in theobstructed viscus presumably leads to a progressive increase in intraluminal pressuresufficient to cause eventual collapse of the draining veins. Ischemic injury then favorsbacterial proliferation with additional inflammatory edema and exudation, furtherembarrassing the blood supply. Nevertheless, a significant minority of inflamed
appendices have no demonstrable luminal obstruction, and the pathogenesis of theinflammation remains unknown.Morphology.At the earliest stages, only a scant neutrophilic exudate may be found throughout themucosa, submucosa, and muscularis propria. Subserosal vessels are congested, and oftenthere is a modest perivascular neutrophilic infiltrate. The inflammatory reactiontransforms the normal glistening serosa into a dull, granular, red membrane; thistransformation signifies early acute appendicitis for the operating surgeon. At a laterstage, a prominent neutrophilic exudate generates a fibrinopurulent reaction over theserosa ( Fig. 17-66 ). As the inflammatory process worsens, there is abscess formationwithin the wall, along with ulcerations and foci of suppurative necrosis in the mucosa.This state constitutes acute suppurative appendicitis. Further appendiceal compromiseleads to large areas of hemorrhagic green ulceration of the mucosa and green-blackgangrenous necrosis through the wall, extending to the serosa, creating acutegangrenous appendicitis, which is quickly followed by rupture and suppurativeperitonitis.The histologic criterion for the diagnosis of acute appendicitis is neutrophilic infiltrationof the muscularis propria. Usually, neutrophils and ulcerations are also present within themucosa. Since drainage of an exudate into the appendix from alimentary tract infectionmay also induce a mucosal neutrophilic infiltrate, evidence of muscular wallinflammation is requisite for the diagnosis. 871Figure 17-66 Acute appendicitis. The inflamed appendix shown below is red, swollen, and covered with afibrinous exudate. For comparison, a normal appendix is shown above.Clinical Features.
Acute appendicitis is mainly a disease of adolescents and young adults, but it may occurin any age group and affects males slightly more often than females. The lifetime risk forappendicitis is 7%. Classically, acute appendicitis produces the following manifestations,in the sequence given: (1) pain, at first periumbilical but then localizing to the right lowerquadrant; (2) nausea and/or vomiting; (3) abdominal tenderness, particularly in the regionof the appendix; (4) mild fever; and (5) an elevation of the peripheral white blood cellcount up to 15,000 to 20,000 cell/µL. Regrettably, this classic presentation is more oftennot present. While pain, nausea, and vomiting usually develop, tenderness may bedeceptively absent or present in atypical locations. In some cases, a retrocecal appendixmay generate right flank or pelvic pain, while a malrotated colon may give rise toappendicitis in the left upper quadrant. The peripheral leukocytosis may be minimal or sohigh as to suggest alternative diagnoses. Nonclassic presentations are encountered moreoften in young children and in the very elderly, populations with a host of other plausibleabdominal emergencies.There is general agreement that highly competent surgeons make false-positive diagnosesof acute appendicitis and remove normal appendices about 20% to 25% of the time. Thediscomfort and risks associated with an exploratory laparotomy and discovery of "nodisease" are far outweighed by the morbidity and mortality (about 2%) associated withappendiceal perforation. Besides perforation, uncommon complications of appendicitisinclude pyelophlebitis with thrombosis of the portal venous drainage, liver abscess, andbacteremia. In instances when the appendix is normal, most often no disease of any kindis found during abdominal exploration. Definable conditions that mimic appendicitis aremesenteric lymphadenitis, usually secondary to an enterocolitis (often unrecognized)caused by Yersinia or a virus; systemic viral infection; acute salpingitis; ectopicpregnancy; mittelschmerz (pain caused by trivial pelvic bleeding at the time ofovulation); cystic fibrosis; and Meckel diverticulitis.True chronic inflammation of the appendix is difficult to define as a pathologic entity,although occasionally granulation tissue and fibrosis associated with acute and chronicinflammation of the appendix suggest an organizing acute appendicitis. Much morefrequently, recurrent acute attacks underlie a seemingly chronic condition. Since in someindividuals the appendix is a mere fibrous cord from birth, it cannot be assumed thatappendiceal fibrosis is the result of a previous inflammation.Tumors of the AppendixThe most common appendiceal tumor is the carcinoid, discussed earlier. It is usuallydiscovered incidentally at the time of surgery or examination of a resected appendix. This neoplasm most frequently involves the distal tip of the appendix, where it producesa solid bulbous swelling up to 2 to 3 cm in diameter. Although intramural and transmuralextension may be evident, nodal metastases are very infrequent, and distant spread is rare.One unique type of appendiceal carcinoid tumor is goblet cell carcinoid (adenocarcinoid).Histologically, the tumor shows a typical carcinoid pattern, but with plump mucinvacuole-containing cells. The biologic behavior of the tumor is between that of typical
carcinoid and adenocarcinoma. Genetic alterations have been found in both typicalcarcinoid tumors and goblet cell carcinoids.Conventional adenomas or non-mucin-producing adenocarcinomas of the appendix maycause a typical neoplastic enlargement of this organ. Hyperplastic polyps may occur inthis location as well. Benign and malignant mesenchymal growths resemble theircounterparts in other areas.MUCOCELE AND PSEUDOMYXOMA PERITONEIMucocele is the macroscopic description of a dilated appendix filled with mucin. The truepathologic nature of mucocele runs the gamut from an innocuous obstructed appendixcontaining inspissated mucin, to a mucin-secreting adenoma (mucinous cystadenoma)and adenocarcinoma (mucinous cystadenocarcinoma). In the last instance, invasionthrough the appendiceal wall with intraperitoneal seeding and spread of tumor may occur.Morphology.All mucinous lesions are associated with appendiceal dilatation secondary to mucinoussecretions. With the simple mucocele, globular enlargement of the appendix byinspissated mucus occurs, usually the result of obstruction by a fecalith or other lesionsuch as an inflammatory stricture. Eventually, the distention produces sufficient atrophyof the mucin-secreting mucosal cells and the secretions stop. Rarely, a focus of mucin-secreting hyperplastic epithelium appears to be the culprit. This condition is usuallyasymptomatic; rarely a mucocele ruptures, spilling otherwise innocuous mucus into theperitoneal cavity.The most common mucinous neoplasm is the benign mucinous cystadenoma, whichreplaces the appendiceal mucosa and is histologically identical to analogous tumors in theovary. The luminal dilation is associated with appendiceal perforation in 20% ofinstances, producing localized collections of mucus attached to the serosa of the appendixor lying free within the peritoneal cavity. Histologic examination of the mucus, however,reveals no malignant cells. 872Malignant mucinous cystadenocarcinomas are one fifth as common as cystadenomas.Macroscopically they produce mucin-filled cystic dilatation of the appendixindistinguishable from that seen with benign cystadenomas. Penetration of theappendiceal wall by invasive cells and spread beyond the appendix in the form oflocalized or disseminated peritoneal implants, however, is frequently present ( Fig.17-67 ). In its fully developed state, continued cellular proliferation and mucin secretionfills the abdomen with tenacious, semisolid mucin—pseudomyxoma peritoneii.Anaplastic adenocarcinomatous cells can be found, distinguishing this process frommucinous spillage. Instances in which pseudomyxoma peritoneii is accompanied by both
appendiceal and ovarian mucinous adenocarcinomas are usually ascribed to spread of anappendiceal primary lesion.Mucoceles are generally encountered as an incidental lesion. Mucinous cystadenomasand adenocarcinomas may present with pain, attributable to distention of the viscus.Laparotomy for presumed acute appendicitis is a typical diagnosticFigure 17-67 Mucinous cystadenocarcinoma of the appendix, with spread into the immediateperiappendiceal tissues.setting. For lesions confined to the resected specimen (appendix or more radicalexcision), the outlook is excellent. Pseudomyxoma peritoneii may be held in check foryears by repeated debulking procedures but in most instances eventually runs itsinexorable fatal course.PeritoneumInflammationPeritonitis may result from bacterial invasion or chemical irritation. The most commoncauses of peritonitis are as follows. • Sterile peritonitis from mild leakage of bile or pancreatic enzymes • Perforation or rupture of the biliary system, which evokes a highly irritating peritonitis, usually complicated by bacterial superinfection • Acute hemorrhagic pancreatitis (see Chapter 19 ), with leakage of pancreatic enzymes and digestion of adipose tissue to produce fatty acids. These in turn precipitate with calcium to produce chalky white precipitates in areas of fat digestion and necrosis. Globules of free fat may be found floating in the peritoneal fluid, and bacterial permeation of the bowel wall leads to a frank suppurative exudate after 24 to 48 hours. • Surgical procedures. The reaction to surgically introduced foreign material such as talc is usually localized and minimal, leaving residual foreign-body type
granulomas and fibrous tissue. Abrasion of serosal surfaces during abdominal surgery may lead to fibrous adhesions between visceral structures. While usually asymptomatic, these occasionally are the points of internal herniation or intestinal obstruction. • Gynecologic conditions. Endometriosis may introduce irritant blood into the peritoneal cavity, and ruptured dermoid cysts may invoke an intense peritoneal granulomatous reaction.PERITONEAL INFECTIONBacterial peritonitis is almost invariably secondary to extension of bacteria through thewall of a hollow viscus or to rupture of a viscus. The more common disorders leading tosuch bacterial disseminations are appendicitis, ruptured peptic ulcer, cholecystitis,diverticulitis, strangulation of bowel, acute salpingitis, abdominal trauma,, andperitoneal dialysis. Virtually every bacterial organism has been implicated, mostcommonly E. coli, alpha- and beta-hemolytic streptococci, Staphylococcus aureus,enterococci, gram-negative rods, and Clostridium perfringens. The last organism is afrequent inhabitant of the gut and contributor to peritonitis but rarely causes gas gangrenein the abdominal cavity. Gynecologic infections may introduce gonococcus andChlamydia.Spontaneous bacterial peritonitis may develop in the absence of an obvious source ofcontamination. It is an uncommon disorder seen most often in children, particularly thosewith the nephrotic syndrome. Among adults, 10% of cirrhotic patients with ascitesdevelop spontaneous bacterial peritonitis during the course of their illness. The usualcausal agents of the latter are E. coli and pneumococci, but the manner by 873which they invade the peritoneal cavity is unknown, possibly blood-borne.Morphology.Depending on the duration of the peritonitis, the membranes show the following changes.Approximately 2 to 4 hours after initiation, there is loss of the gray, glistening quality ofthe peritoneal surface, and it becomes dull and lusterless. At this time, there is a smallaccumulation of essentially serous or slightly turbid fluid. Later the exudate becomescreamy and obviously suppurative. In some cases, it may be extremely thick and plasticand even inspissated, especially in dehydrated patients. The volume of exudates variesenormously. In many cases, it may be localized by the omentum and viscera to a smallarea of the abdominal cavity. In generalized peritonitis, it is important to remember thatan exudate may accumulate under and above the liver to form subhepatic andsubdiaphragmatic abscesses. Collections in the lesser omental sac may likewise createresidual persistent foci of infection.
The inflammatory process is typical of an acute bacterial infection anywhere andproduces the characteristic neutrophilic infiltration with fibrinopurulent exudation. Thereaction usually remains superficial and does not penetrate deeply into the visceralstructures or abdominal wall. Tuberculous peritonitis tends to produce a plastic exudatestudded with minute, pale granulomas.These inflammatory processes can heal either spontaneously or with therapy. In thecourse of healing, the following may occur: (1) The exudate may be totally resolved,leaving no residual fibrosis; (2) residual, walled-off abscesses may persist, eventually toheal or serve as foci of new infection; or (3) organization of the exudate may occur, withthe formation of fibrous adhesions, which may be delicate or quite dense.SCLEROSING RETROPERITONITISDense fibromatous overgrowth of the retroperitoneal tissues may sometimes develop,designated sclerosing retroperitonitis or idiopathic retroperitoneal fibrosis (also calledOrmond disease). In some instances the mesentery is also involved. The fibrousovergrowth is entirely nondistinctive and, although infiltrative, does not displayanaplasia. There is usually an accompanying inflammatory infiltrate of lymphocytes,plasma cells, and neutrophils, suggesting inflammatory rather than neoplastic disease.The fibrosis may encroach on the ureters to produce hydronephrosis. Alternatively,fibrous tissue may surround retroperitoneal organs and extend into the mesentery. Insome ways this process is an analogue of the desmoid tumor. The cause of this curiouscondition is obscure; in some instances there is a history of intake of the drugmethysergide, an ergot derivative used for migraine, or history of previous surgery orradiation therapy. However, most cases have no obvious cause. Similar fibrotic changesseen in other sites (mediastinal fibrosis, sclerosing cholangitis, and Riedel fibrosingthyroiditis) suggest that the disorder is autoimmune and systemic in origin, preferentiallyinvolving the retroperitoneum.MESENTERIC CYSTSLarge to small cystic masses are sometimes found within the mesenteries in theabdominal cavity or attached to the peritoneal lining of the abdominal wall. These cystssometimes offer difficult clinical problems because they present on palpation asabdominal masses. Many classifications have been attempted; the most widely used isbased on pathogenetic origins: (1) those arising from sequestered lymphatic channels; (2)those derived from pinched-off enteric diverticula of the developing foregut and hindgut;(3) those derived from the urogenital ridge or its derivatives (i.e., the urinary tract andmale and female genital tracts); (4) those derived from walled-off infections or followingpancreatitis, more properly called pseudocysts; and (5) those of malignant origin, mostoften resulting from peritoneal involvement by intra-abdominal adenocarcinomas.TumorsVirtually all tumors of the peritoneum are malignant and can be divided into primary andsecondary forms.
Primary tumors arising from the mesothelium of the peritoneum are extremely rare andare called mesotheliomas. These exactly duplicate mesotheliomas found in the pleura andthe pericardium, but the prognosis is poor. Like the supradiaphragmatic tumors,peritoneal mesotheliomas are associated with asbestos exposure in at least 80% of cases.How inhaled asbestos induces a peritoneal neoplasm remains a mystery. It has beenrecently suggested that genetic factors or viral infections may play a role in the genesis ofperitoneal mesothelioma. The histopathologic diagnosis of mesothelioma is not alwaysstraightforward. In many occasions, immunohistochemical stains are required todifferentiate this tumor from forms of adenocarcinoma.Desmoplastic small round cell tumor is a rare tumor arising from peritoneum. The exacthistogenesis and pathogenesis of this tumor are still not known. Molecular marker studieshave suggested that this tumor is in the family of small round cell tumors such as Ewingsarcoma, rhabdoid myosarcoma, and primitive neuroectodermal tumor. The characteristicgenetic marker for this tumor is the reciprocal chromosome translocation t(11;22)(p13;q12) resulting in EWS-WT1 fusion. Secondary tumors of the peritoneum are, in contrast, quite common. In any form ofadvanced cancer, penetration to the serosal membrane or metastatic seeding (peritonealcarcinomatosis) may occur. The most common tumors producing diffuse serosalimplantation are ovarian and pancreatic. Appendiceal mucinous carcinomas may producepseudomyxoma peritoneii, as described earlier. However, any type of intra-abdominalmalignancy, and occasionally tumors from extra-abdominal locations, may be implicatedin peritoneal seeding.Additional mention might be made of the very uncommon tumors that may arise fromretroperitoneal tissues (i.e., fat, fibrous tissue, blood vessels, lymphatics, nerves, and thelymph nodes alongside the aorta). These native structures may give rise to benign ormalignant tumors derived from any of the indigenous mesenchymal cell types,resembling their counterparts arising elsewhere in the body.References1. DeNardi FG, Riddell RH: The normal esophagus. Am J Surg Pathol 15:296, 1991.2. HornbyPJ, Abrahams TP, Partosoedarso ER: Central mechanisms of lower esophageal sphincter control.Gastroenterol Clin North Am 31:S11, v–vi, 2002.3. Rittler M, Paz JE, Castilla EE: VATERL: an epidemiologic analysis of risk factors. Am J Med Genet73:162, 1997.4. Hirano I: Pathophysiology of achalasia. Curr Gastroenterol Rep 1:198, 1999.5. Richter JE: Oesophageal motility disorders. Lancet 358:823, 2001.
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