Lesson 20

These prominent purplish dilated veins near the gastroesophageal junction are a source of bleeding with hematemesis. Submucosal varices occur in patients with portal hypertension (usually from micronodular cirrhosis resulting from chronic alcoholism or schistosomiasis) because the sub-mucosal esophageal plexus of veins is a collateral channel for portal venous drainage. This plexus of veins also drains part of the upper stomach, but it is generically called the esophageal plexus of veins; bleeding here is termed esophageal variceal bleeding. 

Islands of reddish metaplastic mucosa are shown here in the lower esophagus, above the gastroesophageal junction, with remaining surrounding white squamous mucosa. Chronic GERD with esophageal mucosal injury can lead to metaplasia of the normal esophageal squa-mous mucosa into gastric-type columnar mu-cosa, but with intestinal-type goblet cells, known as Barrett esophagus. Ten percent of patients with chronic gastric reflux may develop Barrett esophagus. Ulceration leads to bleeding and pain; inflammation with stricture may ensue. 

Note the abnormal columnar epithelium on the left of this image and the normal squamous epithelium on the right. This is “typical” Barrett mucosa on the left because there is intestinal metaplasia with goblet cells in the columnar mucosa. Chronic reflux of gastric contents into the lower esophagus over many years predis-poses to development of this metaplasia. Barrett esophagus is mostly diagnosed on endoscopy with biopsy in persons 40 to 60 years old. There is a long-term risk (>30- to 40-fold compared with the general population) for development of esophageal adenocarcinoma when more than 3 cm of Barrett mucosa is present in the esophagus. 

Normal tan upper esophageal mucosa is at the far left. The distal esophagus is replaced by Bar-rett mucosa, producing a darker, slightly erythem-atous gross appearance. In the distal esophagus arising near the gastroesophageal junction is a large ulcerating adenocarcinoma with a dark center that extends into the upper stomach. Adenocarcinomas most often arise in Barrett esophagus, with frequent mutation of TP53,followed by CDKN2A gene downregulation, then by nuclear translocation of β-catenin and ERBB2amplification. As with squamous cell carcinoma, there are often no early symptoms, so the cancer is advanced at the time of diagnosis, with a poor prognosis. 

The gastric mucosa of the fundus is diffusely hyperemic, with multiple petechiae, and with small erosions but no ulcerations. Acute gas-tritis (also called hemorrhagic gastritis, or acute erosive gastritis if mucosal erosions are present) can be caused by ischemia (from shock, burns, or trauma) or toxins (e.g., alcohol, salicylates, or NSAIDs). Damage to the mucosal barrier allows back-diffusion of acid. Patients may be asymp-tomatic or have massive hemorrhage. The lesions can progress to erosions or ulcerations. The stress of burn injuries (Curling ulcer) or central nervous system trauma (Cushing ulcer) can cause acid hypersecretion. 

Microscopic findings include hemorrhage, ede-ma, and variable degrees of acute inflammation with neutrophilic infiltrates. The gastric mucosa here shows infiltration of glands and lamina pro-pria by neutrophils. Typical clinical findings range from mild to severe epigastric pain, nausea, and vomiting. In severe cases there can be significant hematemesis, particularly in patients with a his-tory of chronic alcohol abuse; this can be termed acute hemorrhagic gastritis. Although the pres-ence of gastric acid is a necessary antecedent to ulceration, the amount of acid is not typically the determining factor for development of most gastric ulcerations. 

Chronic nonspecific (antral) gastritis is typically the result of Helicobacter pylori infection. Other causes include bile reflux and drugs (salicylates and alcohol). The inflammatory cell infiltrates are composed mainly of lymphocytes and plasma cells, and occasionally some neutrophils, shown here at the left. Mucosal atrophy and intestinal metaplasia are sequelae that can be the first step toward development of gastric adenocarcinoma. An autoimmune form of gastritis can occur when antiparietal or intrinsic factor antibodies are present, leading to atrophic gastritis and perni-cious anemia. Fasting serum gastrin levels are inversely proportional to gastric acid production, and a high serum gastrin level suggests atrophic gastritis. 

H. pylori is a small, spiral, rod-shaped, gram-negative bacterium residing under microaerobic conditions in a neutral microenvironment between the mucus and the superficial columnar mucosal cells. The organisms here are pale pink rods with H&E staining. H. pylori strains that possess the cagA pathogenicity island induce more severe gastritis and augment the risk for developing peptic ulcer disease and gastric cancer. These organisms do not invade or directly damage the mucosa, but rather change the microenvironment of the stomach to promote mucosal damage. H. pylori organisms contain urease and produce a protective surrounding cloud of ammonia to resist gastric acid. The urea breath test is used to detect the presence of H. pylori. 

H. pylori organisms stimulate cytokine pro-duction by epithelial cells that recruit and activate immune and inflammatory cells in the underlying lamina propria. This infection is thought to be acquired in childhood, but inflammatory changes progress throughout life. Colonization rates vary from 10% to 80% around the world. Only a few of the persons infected with H. pylori develop the complications of chronic gastritis, gastric ulcers, duodenal ulcers, mucosa-associated lymphoid tissue (MALT) lymphoma, or adenocarcinoma. H. pylori is found in the surface epithelial mucus of most patients with active gastritis. The organ-isms are shown here with methylene blue stain. 

An ulcer is an area of full-thickness loss of the mucosa (an erosion is a partial-thickness loss). Ul-cers can be complicated by hemorrhage, penetra-tion (extension into an adjacent organ), perforation (communication with the peritoneal cavity), and stricture (as a result of scarring). A 1-cm, shal-low, and sharply demarcated acute gastric ulcer with surrounding hyperemia is shown here in the upper fundus. This ulcer is probably benign. All gastric ulcers should undergo biopsy because of the risk for malignancy. Isolated gastric ulcers may be seen with chronic atrophic gastritis; they are usually located in the antrum and lesser curve or at the junction of the antrum and body. H. pyloriis the most common cause, followed by NSAID use. Although acid is required for ulceration, most patients are normochlorhydric or hypochlorhydric. 

Note the loss of the epithelium and extension of the ulcer downward to the muscularis. This ulcer is sharply demarcated, with normal gastric mucosa on the left falling away into a deep ulcer crater whose base contains inflamed, necrotic debris. An arterial branch () at the ulcer base is eroded and bleeding. Ulcers penetrate more deeply over time if they remain active and do not heal. Penetration leads to pain. If the ulcer penetrates through the muscularis and through adventitia, the ulcer is said to “perforate,” leading to an acute abdomen with peritonitis, and an abdominal radiograph may show free air. 

The shallow gastric ulcer shown is about 2 to 4 cm in size. This ulcer on biopsy proved to be malignant, so the stomach was resected. In the United States, most gastric cancers are discovered at a late stage when the neoplasm has invaded or metastasized, whereas in Japan screening programs detect early gastric cancers. All gastric ulcers and all gastric masses must undergo biopsy because it is impossible to de-termine malignancy from their gross appearance. In contrast, virtually all duodenal peptic ulcers are benign. Worldwide, gastric carcinoma is the second most common cancer, but the incidence has been declining for decades in the United States. 

This intestinal type of gastric adenocarcinoma has irregular shapes and sizes of neoplastic glands infiltrating into the submucosa. Some of the cells show mitoses. The cells have an increased nuclear-to-cytoplasmic ratio and nuclear hyperchromatism. There is a desmoplastic stromal reaction to these infiltrating glands. Genetic abnormalities in the intestinal type of gastric cancer include p53 mutation, abnormal E-cadherin expression, and instability of TGFβand BAX genes. 

This diffuse type of gastric adenocarcinoma is so poorly differentiated that mostly infiltrating neo-plastic cells with marked pleomorphism are seen. Many of the neoplastic cells have cytoplasm filled with clear vacuoles of mucin, displacing the cell nucleus to the periphery. This is the “signet ring” cell pattern that is typical of the diffuse type of gastric adenocarcinoma, which tends to be highly infiltrative and has a poor prognosis. Muta-tions in CDH1 that encode E-cadherin involved in epithelial intercellular adhesion are found with some diffuse gastric carcinomas, including familial forms. a

The dark-red to gray infarcted small intesti-nal loops contrasts with the pale pink normal transverse colon at the top. In some organs, such as bowel with anastomosing blood sup-plies or liver with a dual blood supply, infarction is more difficult. This bowel was caught in a hernia created by internal adhesions from prior surgery. A similar finding could result from incarceration of bowel in an inguinal hernia sac. The mesen-teric blood supply was constricted here. Bowel ischemia often produces acute abdominal pain with distention. Lack of peristalsis, marked by absence of bowel sounds, is known as ileus. 

The mucosal surface of the bowel shows early red hyperemia (left panel) and necrosis (right panel) with hyperemia extending all the way from mucosa to submucosal and muscular wall vessels. The submucosa and muscularis are still intact, however. With more advanced ischemia and necrosis, the small intestinal mucosa can show hemorrhage with acute inflammation. Progression of ischemia produces transmural necrosis extending into submucosa and muscularis. Patients can have abdominal pain, vomiting, and bloody or melanotic stools. With ischemic necro-sis, intestinal bacterial organisms can gain access to blood, producing septicemia, or to peritoneal cavity, producing peritonitis and leading to shock. 

The colonic mucosal surface shown is partially covered by yellow-green exudate. The mucosa is erythematous and superficially denuded, but not eroded. It may cause an acute or chronic diarrheal illness associated with fever, leukocytosis, abdominal pain, and cramps. Broad-spectrum antibiotic usage (e.g., clindamycin) or immunosuppression allows overgrowth of normally suppressed intestinal bacterial flora, such as Clostridium difficile, or other organisms such as Staphylococcus aureus, Salmonella, or fungi such as Candida, to cause this antibiotic-associated colitis. Exotoxins elaborated by the bacteria damage the mucosa by inducing cyto-kine production to cause cellular apoptosis. 

The underlying colonic mucosa is intact, so grossly bloody diarrhea is unlikely, but there is a marked overlying exudate with necrotic epithe-lial cells admixed with inflammatory cells. The exudate within crypts may be so extensive that it erupts from the surface in volcano-like fashion (more like Mauna Loa, as shown here). C. difficiletoxins disrupt the epithelial cytoskeleton, with loss of tight junction barrier function, and pro-mote cytokine release and apoptosis. Recurrent infection may occur. 

The center portion of terminal ileum shown here has a thickened wall, and the mucosa has lost the regular folds and contains deep fissures. The serosal surface shows reddish indurated adipose tissue that creeps over the surface. The areas of inflammation tend to be discontinuous throughout the bowel (“skip” lesions). Although any portion of the GI tract may be involved with CD, the small intestine—and the terminal ileum in particular—is most likely to be affected. CD is more common in the United States and Western Europe; women are affected more often than men. A genetic susceptibility may be related to the presence of certain HLA types and to NOD2gene mutations that may be related to the mi-crobe receptor triggering NF-κB transcription fac-tor production, which promotes cytokine release driving inflammation. 

The granulomatous inflammation of CD is shown here with epithelioid cells, giant cells, and many lymphocytes. Both TH1 and TH17 immune responses participate. Most patients have a relapsing course over decades, some have quiescent disease for many years, and others have continuously active disease after onset. Saccharomyces cerevisiae IgG antibodies are found in 80% of CD patients, but only 20% of patients with ulcerative colitis (UC). S. cerevisiaeIgA antibodies are found in 35% of CD patients, but less than 1% of UC patients. Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) are found in 75% of UC patients, but in only 20% of CD patients. 

On the left is a colectomy specimen with extensive UC beginning in the rectum and extending all the way to the ileocecal valve. There is diffuse mucosal inflammation with focal ulceration, erythema, and granularity. As the disease progresses, the mucosal erosions coalesce to linear ulcers that undermine remaining mucosa, leaving islands of residual mucosa called pseudopolyps. On the right,these pseudopolyps occur in a case of severe UC. The remaining mucosa has been ulcerated away, leaving only hyperemic submu-cosa and muscularis.

On the left is a colectomy specimen with extensive UC beginning in the rectum and extending all the way to the ileocecal valve. There is diffuse mucosal inflammation with focal ulceration, erythema, and granularity. As the disease progresses, the mucosal erosions coalesce to linear ulcers that undermine remaining mucosa, leaving islands of residual mucosa called pseudopolyps. On the right,these pseudopolyps occur in a case of severe UC. The remaining mucosa has been ulcerated away, leaving only hyperemic submu-cosa and muscularis.

The inflammation of UC is confined primarily to the mucosa, shown here as an inflammatory process that undermines the surround-ing mucosa to produce a flask-shaped ulceration. An exudate is present over the surface. Acute and chronic inflammatory cells can be present. The stools are typically of low volume but may contain blood and mucus. A relapsing but mild course is most com-mon, seen in 60% of patients, although some patients may have a single episode, and others have almost continuous attacks. One third of patients may undergo colectomy within 3 years of onset because of uncontrolled colitis. In about 10% of inflammatory bowel disease cases, a clear distinction between CD and UC cannot be made, and the term applied is indeterminate colitis. 

The colonic mucosa of active UC shows “crypt abscesses,” in which a neutrophilic exudate is found within the glandular lumina of the crypts of Lieberkühn. The submucosa also shows intense inflammation. Inflamed crypts with architectural distortion show loss of goblet cells and hyper-chromatic nuclei with inflammatory atypia. Crypt abscesses are a histologic finding more typical of UC than CD, but there is overlap between these two forms of idiopathic inflammatory bowel disease, and not all cases can be classified com-pletely in all patients. 

This benign neoplasm is formed of new glandular or villous architecture with dysplastic epithelium. This small pedunculated adenomatous polyp on a small stalk is shown to have more crowded, disorganized but rounded glands (a tubular pattern) than the normal underlying colonic mucosa. Goblet cells are less numerous in the polyp, and the crowded cells lining the glands of the polyp have hyperchromatic nuclei. This small benign neoplasm is still well differentiated and circumscribed, without invasion of the stalk. Accumulation of additional mutations over time and with continued growth of the polyp could give rise to malignant transformation. 

The exophytic growth pattern of the carcinoma shown can obstruct the colonic lumen. One of the complications of a carcinoma is obstruction (usually partial). A change in stool or bowel habits can be created by the mass effect. A diet low in fiber and high in refined foods and fats predisposes to colon cancer. NSAIDs promote adenoma regression to protect against carcinogenesis. 

This is a resected appendix from abdominal lapa-roscopic surgery. There is a serosal tan-yellow exudate, but the main features of this early acute appendicitis are edema and hyperemia. This patient had a fever and an elevated total white blood cell count with a left shift (increased band neutrophils) noted on the peripheral blood smear. The patient had minimal abdominal pain, but had flank pain because the appendix had a retrocecal orientation. 

Acute appendicitis is marked by mucosal inflammation and necrosis. As shown here, numerous neutrophils extend into and through the wall of the appendix. A peripheral neutrophilia with bandemia is often present as well. This condition is treated surgically by removal of the inflamed appendix before potential complications of rup-ture or sepsis occur. If the inflammation is limited to the serosa (periappendicitis), it is likely that the instigating process is somewhere else in the ab-domen and that the appendix is just an “innocent bystander.”