Aphthous Ulcers (Canker Sores)

These common superficial mucosal ulcerations affect up to 40% of the population. They are more common in the first two decades of life, extremely painful, and recurrent. Although the cause of aphthous ulcers is not known, they do tend to be more prevalent within some families and may be associated with celiac disease, inflammatory bowel disease (IBD), and Behçet disease. Lesions can be solitary or multiple; typically, they are shallow, hyperemic ulcerations covered by a thin exudate and rimmed by a narrow zone of erythema (Fig. 14–1). In most cases they resolve spontaneously in 7 to 10 days but can recur.

Figure 14–1 Aphthous ulcer. Single ulceration with an erythematous halo surrounding a yellowish fibrinopurulent membrane.

Herpes Simplex Virus Infections

Most orofacial herpetic infections are caused by herpes simplex virus type 1 (HSV-1), with the remainder being caused by HSV-2 (genital herpes). With changing sexual practices, oral HSV-2 is increasingly common. Primary infections typically occur in children between 2 and 4 years of age and are often asymptomatic. However, in 10% to 20% of cases the primary infection manifests as acute herpetic gingivostomatitis, with abrupt onset of vesicles and ulcerations throughout the oral cavity. Most adults harbor latent HSV-1, and the virus can be reactivated, resulting in a so-called “cold sore” or recurrent herpetic stomatitis. Factors associated with HSV reactivation include trauma, allergies, exposure to ultraviolet light, upper respiratory tract infections, pregnancy, menstruation, immunosuppression, and exposure to extremes of temperature. These recurrent lesions, which occur at the site of primary inoculation or in adjacent mucosa innervated by the same ganglion, typically appear as groups of small (1 to 3 mm) vesicles. The lips (herpes labialis), nasal orifices, buccal mucosa, gingiva, and hard palate are the most common locations. Although lesions typically resolve within 7 to 10 days, they can persist in immunocompromised patients, who may require systemic antiviral therapy. Morphologically, the lesions resemble those seen in esophageal herpes (see Fig. 14–8) and genital herpes (Chapter 17). The infected cells become ballooned and have large eosinophilic intranuclear inclusions. Adjacent cells commonly fuse to form large multinucleated polykaryons.

Oral Candidiasis (Thrush)

Candidiasis is the most common fungal infection of the oral cavity. Candida albicans is a normal component of the oral flora and only produces disease under unusual circumstances. Modifying factors include:

Broad-spectrum antibiotics that alter the normal microbiota can also promote oral candidiasis. The three major clinical forms of oral candidiasis are pseudomembranous, erythematous, and hyperplastic. The pseudomembranous form is most common and is known as thrush. This condition is characterized by a superficial, curdlike, gray to white inflammatory membrane composed of matted organisms enmeshed in a fibrinosuppurative exudate that can be readily scraped off to reveal an underlying erythematous base. In mildly immunosuppressed or debilitated individuals, such as diabetics, the infection usually remains superficial, but can spread to deep sites in association with more severe immunosuppression, including that seen in organ or hematopoietic stem cell transplant recipients, as well as patients with neutropenia, chemotherapy-induced immunosuppression, or AIDS.

Fibrous Proliferative Lesions

Fibromas (Fig. 14–2, A) are submucosal nodular fibrous tissue masses that are formed when chronic irritation results in reactive connective tissue hyperplasia. They occur most often on the buccal mucosa along the bite line and are thought to be reactions to chronic irritation. Treatment is complete surgical excision and removal of the source of irritation.

Figure 14–2 Fibrous proliferations. A, Fibroma. Smooth pink exophytic nodule on the buccal mucosa. B, Pyogenic granuloma. Erythematous hemorrhagic exophytic mass arising from the gingival mucosa.

Pyogenic granulomas (Fig. 14–2, B) are pedunculated masses usually found on the gingiva of children, young adults, and pregnant women. These lesions are richly vascular and typically are ulcerated, which gives them a red to purple color. In some cases, growth can be rapid and raise fear of a malignant neoplasm. However, histologic examination demonstrates a dense proliferation of immature vessels similar to that seen in granulation tissue. Pyogenic granulomas can regress, mature into dense fibrous masses, or develop into a peripheral ossifying fibroma. Complete surgical excision is definitive treatment.

Leukoplakia and Erythroplakia

Leukoplakia is defined by the World Health Organization as “a white patch or plaque that cannot be scraped off and cannot be characterized clinically or pathologically as any other disease.” This clinical term is reserved for lesions that arise in the oral cavity in the absence of any known etiologic factor (Fig. 14–3, A). Accordingly, white patches caused by obvious irritation or entities such as lichen planus and candidiasis are not considered leukoplakia. Approximately 3% of the world’s population has leukoplakic lesions, of which 5% to 25% are premalignant and may progress to squamous cell carcinoma. Thus, until proved otherwise by means of histologic evaluation, all leukoplakias must be considered precancerous. A related but less common lesion, erythroplakia, is a red, velvety, possibly eroded area that is flat or slightly depressed relative to the surrounding mucosa. Erythroplakia is associated with a much greater risk of malignant transformation than leukoplakia. While leukoplakia and erythroplakia may be seen in adults at any age, they typically affect persons between the ages of 40 and 70 years, with a 2 : 1 male preponderance. Although the etiology is multifactorial, tobacco use (cigarettes, pipes, cigars, and chewing tobacco) is the most common risk factor for leukoplakia and erythroplakia.

Figure 14–3 Leukoplakia. A, Clinical appearance of leukoplakia is highly variable. In this example, the lesion is smooth with well-demarcated borders and minimal elevation. B, Histologic appearance of leukoplakia showing dysplasia, characterized by nuclear and cellular pleomorphism and loss of normal maturation.

Squamous Cell Carcinoma

Approximately 95% of cancers of the oral cavity are squamous cell carcinomas, with the remainder largely consisting of adenocarcinomas of salivary glands, as discussed later. This aggressive epithelial malignancy is the sixth most common neoplasm in the world today. Despite numerous advances in treatment, the overall long-term survival rate has been less than 50% for the past 50 years. This dismal outlook is due to several factors, most notably the fact that oral cancer often is diagnosed at an advanced stage.

Multiple primary tumors may be present at initial diagnosis but more often are detected later, at an estimated rate of 3% to 7% per year; patients who survive 5 years after diagnosis of the initial tumor have up to a 35% chance of developing at least one new primary tumor within that interval. The development of these secondary tumors can be particularly devastating for persons whose initial lesions were small. Thus, despite a 5-year survival rate greater than 50% for patients with small tumors, these patients often die of second primary tumors. Therefore, surveillance and early detection of new premalignant lesions are critical for the long-term survival of patients with oral squamous cell carcinoma.

The elevated risk of additional primary tumors in these patients has led to the concept of “field cancerization.” This hypothesis suggests that multiple primary tumors develop independently as a result of years of chronic mucosal exposure to carcinogens such as alcohol or tobacco (described next).

Morphology

Squamous cell carcinoma may arise anywhere in the oral cavity. However, the most common locations are the ventral surface of the tongue, floor of the mouth, lower lip, soft palate, and gingiva (Fig. 14–4, A). In early stages, these cancers can appear as raised, firm, pearly plaques or as irregular, roughened, or verrucous mucosal thickenings. Either pattern may be superimposed on a background of a leukoplakia or erythroplakia. As these lesions enlarge, they typically form ulcerated and protruding masses that have irregular and indurated or rolled borders. Histopathologic analysis has shown that squamous cell carcinoma develops from dysplastic precursor lesions. Histologic patterns range from well-differentiated keratinizing neoplasms (Fig. 14–4, B) to anaplastic, sometimes sarcomatoid tumors. However, the degree of histologic differentiation, as determined by the relative degree of keratinization, does not necessarily correlate with biologic behavior. Typically, oral squamous cell carcinoma infiltrates locally before it metastasizes. The cervical lymph nodes are the most common sites of regional metastasis; frequent sites of distant metastases include the mediastinal lymph nodes, lungs, and liver.

Figure 14–4 Oral squamous cell carcinoma. A, Clinical appearance demonstrating ulceration and induration of the oral mucosa. B, Histologic appearance demonstrating numerous nests and islands of malignant keratinocytes invading the underlying connective tissue stroma.

Xerostomia

Xerostomia is defined as a dry mouth resulting from a decrease in the production of saliva. Its incidence varies among populations, but has been reported in more than 20% of individuals above the age of 70 years. It is a major feature of the autoimmune disorder Sjögren syndrome, in which it usually is accompanied by dry eyes (Chapter 4). A lack of salivary secretions is also a major complication of radiation therapy. However, xerostomia is most frequently observed as a result of many commonly prescribed classes of medications including anticholinergic, antidepressant/antipsychotic, diuretic, antihypertensive, sedative, muscle relaxant, analgesic, and antihistaminic agents. The oral cavity may merely reveal dry mucosa and/or atrophy of the papillae of the tongue, with fissuring and ulcerations, or, in Sjögren syndrome, concomitant inflammatory enlargement of the salivary glands. Complications of xerostomia include increased rates of dental caries and candidiasis, as well as difficulty in swallowing and speaking.

Sialadenitis

Sialadenitis, or inflammation of the salivary glands, may be induced by trauma, viral or bacterial infection, or autoimmune disease. The most common form of viral sialadenitis is mumps, which may produce enlargement of all salivary glands but predominantly involves the parotids. The mumps virus is a paramyxovirus related to the influenza and parainfluenza viruses. Mumps produces interstitial inflammation marked by a mononuclear inflammatory infiltrate. While mumps in children is most often a self-limited benign condition, in adults it can cause pancreatitis or orchitis; the latter sometimes causes sterility.

The mucocele is the most common inflammatory lesion of the salivary glands, and results from either blockage or rupture of a salivary gland duct, with consequent leakage of saliva into the surrounding connective tissue stroma. Mucocele occurs most often in toddlers, young adults, and the aged, and typically manifests as a fluctuant swelling of the lower lip that may change in size, particularly in association with meals (Fig. 14–5, A). Histologic examination demonstrates a cystlike space lined by inflammatory granulation tissue or fibrous connective tissue that is filled with mucin and inflammatory cells, particularly macrophages (Fig. 14–5, B). Complete excision of the cyst and the minor salivary gland lobule constitutes definitive treatment.

Figure 14–5 Mucocele. A, Fluctuant fluid-filled lesion on the lower lip subsequent to trauma. B, Cystlike cavity (right) filled with mucinous material and lined by organizing granulation tissue.

Bacterial sialadenitis is a common infection that most often involves the major salivary glands, particularly the submandibular glands. The most frequent pathogens are Staphylococcus aureus and Streptococcus viridans. Duct obstruction by stones (sialolithiasis) is a common antecedent to infection; it may also be induced by impacted food debris or by edema consequent to injury. Dehydration and decreased secretory function also may predispose to bacterial invasion and sometimes are associated with long-term phenothiazine therapy, which suppresses salivary secretion. Systemic dehydration, with decreased salivary secretions, may predispose to suppurative bacterial parotitis in elderly patients following major thoracic or abdominal surgery. This obstructive process and bacterial invasion lead to a nonspecific inflammation of the affected glands that may be largely interstitial or, when induced by staphylococcal or other pyogens, may be associated with overt suppurative necrosis and abscess formation.

Autoimmune sialadenitis, also called Sjögren syndrome, is discussed in Chapter 4.

Neoplasms

Despite their relatively simple morphology, the salivary glands give rise to at least 30 histologically distinct tumors. As indicated in Table 14–1, a small number of these neoplasms account for more than 90% of tumors. Overall, salivary gland tumors are relatively uncommon and represent less than 2% of all human tumors. Approximately 65% to 80% arise within the parotid, 10% in the submandibular gland, and the remainder in the minor salivary glands, including the sublingual glands. Approximately 15% to 30% of tumors in the parotid glands are malignant. By contrast, approximately 40% of submandibular, 50% of minor salivary gland, and 70% to 90% of sublingual tumors are cancerous. Thus, the likelihood that a salivary gland tumor is malignant is inversely proportional, roughly, to the size of the gland.

Table 14–1 Histopathologic Classification and Prevalence of the Most Common Benign and Malignant Salivary Gland Tumors

NOS, not otherwise specified.

Data from Ellis GL, Auclair PL, Gnepp DR: Surgical Pathology of the Salivary Glands, Vol 25: Major Problems in Pathology, Philadelphia, WB Saunders, 1991.

Salivary gland tumors usually occur in adults, with a slight female predominance, but about 5% occur in children younger than 16 years of age. Whatever the histologic pattern, parotid gland neoplasms produce swelling in front of and below the ear. In general, when they are first diagnosed, both benign and malignant lesions are usually 4 to 6 cm in diameter and are mobile on palpation except in the case of neglected malignant tumors. Benign tumors may be present for months to several years before coming to clinical attention, while cancers more often come to attention promptly, probably because of their more rapid growth. However, there are no reliable criteria to differentiate benign from malignant lesions on clinical grounds, and histopathologic evaluation is essential.

Pleomorphic Adenoma

Pleomorphic adenomas present as painless, slow-growing, mobile discrete masses. They represent about 60% of tumors in the parotid, are less common in the submandibular glands, and are relatively rare in the minor salivary glands. Pleomorphic adenomas are benign tumors that consist of a mixture of ductal (epithelial) and myoepithelial cells, so they exhibit both epithelial and mesenchymal differentiation. Epithelial elements are dispersed throughout the matrix, which may contain variable mixtures of myxoid, hyaline, chondroid (cartilaginous), and even osseous tissue. In some pleomorphic adenomas, the epithelial elements predominate; in others, they are present only in widely dispersed foci. This histologic diversity has given rise to the alternative, albeit less preferred name mixed tumor. The tumors consistently overexpress the transcription factor PLAG1, often because of chromosomal rearrangements involving the PLAG1 gene, but how PLAG1 contributes to tumor development is unknown.

Pleomorphic adenomas recur if incompletely excised: Recurrence rates approach 25% after simple enucleation of the tumor, but are only 4% after wider resection. In both settings, recurrence stems from a failure to recognize minute extensions of tumor into surrounding soft tissues.

Carcinoma arising in a pleomorphic adenoma is referred to variously as a carcinoma ex pleomorphic adenoma or malignant mixed tumor. The incidence of malignant transformation increases with time from 2% of tumors present for less than 5 years to almost 10% for those present for more than 15 years. The cancer usually takes the form of an adenocarcinoma or undifferentiated carcinoma. Unfortunately, these are among the most aggressive malignant neoplasms of salivary glands, with mortality rates of 30% to 50% at 5 years.

Morphology

Pleomorphic adenomas typically manifest as rounded, well-demarcated masses rarely exceeding 6 cm in the greatest dimension. Although they are encapsulated, in some locations (particularly the palate), the capsule is not fully developed, and expansile growth produces protrusions into the surrounding tissues. The cut surface is gray-white and typically contains myxoid and blue translucent chondroid (cartilage-like) areas. The most striking histologic feature is their characteristic heterogeneity. Epithelial elements resembling ductal or myoepithelial cells are arranged in ducts, acini, irregular tubules, strands, or even sheets. These typically are dispersed within a mesenchyme-like background of loose myxoid tissue containing islands of chondroid and, rarely, foci of bone (Fig. 14–6). Sometimes the epithelial cells form well-developed ducts lined by cuboidal to columnar cells with an underlying layer of deeply chromatic, small myoepithelial cells. In other instances there may be strands or sheets of myoepithelial cells. Islands of well-differentiated squamous epithelium also may be present. In most cases, no epithelial dysplasia or mitotic activity is evident. No difference in biologic behavior has been observed between the tumors composed largely of epithelial elements and those composed largely of mesenchymal elements.

Figure 14–6 Pleomorphic adenoma. A, Low-power view showing a well-demarcated tumor with adjacent normal salivary gland parenchyma. B, High-power view showing epithelial cells as well as myoepithelial cells within chondroid matrix material.

Mechanical Obstruction

Atresia, fistulas, and duplications may occur in any part of the gastrointestinal tract. When they involve the esophagus, they are discovered shortly after birth, usually because of regurgitation during feeding, and must be corrected promptly. Absence, or agenesis, of the esophagus is extremely rare. Atresia, in which a thin, noncanalized cord replaces a segment of esophagus, is more common. Atresia occurs most commonly at or near the tracheal bifurcation and usually is associated with a fistula connecting the upper or lower esophageal pouches to a bronchus or the trachea. This abnormal connection can result in aspiration, suffocation, pneumonia, or severe fluid and electrolyte imbalances.

Passage of food can be impeded by esophageal stenosis. The narrowing generally is caused by fibrous thickening of the submucosa, atrophy of the muscularis propria, and secondary epithelial damage. Stenosis most often is due to inflammation and scarring, which may be caused by chronic gastroesophageal reflux, irradiation, or caustic injury. Stenosis-associated dysphagia usually is progressive; difficulty eating solids typically occurs long before problems with liquids.

Functional Obstruction

Efficient delivery of food and fluids to the stomach requires a coordinated wave of peristaltic contractions. Esophageal dysmotility interferes with this process and can take several forms, all of which are characterized by discoordinated contraction or spasm of the muscularis. Because it increases esophageal wall stress, spasm also can cause small diverticula to form.

Increased lower esophageal sphincter (LES) tone can result from impaired smooth muscle relaxation with consequent functional esophageal obstruction. Achalasia is characterized by the triad of incomplete LES relaxation, increased LES tone, and esophageal aperistalsis. Primary achalasia is caused by failure of distal esophageal inhibitory neurons and is, by definition, idiopathic. Degenerative changes in neural innervation, either intrinsic to the esophagus or within the extraesophageal vagus nerve or the dorsal motor nucleus of the vagus, also may occur. Secondary achalasia may arise in Chagas disease, in which Trypanosoma cruzi infection causes destruction of the myenteric plexus, failure of LES relaxation, and esophageal dilatation. Duodenal, colonic, and ureteric myenteric plexuses also can be affected in Chagas disease. Achalasia-like disease may be caused by diabetic autonomic neuropathy; infiltrative disorders such as malignancy, amyloidosis, or sarcoidosis; and lesions of dorsal motor nuclei, which may be produced by polio or surgical ablation.

Ectopia

Ectopic tissues (developmental rests) are common in the gastrointestinal tract. The most frequent site of ectopic gastric mucosa is the upper third of the esophagus, where it is referred to as an inlet patch. Although the presence of such tissue generally is asymptomatic, acid released by gastric mucosa within the esophagus can result in dysphagia, esophagitis, Barrett esophagus, or, rarely, adenocarcinoma. Gastric heterotopia, small patches of ectopic gastric mucosa in the small bowel or colon, may manifest with occult blood loss secondary to peptic ulceration of adjacent mucosa.

Esophageal Varices

Instead of returning directly to the heart, venous blood from the gastrointestinal tract is delivered to the liver via the portal vein before reaching the inferior vena cava. This circulatory pattern is responsible for the first-pass effect, in which drugs and other materials absorbed in the intestines are processed by the liver before entering the systemic circulation. Diseases that impede this flow cause portal hypertension, which can lead to the development of esophageal varices, an important cause of esophageal bleeding.

Morphology

Varices can be detected by angiography (Fig. 14–7, A) and appear as tortuous dilated veins lying primarily within the submucosa of the distal esophagus and proximal stomach. Varices may not be obvious on gross inspection of surgical or postmortem specimens, because they collapse in the absence of blood flow (Fig. 14–7, B). The overlying mucosa can be intact (Fig. 14–7, C) but is ulcerated and necrotic if rupture has occurred.

Figure 14–7 Esophageal varices. A, Angiogram showing several tortuous esophageal varices. Although the angiogram is striking, endoscopy is more commonly used to identify varices. B, Collapsed varices are present in this postmortem specimen corresponding to the angiogram in A. The polypoid areas are sites of variceal hemorrhage that were ligated with bands. C, Dilated varices beneath intact squamous mucosa.

Lacerations

The most common esophageal lacerations are Mallory-Weiss tears, which are often associated with severe retching or vomiting, as may occur with acute alcohol intoxication. Normally, a reflex relaxation of the gastroesophageal musculature precedes the antiperistaltic contractile wave associated with vomiting. This relaxation is thought to fail during prolonged vomiting, with the result that refluxing gastric contents overwhelm the gastric inlet and cause the esophageal wall to stretch and tear. Patients often present with hematemesis.

The roughly linear lacerations of Mallory-Weiss syndrome are longitudinally oriented, range in length from millimeters to several centimeters, and usually cross the gastroesophageal junction. These tears are superficial and do not generally require surgical intervention; healing tends to be rapid and complete. By contrast, Boerhaave syndrome, characterized by transmural esophageal tears and mediastinitis, occurs rarely and is a catastrophic event. The factors giving rise to this syndrome are similar to those for Mallory-Weiss tears, but more severe.

Chemical and Infectious Esophagitis

The stratified squamous mucosa of the esophagus may be damaged by a variety of irritants including alcohol, corrosive acids or alkalis, excessively hot fluids, and heavy smoking. Medicinal pills may lodge and dissolve in the esophagus, rather than passing into the stomach intact, resulting in a condition termed pill-induced esophagitis. Esophagitis due to chemical injury generally causes only self-limited pain, particularly odynophagia (pain with swallowing). Hemorrhage, stricture, or perforation may occur in severe cases. Iatrogenic esophageal injury may be caused by cytotoxic chemotherapy, radiation therapy, or graft-versus-host disease. The morphologic changes are nonspecific with ulceration and accumulation of neutrophils. Irradiation causes blood vessel thickening adding some element of ischemic injury.

Infectious esophagitis may occur in otherwise healthy persons but is most frequent in those who are debilitated or immunosuppressed. In these patients, esophageal infection by herpes simplex viruses, cytomegalovirus (CMV), or fungal organisms is common. Among fungi, Candida is the most common pathogen, although mucormycosis and aspergillosis may also occur. The esophagus may also be involved in desquamative skin diseases such as bullous pemphigoid and epidermolysis bullosa and, rarely, Crohn disease.

Infection by fungi or bacteria can be primary or complicate a preexisting ulcer. Nonpathogenic oral bacteria frequently are found in ulcer beds, while pathogenic organisms, which account for about 10% of infectious esophagitis cases, may invade the lamina propria and cause necrosis of overlying mucosa. Candidiasis, in its most advanced form, is characterized by adherent, gray-white pseudomembranes composed of densely matted fungal hyphae and inflammatory cells covering the esophageal mucosa.

The endoscopic appearance often provides a clue to the identity of the infectious agent in viral esophagitis. Herpesviruses typically cause punched-out ulcers (Fig. 14–8, A), and histopathologic analysis demonstrates nuclear viral inclusions within a rim of degenerating epithelial cells at the ulcer edge (Fig. 14–8, B). By contrast, CMV causes shallower ulcerations and characteristic nuclear and cytoplasmic inclusions within capillary endothelium and stromal cells (Fig. 14–8, C). Immunohistochemical staining for viral antigens can be used as an ancillary diagnostic tool.

Figure 14–8 Viral esophagitis. A, Postmortem specimen with multiple herpetic ulcers in the distal esophagus. B, Multinucleate squamous cells containing herpesvirus nuclear inclusions. C, Cytomegalovirus-infected endothelial cells with nuclear and cytoplasmic inclusions.

Reflux Esophagitis

The stratified squamous epithelium of the esophagus is resistant to abrasion from foods but is sensitive to acid. The submucosal glands of the proximal and distal esophagus contribute to mucosal protection by secreting mucin and bicarbonate. More important, constant LES tone prevents reflux of acidic gastric contents, which are under positive pressure. Reflux of gastric contents into the lower esophagus is the most frequent cause of esophagitis and the most common outpatient gastrointestinal diagnosis in the United States. The associated clinical condition is termed gastroesophageal reflux disease (GERD).

Morphology

Simple hyperemia, evident to the endoscopist as redness, may be the only alteration. In mild GERD the mucosal histology is often unremarkable. With more significant disease, eosinophils are recruited into the squamous mucosa, followed by neutrophils, which usually are associated with more severe injury (Fig. 14–9, A). Basal zone hyperplasia exceeding 20% of the total epithelial thickness and elongation of lamina propria papillae, such that they extend into the upper third of the epithelium, also may be present.

Figure 14–9 Esophagitis. A, Reflux esophagitis with scattered intraepithelial eosinophils. B, Eosinophilic esophagitis with numerous intraepithelial eosinophils.

Eosinophilic Esophagitis

The incidence of eosinophilic esophagitis is increasing markedly. Symptoms include food impaction and dysphagia in adults and feeding intolerance or GERD-like symptoms in children. The cardinal histologic feature is epithelial infiltration by large numbers of eosinophils, particularly superficially (Fig. 14–9, B) and at sites far from the gastroesophageal junction. Their abundance can help to differentiate eosinophilic esophagitis from GERD, Crohn disease, and other causes of esophagitis. Certain clinical characteristics, particularly failure of high-dose proton pump inhibitor treatment and the absence of acid reflux, are also typical. A majority of persons with eosinophilic esophagitis are atopic, and many have atopic dermatitis, allergic rhinitis, asthma, or modest peripheral eosinophilia. Treatments include dietary restrictions to prevent exposure to food allergens, such as cow milk and soy products, and topical or systemic corticosteroids.

Barrett Esophagus

Barrett esophagus is a complication of chronic GERD that is characterized by intestinal metaplasia within the esophageal squamous mucosa. The incidence of Barrett esophagus is rising; it is estimated to occur in as many as 10% of persons with symptomatic GERD. White males are affected most often and typically present between 40 and 60 years of age. The greatest concern in Barrett esophagus is that it confers an increased risk of esophageal adenocarcinoma. Molecular studies suggest that Barrett epithelium may be more similar to adenocarcinoma than to normal esophageal epithelium, consistent with the view that Barrett esophagus is a premalignant condition. In keeping with this, epithelial dysplasia, considered to be a preinvasive lesion, develops in 0.2% to 1.0% of persons with Barrett esophagus each year; its incidence increases with duration of symptoms and increasing patient age. Although the vast majority of esophageal adenocarcinomas are associated with Barrett esophagus, it should be noted that most persons with Barrett esophagus do not develop esophageal cancer.

Morphology

Barrett esophagus is recognized endoscopically as tongues or patches of red, velvety mucosa extending upward from the gastroesophageal junction. This metaplastic mucosa alternates with residual smooth, pale squamous (esophageal) mucosa proximally and interfaces with light-brown columnar (gastric) mucosa distally (Fig. 14–10, A and B). High-resolution endoscopes have increased the sensitivity of Barrett esophagus detection.

Figure 14–10 Barrett esophagus. A, Normal gastroesophageal junction. B, Barrett esophagus. Note the small islands of paler squamous mucosa within the Barrett mucosa. C, Histologic appearance of the gastroesophageal junction in Barrett esophagus. Note the transition between esophageal squamous mucosa (left) and metaplastic mucosa containing goblet cells (right).

Most authors require both endoscopic evidence of abnormal mucosa above the gastroesophageal junction and histologically documented gastric or intestinal metaplasia for diagnosis of Barrett esophagus. Goblet cells, which have distinct mucous vacuoles that stain pale blue by H&E and impart the shape of a wine goblet to the remaining cytoplasm, define intestinal metaplasia and are a feature of Barrett esophagus (Fig. 14–10, C). Dysplasia is classified as low-grade or high-grade on the basis of morphologic criteria. Intramucosal carcinoma is characterized by invasion of neoplastic epithelial cells into the lamina propria.

Adenocarcinoma

Esophageal adenocarcinoma typically arises in a background of Barrett esophagus and long-standing GERD. Risk of adenocarcinoma is greater in patients with documented dysplasia and is further increased by tobacco use, obesity, and previous radiation therapy. Conversely, reduced adenocarcinoma risk is associated with diets rich in fresh fruits and vegetables.

Esophageal adenocarcinoma occurs most frequently in whites and shows a strong gender bias, being seven times more common in men than in women. However, the incidence varies by a factor of 60 worldwide, with rates being highest in developed Western countries, including the United States, the United Kingdom, Canada, Australia, and the Netherlands, and lowest in Korea, Thailand, Japan, and Ecuador. In countries where esophageal adenocarcinoma is more common, the incidence has increased markedly since 1970, more rapidly than for almost any other cancer. As a result, esophageal adenocarcinoma, which represented less than 5% of esophageal cancers before 1970, now accounts for half of all esophageal cancers in the United States.

Morphology

Esophageal adenocarcinoma usually occurs in the distal third of the esophagus and may invade the adjacent gastric cardia (Fig. 14–11, A). While early lesions may appear as flat or raised patches in otherwise intact mucosa, tumors may form large exophytic masses, infiltrate diffusely, or ulcerate and invade deeply. On microscopic examination, Barrett esophagus frequently is present adjacent to the tumor. Tumors typically produce mucin and form glands (Fig. 14–11, B).

Figure 14–11 Esophageal adenocarcinoma. A, Adenocarcinoma usually occurs distally and, as in this case, often involves the gastric cardia. B, Esophageal adenocarcinoma growing as back-to-back glands.

Squamous Cell Carcinoma

In the United States, esophageal squamous cell carcinoma typically occurs in adults older than 45 years of age and affects males four times more frequently than females. Risk factors include alcohol and tobacco use, poverty, caustic esophageal injury, achalasia, Plummer-Vinson syndrome, frequent consumption of very hot beverages, and previous radiation therapy to the mediastinum. It is nearly 6 times more common in African Americans than in whites—a striking risk disparity that cannot be accounted for by differences in rates of alcohol and tobacco use. The incidence of esophageal squamous cell carcinoma can vary by more than 100-fold between and within countries, being more common in rural and underdeveloped areas. The countries with highest incidences are Iran, central China, Hong Kong, Argentina, Brazil, and South Africa.

Morphology

In contrast to the distal location of most adenocarcinomas, half of squamous cell carcinomas occur in the middle third of the esophagus (Fig. 14–12, A). Squamous cell carcinoma begins as an in situ lesion in the form of squamous dysplasia. Early lesions appear as small, gray-white plaquelike thickenings. Over months to years they grow into tumor masses that may be polypoid and protrude into and obstruct the lumen. Other tumors are either ulcerated or diffusely infiltrative lesions that spread within the esophageal wall, where they cause thickening, rigidity, and luminal narrowing. These cancers may invade surrounding structures including the respiratory tree, causing pneumonia; the aorta, causing catastrophic exsanguination; or the mediastinum and pericardium.

Figure 14–12 Esophageal squamous cell carcinoma.

A, Squamous cell carcinoma most frequently is found in the midesophagus, where it commonly causes strictures. B, Squamous cell carcinoma composed of nests of malignant cells that partially recapitulate the stratified organization of squamous epithelium.

Most squamous cell carcinomas are moderately to well differentiated (Fig. 14–12, B). Less common histologic variants include verrucous squamous cell carcinoma, spindle cell carcinoma, and basaloid squamous cell carcinoma. Regardless of histologic type, symptomatic tumors are generally very large at diagnosis and have already invaded the esophageal wall. The rich submucosal lymphatic network promotes circumferential and longitudinal spread, and intramural tumor nodules may be present several centimeters away from the principal mass. The sites of lymph node metastases vary with tumor location: Cancers in the upper third of the esophagus favor cervical lymph nodes; those in the middle third favor mediastinal, paratracheal, and tracheobronchial nodes; and those in the lower third spread to gastric and celiac nodes.

Acute Gastritis

Acute gastritis is a transient mucosal inflammatory process that may be asymptomatic or cause variable degrees of epigastric pain, nausea, and vomiting. In more severe cases there may be mucosal erosion, ulceration, hemorrhage, hematemesis, melena, or, rarely, massive blood loss.

Pathogenesis

The gastric lumen is strongly acidic, with a pH close to one—more than a million times more acidic than the blood. This harsh environment contributes to digestion but also has the potential to damage the mucosa. Multiple mechanisms have evolved to protect the gastric mucosa (Fig. 14–13). Mucin secreted by surface foveolar cells forms a thin layer of mucus that prevents large food particles from directly touching the epithelium. The mucus layer also promotes formation of an “unstirred” layer of fluid over the epithelium that protects the mucosa and has a neutral pH as a result of bicarbonate ion secretion by surface epithelial cells. Finally, the rich vascular supply to the gastric mucosa delivers oxygen, bicarbonate, and nutrients while washing away acid that has back-diffused into the lamina propria. Acute or chronic gastritis can occur after disruption of any of these protective mechanisms. For example, reduced mucin synthesis in elderly persons is suggested to be one factor that explains their increased susceptibility to gastritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with cytoprotection normally provided by prostaglandins or reduce bicarbonate secretion, both of which increase the susceptibility of the gastric mucosa to injury. Ingestion of harsh chemicals, particularly acids or bases, either accidentally or as a suicide attempt, also results in severe gastric injury, predominantly as a consequence of direct damage to mucosal epithelial and stromal cells. Direct cellular injury also is implicated in gastritis due to excessive alcohol consumption, NSAIDs, radiation therapy, and chemotherapy.

Figure 14–13 Mechanisms of gastric injury and protection. This diagram illustrates the progression from more mild forms of injury to ulceration that may occur with acute or chronic gastritis. Ulcers include layers of necrotic debris (N), inflammation (I), and granulation tissue (G); a fibrotic scar (S), which develops over time, is present only in chronic lesions.

Acute Peptic Ulceration

Focal, acute peptic injury is a well-known complication of therapy with NSAIDs as well as severe physiologic stress. Such lesions include

Chronic Gastritis

The symptoms and signs associated with chronic gastritis typically are less severe but more persistent than those of acute gastritis. Nausea and upper abdominal discomfort may occur, sometimes with vomiting, but hematemesis is uncommon. The most common cause of chronic gastritis is infection with the bacillus Helicobacter pylori. Autoimmune gastritis, the most common cause of atrophic gastritis, represents less than 10% of cases of chronic gastritis and is the most common form of chronic gastritis in patients without H. pylori infection. Less common causes include radiation injury and chronic bile reflux.

Helicobacter pylori Gastritis

The discovery of the association of H. pylori with peptic ulcer disease revolutionized the understanding of chronic gastritis. These spiral-shaped or curved bacilli are present in gastric biopsy specimens from almost all patients with duodenal ulcers and a majority of those with gastric ulcers or chronic gastritis. Acute H. pylori infection does not produce sufficient symptoms to require medical attention in most cases; rather the chronic gastritis ultimately causes the afflicted person to seek treatment. H. pylori organisms are present in 90% of patients with chronic gastritis affecting the antrum. In addition, the increased acid secretion that occurs in H. pylori gastritis may result in peptic ulcer disease of the stomach or duodenum; H. pylori infection also confers increased risk of gastric cancer.

Epidemiology

In the United States, H. pylori infection is associated with poverty, household crowding, limited education, African American or Mexican American ethnicity, residence in areas with poor sanitation, and birth outside of the United States. Colonization rates exceed 70% in some groups and range from less than 10% to more than 80% worldwide. In high-prevalence areas, infection often is acquired in childhood and then persists for decades. Thus, the incidence of H. pylori infection correlates most closely with sanitation and hygiene during an individual’s childhood.

  Pathogenesis

H. pylori infection most often manifests as a predominantly antral gastritis with high acid production, despite hypogastrinemia. The risk of duodenal ulcer is increased in these patients, and in most cases, gastritis is limited to the antrum.

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

• Flagella, which allow the bacteria to be motile in viscous mucus

• Urease, which generates ammonia from endogenous urea, thereby elevating local gastric pH around the organisms and protecting the bacteria from the acidic pH of the stomach

• Adhesins, which enhance bacterial adherence to surface foveolar cells

• Toxins, such as that encoded by cytotoxin-associated gene A (CagA), that may be involved in ulcer or cancer development by poorly defined mechanisms

These factors allow H. pylori to create an imbalance between gastroduodenal mucosal defenses and damaging forces that overcome those defenses. Over time, chronic antral H. pylori gastritis may progress to pangastritis, resulting in multifocal atrophic gastritis, reduced acid secretion, intestinal metaplasia, and increased risk of gastric adenocarcinoma in a subset of patients. The underlying mechanisms contributing to this progression are not clear, but interactions between the host immune system and the bacterium seem to be critical.

Morphology

Gastric biopsy specimens generally demonstrate H. pylori in infected persons (Fig. 14–14, A). The organism is concentrated within the superficial mucus overlying epithelial cells in the surface and neck regions. The inflammatory reaction includes a variable number of neutrophils within the lamina propria, including some that cross the basement membrane to assume an intraepithelial location (Fig. 14–14, B) and accumulate in the lumen of gastric pits to create pit abscesses. The superficial lamina propria includes large numbers of plasma cells, often in clusters or sheets, as well as increased numbers of lymphocytes and macrophages. When intense, inflammatory infiltrates may create thickened rugal folds, mimicking infiltrative lesions. Lymphoid aggregates, some with germinal centers, frequently are present (Fig. 14–14, C) and represent an induced form of mucosa-associated lymphoid tissue (MALT) that has the potential to transform into lymphoma. Intestinal metaplasia, characterized by the presence of goblet cells and columnar absorptive cells (Fig. 14–14, D), also may be present and is associated with increased risk of gastric adenocarcinoma. H. pylori shows tropism for gastric foveolar epitheleum and generally is not found in areas of intestinal metaplasia, acid-producing mucosa of the gastric body, or duodenal epithelium. Thus, an antral biopsy is preferred for evaluation of H. pylori gastritis.

Figure 14–14 Chronic gastritis. A, Spiral-shaped Helicobacter pylori bacilli are highlighted in this Warthin-Starry silver stain. Organisms are abundant within surface mucus. B, Intraepithelial and lamina propria neutrophils are prominent. C, Lymphoid aggregates with germinal centers and abundant subepithelial plasma cells within the superficial lamina propria are characteristic of H. pylori gastritis. D, Intestinal metaplasia, recognizable as the presence of goblet cells admixed with gastric foveolar epithelium, can develop and is a risk factor for development of gastric adenocarcinoma.

Clinical Features

In addition to histologic identification of the organism, several diagnostic tests have been developed including a noninvasive serologic test for anti–H. pylori antibodies, fecal bacterial detection, and the urea breath test based on the generation of ammonia by bacterial urease. Gastric biopsy specimens also can be analyzed by the rapid urease test, bacterial culture, or polymerase chain reaction (PCR) assay for bacterial DNA. Effective treatments include combinations of antibiotics and proton pump inhibitors. Patients with H. pylori gastritis usually improve after treatment, although relapses can follow incomplete eradication or reinfection.

Peptic Ulcer Disease

Peptic ulcer disease (PUD) most often is associated with H. pylori infection or NSAID use. In the US, the latter is becoming the most common cause of gastric ulcers as H. pylori infection rates fall and low-dose aspirin use in the aging population increases. PUD may occur in any portion of the gastrointestinal tract exposed to acidic gastric juices but is most common in the gastric antrum and first portion of the duodenum. PUD also may occur in the esophagus as a result of GERD or acid secretion by ectopic gastric mucosa, and in the small intestine secondary to gastric heteropia within a Meckel diverticulum.

Epidemiology

PUD is common and is a frequent cause of physician visits worldwide. It leads to treatment of over 3 million people, 190,000 hospitalizations, and 5000 deaths in the United States each year. The lifetime risk of developing an ulcer is approximately 10% for males and 4% for females.

Pathogenesis

H. pylori infection and NSAID use are the primary underlying causes of PUD. The imbalances of mucosal defenses and damaging forces that cause chronic gastritis (Fig. 14–13) are also responsible for PUD. Thus, PUD generally develops on a background of chronic gastritis. Although more than 70% of PUD cases are associated with H. pylori infection, only 5% to 10% of H. pylori–infected persons develop ulcers. It is probable that host factors as well as variation among H. pylori strains determine the clinical outcomes.

Gastric hyperacidity is fundamental to the pathogenesis of PUD. The acidity that drives PUD may be caused by H. pylori infection, parietal cell hyperplasia, excessive secretory responses, or impaired inhibition of stimulatory mechanisms such as gastrin release. For example, Zollinger-Ellison syndrome, characterized by multiple peptic ulcerations in the stomach, duodenum, and even jejunum, is caused by uncontrolled release of gastrin by a tumor and the resulting massive acid production. Cofactors in peptic ulcerogenesis include chronic NSAID use, as noted; cigarette smoking, which impairs mucosal blood flow and healing; and high-dose corticosteroids, which suppress prostaglandin synthesis and impair healing. Peptic ulcers are more frequent in persons with alcoholic cirrhosis, chronic obstructive pulmonary disease, chronic renal failure, and hyperparathyroidism. In the latter two conditions, hypercalcemia stimulates gastrin production and therefore increases acid secretion. Finally, psychologic stress may increase gastric acid production and exacerbate PUD.

Morphology

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

Peptic ulcers are solitary in more than 80% of patients. Lesions less than 0.3 cm in diameter tend to be shallow, whereas those over 0.6 cm are likely to be deeper. The classic peptic ulcer is a round to oval, sharply punched-out defect (Fig. 14–15, A). The base of peptic ulcers is smooth and clean as a result of peptic digestion of exudate and on histologic examination is composed of richly vascular granulation tissue (Fig. 14–15, B). Ongoing bleeding within the ulcer base may cause life-threatening hemorrhage. Perforation is a complication that demands emergent surgical intervention.

Figure 14–15 Acute gastric perforation in a patient presenting with free air under the diaphragm. A, Mucosal defect with clean edges. B, The necrotic ulcer base (arrow) is composed of granulation tissue.

Clinical Features

Peptic ulcers are chronic, recurring lesions that occur most often in middle-aged to older adults without obvious precipitating conditions, other than chronic gastritis. A majority of peptic ulcers come to clinical attention after patient complaints of epigastric burning or aching pain, although a significant fraction manifest with complications such as iron deficiency anemia, frank hemorrhage, or perforation. The pain tends to occur 1 to 3 hours after meals during the day, is worse at night, and is relieved by alkali or food. Nausea, vomiting, bloating, and belching may be present. Healing may occur with or without therapy, but the tendency to develop ulcers later remains.

A variety of surgical approaches formerly were used to treat PUD, but current therapies are aimed at H. pylori eradication with antibiotics and neutralization of gastric acid, usually through use of proton pump inhibitors. These efforts have markedly reduced the need for surgical management, which is reserved primarily for treatment of bleeding or perforated ulcers. PUD causes much more morbidity than mortality.

Summary

Acute and Chronic Gastritis

• The spectrum of acute gastritis ranges from asymptomatic disease to mild epigastric pain, nausea, and vomiting. Causative factors include any agent or disease that interferes with gastric mucosal protection. Acute gastritis can progress to acute gastric ulceration.

• The most common cause of chronic gastritis is H. pylori infection; most remaining cases are caused by autoimmune gastritis.

• H. pylori gastritis typically affects the antrum and is associated with increased gastric acid production. The induced mucosa-associated lymphoid tissue (MALT) can transform into lymphoma.

• Autoimmune gastritis causes atrophy of the gastric body oxyntic glands, which results in decreased gastric acid production, antral G cell hyperplasia, achlorhydria, and vitamin B₁₂ deficiency. Anti-parietal cell and anti–intrinsic factor antibodies typically are present.

• Intestinal metaplasia develops in both forms of chronic gastritis and is a risk factor for development of gastric adenocarcinoma.

• Peptic ulcer disease can be caused by H. pylori chronic gastritis and the resultant hyperchlorhydria or NSAID use. Ulcers can develop in the stomach or duodenum and usually heal after suppression of gastric acid production and, if present, eradication of the H. pylori.

Gastric Polyps

Polyps, nodules or masses that project above the level of the surrounding mucosa, are identified in up to 5% of upper gastrointestinal tract endoscopies. Polyps may develop as a result of epithelial or stromal cell hyperplasia, inflammation, ectopia, or neoplasia. Although many different types of polyps can occur in the stomach, only hyperplastic and inflammatory polyps, fundic gland polyps, and adenomas are considered here.

Gastric Adenocarcinoma

Adenocarcinoma is the most common malignancy of the stomach, comprising more than 90% of all gastric cancers. Early symptoms resemble those of chronic gastritis, including dyspepsia, dysphagia, and nausea. As a result, in low-incidence regions such as the United States, the cancer is often at advanced stages when clinical manifestations such as weight loss, anorexia, altered bowel habits, anemia, and hemorrhage trigger diagnostic evaluation.

Epidemiology

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

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

In the United States, gastric cancer rates dropped by more than 85% during the 20th century. Similar declines have been reported in many other Western countries, reflecting the importance of environmental and dietary factors. Despite this decrease in overall gastric adenocarcinoma incidence, cancer of the gastric cardia is on the rise. This trend probably is related to increased rates of Barrett esophagus and may reflect the growing prevalence of chronic GERD and obesity.

Pathogenesis

Gastric cancers are genetically heterogeneous but certain molecular alterations are common. We will consider these first to be followed by the role of H. pylori–induced chronic inflammation and the association of a subset of gastric cancers with EBV infection.

• Mutations: While the majority of gastric cancers are not hereditary, mutations identified in familial gastric cancer have provided important insights into mechanisms of carcinogenesis in sporadic cases. Germline mutations in CDH1, which encodes E-cadherin, a protein that contributes to epithelial intercellular adhesion, are associated with familial gastric cancers, usually of the diffuse type. Mutations in CDH1 are present in about 50% of diffuse gastric tumors, while E-cadherin expression is drastically decreased in the rest, often by methylation of the CDH1 promoter. Thus, the loss of E-cadherin function seems to be a key step in the development of diffuse gastric cancer.

In contrast to CDH1, patients with familial adenomatous polyposis (FAP) who have germline mutations in adenomatous polyposis coli (APC) genes have an increased risk of intestinal-type gastric cancer. Sporadic intestinal-type gastric cancer is associated with several genetic abnormalities including acquired mutations of β-catenin, a protein that binds to both E-cadherin and APC protein; microsatellite instability; and hypermethylation of genes including TGFβRII, BAX, IGFRII, and p16/INK4a. TP53 mutations are present in a majority of sporadic gastric cancers of both histologic types.

• H. pylori: Chronic gastritis, most commonly due to H. pylori infection, promotes the development and progression of cancers that may be induced by diverse genetic alterations (Chapter 5). As is the case with many forms of chronic inflammation, H. pylori–induced chronic gastritis is associated with increased production of proinflammatory proteins, such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF). It is therefore not surprising that polymorphisms associated with enhanced production of these cytokines confer increased risk of chronic gastritis-associated intestinal-type gastric cancer in those with co-existing H. pylori infection.

• EBV: While H. pylori is most commonly associated with gastric cancer, approximately 10% of gastric adenocarcinomas are associated with Epstein-Barr virus (EBV) infection. Although the precise role of EBV in the development of gastric adenocarcinomas remains to be defined, it is notable that EBV episomes in these tumors frequently are clonal, suggesting that infection preceded neoplastic transformation. Further, TP53 mutations are uncommon in the EBV-positive gastric tumors, suggesting that the molecular pathogenesis of these cancers is distinct from that of other gastric adenocarcinomas. Morphologically, EBV-positive tumors tend to occur in the proximal stomach and most commonly have a diffuse morphology with a marked lymphocytic infiltrate.

Morphology

Gastric adenocarcinomas are classified according to their location in the stomach as well as gross and histologic morphology. The Lauren classification that separates gastric cancers into intestinal and diffuse types correlates with distinct patterns of molecular alterations, as discussed above. Intestinal-type cancers tend to be bulky (Fig. 14–16, A) and are composed of glandular structures similar to esophageal and colonic adenocarcinoma. Intestinal-type adenocarcinomas typically grow along broad cohesive fronts to form either an exophytic mass or an ulcerated tumor. The neoplastic cells often contain apical mucin vacuoles, and abundant mucin may be present in gland lumina.

Figure 14–16 Gastric adenocarcinoma. A, Intestinal-type adenocarcinoma consisting of an elevated mass with heaped-up borders and central ulceration. Compare with the peptic ulcer in Figure 14-15, A. B, Linitis plastica. The gastric wall is markedly thickened, and rugal folds are partially lost. C, Signet ring cells with large cytoplasmic mucin vacuoles and peripherally displaced, crescent-shaped nuclei.

Diffuse gastric cancers display an infiltrative growth pattern (Fig. 14–16, B) and are composed of discohesive cells with large mucin vacuoles that expand the cytoplasm and push the nucleus to the periphery, creating a signet ring cell morphology (Fig. 14–16, C). These cells permeate the mucosa and stomach wall individually or in small clusters. A mass may be difficult to appreciate in diffuse gastric cancer, but these infiltrative tumors often evoke a desmoplastic reaction that stiffens the gastric wall and may cause diffuse rugal flattening and a rigid, thickened wall that imparts a “leather bottle” appearance termed linitis plastica.

Clinical Features

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

The depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis remain the most powerful prognostic indicators for gastric cancer. Local invasion into the duodenum, pancreas, and retroperitoneum also is characteristic. When possible, surgical resection remains the preferred treatment for gastric adenocarcinoma. After surgical resection, the 5-year survival rate for early gastric cancer can exceed 90%, even if lymph node metastases are present. By contrast, the 5-year survival rate for advanced gastric cancer remains below 20%, in large part because current chemotherapy regimens are minimally effective. Because of the advanced stage at which most gastric cancers are discovered in the United States, the overall 5-year survival is less than 30%.

Lymphoma

Although extranodal lymphomas can arise in virtually any tissue, they do so most commonly in the gastrointestinal tract, particularly the stomach. In allogeneic hematopoietic stem cell and organ transplant recipients, the bowel also is the most frequent site for Epstein-Barr virus–positive B cell lymphoproliferations. Nearly 5% of all gastric malignancies are primary lymphomas, the most common of which are indolent extranodal marginal zone B cell lymphomas. In the gut, these tumors often are referred to as lymphomas of mucosa-associated lymphoid tissue (MALT), or MALTomas. This entity and the second most common primary lymphoma of the gut, diffuse large B cell lymphoma, are discussed in Chapter 11.

Carcinoid Tumor

Carcinoid tumors arise from neuroendocrine organs (e.g., the endocrine pancreas) and neuroendocrine-differentiated gastrointestinal epithelia (e.g., G-cells). A majority are found in the gastrointestinal tract, and more than 40% occur in the small intestine. The tracheobronchial tree and lungs are the next most commonly involved sites. Gastric carcinoids may be associated with endocrine cell hyperplasia, chronic atrophic gastritis, and Zollinger-Ellison syndrome. These tumors were called “carcinoid” because they are slower growing than carcinomas. The most current WHO classification describes these as low- or intermediate grade neuroendocrine tumors. The grade is based on mitotic activity and the fraction of cells immunohistochemcially positive for Ki67, a mitotic marker. However, it is important to recognize that site within the GI tract and extent of local invasion are also important prognostic indicators (see later). High-grade neuroendocrine tumors, termed neuroendocrine carcinoma, frequently display necrosis and, in the GI tract, are most common in the jejunum.

Morphology

Carcinoid tumors are intramural or submucosal masses that create small polypoid lesions (Fig. 14–17, A). The tumors are yellow or tan in appearance and elicit an intense desmoplastic reaction that may cause kinking of the bowel and obstruction. On histologic examination, carcinoid tumors are composed of islands, trabeculae, strands, glands, or sheets of uniform cells with scant, pink granular cytoplasm and a round to oval stippled nucleus (Fig. 14–17, B).

Figure 14–17 Gastrointestinal carcinoid tumor (neuroendocrine tumor). A, Carcinoid tumors often form a submucosal nodule composed of tumor cells embedded in dense fibrous tissue. B, High magnification shows the bland cytology that typifies carcinoid tumors. The chromatin texture, with fine and coarse clumps, frequently assumes a “salt and pepper” pattern. Despite their innocuous appearance, carcinoids can be aggressive.

Gastrointestinal Stromal Tumor

A wide variety of mesenchymal neoplasms may arise in the stomach. Many are named according to the cell type they most resemble; for example, smooth muscle tumors are called leiomyomas or leiomyosarcomas, nerve sheath tumors are termed schwannomas, and those resembling glomus bodies in the nail beds and at other sites are termed glomus tumors. These tumors are all rare and are not discussed here. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the abdomen, and more than half of these tumors occur in the stomach.