Clinical Features

GERD is an extremely common chronic condition, particularly in Western countries. Estimates based on an assumption that reflux-like symptoms are an indicator of the disease suggest a prevalence rate of 20% to 40%. Clinically, GERD is often classified as erosive or nonerosive based on endoscopic or pathologic features. Risk factors associated with GERD include advanced age, certain lifestyle habits (e.g., alcohol consumption), body mass index, and tobacco smoking, although the clinically relevant contributions of many of these factors are not entirely clear. GERD affects people of all ages, but the risk increases with age and rises dramatically after age 40 years. The symptoms most often associated with GERD are heartburn, acid regurgitation, and dysphagia. Atypical or supraesophageal symptoms include asthma, chronic cough, chronic sore throat, pharyngitis, laryngitis, a globus sensation, and noncardiac chest pain. The clinical and pathogenetic aspects of GERD are discussed further in the section on BE .

Pathogenesis

In the traditional view, reflux esophagitis is caused by reflux of gastric or duodenal fluid into the esophagus. The injurious effect of refluxed gastric acid, bile, pepsin, and duodenal contents on the normal protective mucosal barriers causes injury to the esophageal mucosa. With ongoing reflux injury, surface esophageal cells die, triggering both an inflammatory response (infiltration of neutrophils) and a proliferative response (basal cell and papillary hyperplasia). The cause of reflux is multifactorial. Contributing factors include the presence of a hiatal hernia, a defective or weak lower esophageal sphincter (LES), impaired esophageal peristalsis with transient LES relaxation, delayed gastric emptying, decreased salivary gland secretions, increased gastric acid production, and bile reflux. Although the data have been somewhat conflicting, there is some evidence to support an association among high body mass index, the presence of hiatal hernia, and GERD. Likewise, there is evidence to suggest that Helicobacter pylori infection may actually protect against the development of GERD and its complications. Specifically, corpus gastritis is associated with decreased acid secretion, and GERD is less common in patients with severe corpus gastritis. When acid secretion returns to normal after the eradication of H. pylori , there is an increased risk of developing GERD.

Recent studies of the pathogenesis of GERD in animal models and in vitro indicate that exposing esophageal squamous epithelial cells to acids and bile salts alone can cause epithelial cells to secrete inflammatory cytokines (i.e., interleukin 8 [IL8] and IL1β) that cause inflammatory cells (T-lymphocytes and neutrophils) to migrate into the epithelium. This finding has led to the new hypothesis that it is the inflammatory response, not the direct effect of acid, that is the initial factor responsible for damaging esophageal mucosa. Histologic examination in animal models has demonstrated that infiltration of the submucosa by lymphocytes is an early manifestation of inflammation. Neutrophils involve the mucosal surface later in the course of disease progression. These findings provide further support for an alternative concept for the development of reflux esophagitis in humans.

Pathology

On endoscopic examination, patients with erosive esophagitis reveal erosions, ulcers, strictures, or some combination of these. However, as much as 50% to 60% of all symptomatic patients with objective evidence of GERD have normal mucosa or only mild hyperemia at endoscopy. Furthermore, histologically inflamed esophageal mucosa (esophagitis) may appear normal endoscopically; and conversely, hyperemia does not necessarily indicate the presence of esophagitis microscopically. Because of these endoscopic/pathologic discrepancies, biopsies are always warranted in symptomatic patients to document the presence of tissue injury and to exclude other entities such as infections, BE, and other preneoplastic or inflammatory alterations. This approach is particularly important if empiric reflux therapy has failed.

Biopsies of grossly visible lesions in GERD characteristically reveal evidence of “active” esophagitis, a nonspecific injury pattern that can result from a variety of causes. Pinch biopsies obtained through standard endoscopes are often not adequate for evaluation of early histologic changes resulting from reflux because they usually do not include the entire thickness of the mucosa and are difficult to orient. Endoscopes with a large-caliber biopsy channel and jumbo biopsy forceps should be used to facilitate accurate histologic diagnosis. Use of jumbo forceps does not increase the rate of complications related to endoscopy ; rather, it greatly improves the quality of the histologic specimens.

Histologically, reflux changes are typically distributed over the distal 8 to 10 cm of the esophagus in a patchy fashion, and multiple biopsies are often necessary to consistently demonstrate histologic abnormalities. However, changes are typically worse in the distal esophagus and decrease in intensity more proximally. Because biopsy specimens from the lower 1 to 2 cm of the esophagus, even in asymptomatic subjects, often reveal evidence of mild squamous hyperplasia, diagnostic biopsy specimens should be obtained usually more than 2.0 cm above the level of the gastroesophageal junction (GEJ) in order to diagnose esophagitis reliably. Furthermore, because of a high level of discordance between endoscopic and histologic findings, it is recommended that all symptomatic patients undergo biopsy, regardless of the presence or absence of endoscopic abnormalities. Esophageal biopsies are considered more useful for establishing a diagnosis of GERD in infants than in adults.

Reflux esophagitis produces a characteristic, although nonspecific, tissue injury pattern. Features of untreated active esophagitis include basal cell hyperplasia, elongation of the lamina propria papillae into more than two thirds of the thickness of the mucosa, epithelial cell necrosis, increased intraepithelial inflammation (including eosinophils, neutrophils, and lymphocytes), lack of surface maturation (nucleated cells at surface of epithelium), distended pale squamous “balloon” cells, intercellular edema (acantholysis), and, in severe cases, surface erosions or ulcerations ( Figs. 14.1 to 14.3 ). Intercellular edema or dilated intercellular spaces reflecting increased paracellular permeability may be a useful marker of early injury in the absence of endoscopic evidence of injury.

A, Normal squamous mucosa shows basal and suprabasal cells that involve less than 15% of the thickness of the epithelium. The lamina propria papillae involve approximately 50% of the thickness of the epithelium. B, In reflux esophagitis, there is basal and suprabasal cell hyperplasia, elongation of the lamina propria papillae, lack of surface maturation with the presence of nucleated squamous cells at the surface of the epithelium, and increased inflammation in the lamina propria.

High-power view of the squamous mucosa in a patient with reflux esophagitis. A, Neutrophils are identified within the squamous epithelium. B, There is an increased intraepithelial component of squiggly T lymphocytes. C, There is an increased number of eosinophils. In addition, the squamous cells are reactive appearing, with prominent nucleoli. Intercellular edema is evident, particularly in B.

Reflux esophagitis. A, Mild reflux esophagitis shows reactive squamous cells, increased intraepithelial lymphocytes, and prominent intercellular edema, particularly in the basal and middle portions of the epithelium. B, Moderate reflux esophagitis shows an increased number of intraepithelial lymphocytes, scattered eosinophils, and few neutrophils. C and D, Severe reflux esophagitis. This portion of the squamous mucosa shows increased intraepithelial neutrophils and ballooning degeneration of the squamous cells, particularly in the middle and superficial portions of the epithelium.

Other Microscopic Features of GERD

Dilation and congestion of lamina propria capillaries are additional characteristic features of reflux esophagitis, but this finding may also occur in specimens from normal controls, albeit in a mild fashion, possibly as a traumatic biopsy artefact. Other features that may be seen in GERD include ballooning degeneration of squamous cells, intercellular edema (acantholysis) that causes minor separation of individual squamous cells, multinucleation of squamous cells, increased mitoses, and decreased surface maturation. The presence of multinucleated (regenerative) cells may mimic herpetic esophagitis ( Fig. 14.4 ). Multinucleated regenerative squamous cells are distinguished from virally infected cells by the lack of characteristic nuclear inclusions and by their prominence at the base of the mucosa and adjacent to ulcers, rather than in the surface cells, which is characteristic of herpes.

A and B, Multinucleated reactive epithelial cells in a patient with severe reflux esophagitis. The multinucleated reactive squamous epithelial cells are most prominent in the basal layer and in areas of mucosa adjacent to ulceration. The multinucleated cells show a low nucleus-to-cytoplasm ratio and perinuclear cytoplasmic clearing. In addition, there is prominent intercellular edema, epithelial degeneration, increased inflammation, and ulceration.

Differential Diagnosis of GERD

The differential diagnosis of GERD includes infectious esophagitis; pill esophagitis; esophagitis caused by ingestion of corrosive agents such as lye; chemotherapy- and radiation-induced esophagitis; primary EOE; systemic diseases such as collagen vascular disease, Crohn’s disease, Stevens-Johnson syndrome, various bullous diseases, lichen planus, and graft-versus-host disease; and trauma. Many of these conditions share overlapping morphologic features with GERD. Therefore, an accurate diagnosis of “reflux” esophagitis requires correlation with the patient’s clinical, endoscopic, manometric, and histologic data. In the absence of clinical information, a diagnosis of reflux esophagitis cannot be established on the basis of biopsy findings alone. The histologic features are essentially nonspecific. In fact, in this scenario, a “top line” diagnosis of “active esophagitis consistent with reflux” rather than “reflux esophagitis” should be used.

Reactive Squamous Hyperplasia versus Dysplasia

On occasion, marked reactive (pseudoepitheliomatous) hyperplasia related to reflux esophagitis may resemble squamous dysplasia histologically ( Fig. 14.5 ). The most helpful distinguishing feature is the presence of cytoarchitectural uniformity in cases of hyperplasia, compared with cytoarchitectural pleomorphism in cases of dysplasia or carcinoma.

A, Marked reactive (pseudoepitheliomatous) hyperplasia in a patient with severe reflux esophagitis. Squamous cells are reactive and hyperchromatic and possess prominent nucleoli but do not show significant loss of polarity or nuclear overlap. The papillae are of uniform length and width, and the nuclei, although mildly atypical, are uniform in appearance (inset A) . B, In high-grade squamous dysplasia, the papillae vary in size and shape, and there is considerable nuclear pleomorphism, hyperchromasia, and nuclear overlapping (inset B) .

The mucosal architecture in hyperplastic lesions retains its uniformity, showing elongation of papillae that extend to roughly equal depths within the deep lamina propria and are usually of similar width. In contrast, dysplastic squamous epithelium typically displays architectural distortion with absent, sharply angulated, or markedly irregular papillae in terms of their length and width ( Table 14.1 ; see also Chapter 24 for details).

Cytologically, hyperplastic squamous epithelial cells are uniform and do not show loss of polarity or overlapping nuclei. The nuclei may be uniformly enlarged; however, they have smooth nuclear membranes, open chromatin, often prominent nucleoli, and increased mitoses but no atypical mitoses. Dysplastic squamous epithelial cells are typically more pleomorphic in size and shape, are more hyperchromatic, have irregular nuclear contours, and reveal nuclear overlapping and loss of polarity (see Fig. 14.5 ).

Reactive Changes in Ulcers versus Dysplasia or Carcinoma

Granulation tissue within the base of erosions or ulcers may exhibit large atypical endothelial cells and fibroblasts ( Fig. 14.6 ). They are usually distributed in a scattered fashion within otherwise typical granulation tissue. These cells do not form solid clusters of cells and have a normal, or even decreased, nucleus-to-cytoplasm (N : C) ratio. In contrast, carcinoma usually demonstrates groups or sheets of cohesive cells with overlapping nuclei and an increased N : C ratio. In difficult cases, immunohistochemistry for cytokeratins can be helpful in differentiating true carcinoma (positive) from reactive “pseudosarcomatous” alterations of the stromal cells (negative).

High-power view of the base of an esophageal ulcer showing increased inflammation and marked, somewhat atypical reactive mesenchymal cells. Although the nuclei are enlarged and irregular in shape, the nucleus-to-cytoplasm ratio of the cells is still maintained. The cells are scattered rather than grouped together, as one would expect in a malignant process.

Rarely, the inflammatory exudate within the ulcer or erosion may contain abundant activated and atypical lymphocytes that can simulate lymphoma ( Fig. 14.7 ). In general, these cells are benign when confined to the surface exudate. The infiltrate should raise concern for a lymphoma if it involves the underlying tissue in a dense, confluent, and homogeneous manner.

High-power view of an exudate from a benign ulcer in a patient with reflux esophagitis shows abundant cleaved and activated lymphocytes and macrophages that may simulate a lymphoma histologically. If the lymphocytic infiltrate is limited to the luminal exudate, without infiltration of the underlying tissue, it should be considered benign.

Natural History and Treatment of GERD

The natural history of GERD in the general population remains uncertain because of the widespread use of acid inhibitors. GERD has three phenotypic presentations: nonerosive reflux disease (NERD), erosive esophagitis, and BE. Most patients with GERD (50% to 70%) have normal mucosa on endoscopy and therefore are diagnosed with NERD. Some researchers have proposed that NERD is a discrete entity because of its unique physiologic characteristics, which include a more competent antireflux barrier. However, most authorities believe that GERD is a progressive disease that starts with NERD and progresses with time, to erosive esophagitis or BE or both, in selected high-risk individuals. Some data suggest that progression from NERD to erosive esophagitis occurs in as much as 30% of patients annually, but it is unknown whether NERD can progress directly to BE without an erosive phase. Between 1% and 22% of patients with erosive esophagitis progress to a more severe form of disease, whereas regression to a less severe form of disease occurs in 6% to 42% of patients, depending on whether acid inhibitors have been used. Erosive esophagitis is a risk factor for BE. Barrett’s esophagus develops in between 1% to 13% of patients with erosive esophagitis annually. In a recent prospective, follow-up endoscopic study to evaluate the risk of BE in a Swedish general population (the Kalixanda study database), the incidence of BE was 9.9 per 1000 person-years, and the prevalence of BE in this GERD cohort increased from 3% to 8% during a 5-year follow-up period. In fact, progression of GERD to BE in the general population may be higher than previously recognized.

The vast majority of patients with GERD have a recurrent but nonprogressive form of disease that is controlled adequately with acid inhibitor therapy.

Current medical forms of therapy, such as proton pump inhibitors (PPIs) and other acid inhibitors, are highly effective at relieving symptoms. However, progressive disease develops in some patients despite ongoing therapy. In one study, as much as 82% of patients who showed healing of their esophagitis with omeprazole relapsed within 6 months after cessation of therapy. In a 10-year follow-up study of 101 patients with reflux esophagitis, significant morbidity related to GERD developed in almost 75%, showing quality of life scores significantly lower than those of a non–GERD control population. Surgical treatment is considered an option for patients with chronic GERD who are not responsive to medical therapy or have a defective LES.

Clinical Features

Herpes esophagitis occurs primarily in immunosuppressed patients. Common causes of immunosuppression include prior chemotherapy, solid organ and bone marrow transplantation, and acquired immunodeficiency syndrome (AIDS). Herpes esophagitis also may occur in otherwise healthy young adults with normal immune function, who usually have a self-limited infection that resolves within 1 to 2 weeks. Symptoms of herpetic esophagitis include odynophagia, dysphagia, epigastric pain, fever, and upper GI bleeding, but some patients are asymptomatic. Coexistent herpes labialis and oropharyngeal ulcers are seen in approximately one fourth of patients. Herpetic ulcers in the esophagus may serve as a portal of entry for other pathogens and can be associated with herpetic pneumonitis. Endoscopically, herpetic ulcers are typically shallow, sharply punched-out lesions and are often surrounded by relatively normal-appearing mucosa.

Pathology

Herpes simplex or varicella-zoster virus infects esophageal squamous epithelium. Accordingly, the characteristic inclusion bodies are limited to the squamous epithelial cells, typically accentuated at the superficial lateral margin of ulcers and erosions. In fact, biopsy specimens obtained distant from the immediate edge of the ulcer lesion may not be diagnostic. Microscopic diagnostic criteria include the presence of Cowdry A intranuclear viral inclusion bodies, ground-glass nuclei, nuclear molding, multinucleated giant cells, and ballooning degeneration of infected cells ( Fig. 14.8 ). Cowdry A inclusions are eosinophilic to amphophilic round bodies separated by a clear zone from a thickened nuclear membrane. Ground-glass nuclei have a smooth, homogeneous chromatin pattern with a pale basophilic quality. Multinucleated giant cell changes in squamous epithelial cells may occur in reflux esophagitis and should not be confused with the cytopathic effects of herpesvirus infection. Reactive cells have prominent nucleoli and perinucleolar clearing, but nuclear inclusion bodies are not present. Large numbers of mononuclear cells, primarily aggregates of macrophages with convoluted nuclei, in the surface exudate adjacent to the infected epithelium have been noted as a characteristic finding in herpetic ulcers and should make the pathologist suspect herpesvirus infection. However, similar cells may be observed in nonherpetic ulcers throughout the GI tract in the absence of herpesvirus infection, so this finding is not specific. Herpes simplex type I is the most common cause of herpetic esophagitis, but on morphologic grounds, this type cannot be distinguished from herpes simplex type II or varicella-zoster. Immunohistochemical staining and in situ hybridization, if clinically indicated, can help distinguish these three viral species.

High-power view of herpes esophagitis showing diagnostic Cowdry A inclusions and multinucleated cells with nuclear molding. These cells are most prominent in the superficial portions of the epithelium and particularly adjacent to areas of ulceration.

Differential Diagnosis

On occasion, herpetic esophagitis may be difficult to distinguish from squamous dysplasia/carcinoma ( Table 14.2 ). The nuclear inclusions characteristic of herpetic esophagitis may be mistaken for macronucleoli typical of malignant cells. However, in herpes esophagitis, one usually sees a halo located between the nuclear inclusion and the nuclear membrane. In addition, the ground-glass chromatin pattern that is characteristic of virally infected cells shows little structure and is pale, in contrast to the variably granulated and darkly stained chromatin typical of malignant cells. Radiation-induced esophagitis also may be mistaken for herpetic esophagitis, because radiation can result in the formation of enlarged squamous cells with multiple nuclei, nucleoli, and pale chromatin. However, careful attention to the presence or absence of characteristic Cowdry A inclusions and ground-glass nuclei allows their distinction.

Treatment

Empiric treatment for herpetic lesions is often initiated on the basis of clinical suspicion, even in the absence of histologic confirmation. Acyclovir (Zovirax) can be administered orally and helps initiate healing of active disease, but it does not prevent recurrences. Other medications, including famciclovir (Famvir) and valacyclovir (Valtrex), have also been shown to be effective therapy for herpes esophagitis. Intravenous medications may be indicated for severe disease.

Clinical Features

Cytomegalovirus (CMV) is a member of the human herpesvirus family, with an estimated prevalence rate among adults ranging from 40% to 60% of all cases of infectious esophagitis in resource-rich countries. Like other herpesviruses, CMV is not normally cleared from the body but instead is kept in a state of latency by the immune system. Therefore, chronic CMV infection only rarely causes disease among immunocompetent persons, but it does represent a major cause of morbidity and mortality in immunocompromised patients(especially patients infected with the human immunodeficiency virus [HIV] whose CD4 counts are lower than 50 cells/µL), transplant recipients, patients with malignancies, and patients who have received immunosuppressive therapy.

CMV esophagitis, although less common than herpetic esophagitis, is not infrequently found in patients with AIDS. In one study, CMV infection was found either alone or in combination with Candida and herpes in 30% of AIDS patients. Similar to herpes simplex or varicella-zoster esophagitis, CMV esophagitis may also rarely occur in immunocompetent individuals.

Presenting symptoms may include odynophagia, nausea, substernal pain, and fever. Endoscopically, CMV esophagitis has a variable appearance. Most patients with CMV esophagitis have multiple, well-circumscribed ulcers, most often located in the middle to distal esophagus. Deep linear ulcers and shallow ulcers, erythema, diffuse erosive esophagitis, and an inflammatory exudate also may be seen in the setting of CMV esophagitis, but these findings lack diagnostic specificity. Viral culture is not used routinely because detection of the virus does not confirm active disease.

Pathology

CMV-infected cells typically show marked cytomegaly and nucleomegaly with large ovoid intranuclear inclusions and thick marginated chromatin ( Fig. 14.9 ). The inclusion bodies may be brightly eosinophilic or deeply basophilic and are usually separated from the nuclear membrane by a halo. In addition, small eosinophilic to basophilic granular inclusions may be evident in the cytoplasm of infected cells. Cytoplasmic inclusions typically appear within minute vacuoles. CMV infects mesenchymal and columnar cells, but not squamous cells. Therefore, it is important for endoscopists to biopsy or brush the base of esophageal ulcers to optimize the chance of sampling diagnostic cells. No single technique is 100% sensitive in establishing a diagnosis of CMV esophagitis. A combination of diagnostic modalities is often used. If a careful search of well-prepared, routinely stained tissue sections or cytology preparations fails to reveal CMV inclusions, or at least suspicious cells, then additional ancillary immunohistochemical or in situ hybridization tests may be helpful. Immunohistochemistry may highlight infected cells without typical CMV morphology on routine stained sections and can be more sensitive than light microscopy. As previously mentioned, CMV esophagitis may coexist with herpes and Candida infection in both transplant recipients and patients with AIDS.

High-power view of cytomegalovirus esophagitis shows characteristic nuclear and cytoplasmic inclusions in glandular epithelium.

Treatment

A variety of medications, such as ganciclovir, valganciclovir, foscarnet, and cidofovir, may be effective for the treatment of CMV esophagitis. The specific choice of therapy depends on the site and severity of infection, the level of underlying immunosuppression, the patient’s ability to tolerate and adhere to the treatment regimen, and the potential drug interactions.

Clinical Features

Fungal esophagitis is most commonly caused by Candida albicans or Candida tropicalis ( Fig. 14.10 ). Fungal infection occurs primarily in patients with some type of underlying disease (e.g., AIDS, other immunosuppressive disorders, diabetes) and in patients who have undergone treatment with broad-spectrum antibiotics, acid-suppressive therapy, or inhaled corticosteroids. It also may be found in otherwise healthy patients. Clinically, the presenting symptoms are dysphagia and odynophagia, but some patients remain asymptomatic, with the infection discovered incidentally at esophagoscopy performed for other reasons, especially in elderly patients.

A and B, Candida esophagitis shows abundant pseudohyphae and budding yeast forms, as highlighted with the periodic acid–Schiff fungus stain.

At endoscopy, esophageal candidiasis typically appears as white plaques of fibrinopurulent exudate, which may be focal or confluent, overlying erythematous mucosa. These plaques can be scraped away to reveal ulceration underneath.

Pathology

Morphologically, pseudohyphae and budding yeast forms can be demonstrated in a background of active esophagitis and are easily identified within the ulcer slough and fibrinopurulent exudate. Because Candida organisms are part of the normal flora of the GI tract, confirmation of this diagnosis requires more than simply identifying budding yeast forms; pseudohyphae should be detected within tissue to document true infection. Pseudohyphae have a linear or ribbon-like appearance in which small indentations, rather than true septations, are typically noted along the long axis of the organisms. Yeast forms have a slight ovoid contour and frequently manifest budding from the tips. In immunosuppressed patients, who occasionally reveal only minimal inflammation, special stains (silver stain, periodic acid–Schiff [PAS]) should be used to detect small numbers of invasive fungal forms within the tissue. However, special stains cannot be used to speciate the type of Candida organisms. C. tropicalis is more virulent than C. albicans because of its increased potential for tissue invasiveness. Candida can colonize preexisting ulcers or any damaged mucosa, and the pathologist should consider the possibility of a dual infection or pathology.

Differential Diagnosis

On occasion, the endoscopist may identify small white plaques that, although they resemble Candida esophagitis, represent glycogenic acanthosis or ectopic sebaceous glands. Glycogenic acanthosis occurs as white mucosal plaques that measure 2 to 5 mm. Diffuse esophageal glycogenic acanthosis may occur as a rare manifestation of Cowden syndrome. Biopsy features include distention of squamous epithelial cells with glycogen, which is evident as pale-staining material that is PAS positive and diastase digestible. Ectopic sebaceous glands, which may also appear as small, pale yellow or white, punctate elevations of the mucosa, are rare but are easily recognized in biopsy material by their close resemblance to normal dermal sebaceous glands.

Treatment

Fluconazole (Diflucan) is the drug of choice because it is safe and well tolerated, although other drugs, such as itraconazole and ketoconazole, are also effective. Amphotericin B is considered a second-line option and is reserved for severe cases and for patients for whom treatment with azole compounds has failed. Echinocandins (e.g., Caspofungin), a new class of antifungal agents that act on fungal cell walls, are being used in randomized trials for patients with Candida esophagitis refractory to azole compounds.

Clinical Features and Pathogenesis

The World Health Organization estimates that approximately 10 million people are infected with Trypanosoma cruzi worldwide. Approximately 100 million are at risk of contracting the infection, and these are mostly in Latin America. Humans are accidental hosts for T. cruzi. They are usually infected at night via contact with feces of blood-sucking triatomine insects. A second mechanism of transmission, responsible for as much as 10% of cases, is transfusion of whole blood or blood derivatives (except for lyophilized products). A third route of transmission is congenital. The likelihood of congenital transmission in children of chagasic mothers ranges from 1% to 10%. After 2 to 4 months, the acute clinical manifestations (inflammation of the eye, conjunctivitis, palpebral edema, periauricular satellite adenopathy, and generalized infection) disappear and the disease enters a period of clinical latency (“indeterminate” form). Studies performed in endemic areas have provided clinical and radiologic evidence of esophageal disorders in 7% to 10% of people with chronic T. cruzi infection, and megaesophagus in 3%. Dysphagia of solid and liquid food is the first and most important symptom of digestive disturbance. It may begin slowly but leads to malnutrition and severe weight loss. Other clinical symptoms include regurgitation, pyrosis, hiccups, cough, and parotid gland hypertrophy. Esophageal pain often appears with deglutition as a consequence of spasmodic contraction of a hypersensitive esophagus. Esophageal involvement is progressive in some patients but not in others, and it evolves independently of heart involvement.

Pathology

Destruction of neuron plexuses in the esophagus by the inflammatory reaction induced by T. cruzi is the main cause of dysperistalsis of the esophagus. It results in gradual narrowing of the distal esophagus with luminal enlargement of the proximal esophagus, sometimes termed chagasic megaesophagus (grade I to IV). Microscopically, distal muscular hypertrophy and mononuclear inflammatory infiltrates occur in the muscle layers. The submucosal and myenteric plexuses show an intense mononuclear infiltrate with associated neuronal injury ( Fig. 14.11 ). A 2010 report indicates that patients with megaesophagus have a significantly decreased amount of S100- and glial fibrillary acidic protein (GFAP)-positive enteroglial cells when compared with seronegative controls and asymptomatic seropositive patients. With disease progression, there is intense neuronal destruction and denervation of the organ, with loss of function.

A and B, Myenteric plexus in a patient with megaesophagus and Chagas disease. Notice the variable infiltration of the myenteric plexus by mononuclear inflammatory cells and the lack of ganglion cells.

Treatment

Only two drugs are effective for the treatment of Chagas disease in the acute and chronic phases: nifurtimox and benznidazole. Both are almost 100% effective in curing the disease if treatment is begun soon after infection, at the onset of the acute phase, but their efficacy diminishes with time and duration of infection. Treatment protocols for the chronic phase of disease remain controversial. In the presence of megaesophagus, dilatation of the esophagogastric junction may be performed by passing a dilator or air-filled balloon through an endoscope. Repeated dilations may be needed to prevent the development of recurrent strictures. Surgery is indicated in some cases. Cardiotomy is the most frequently performed procedure. Injections of botulin toxin into the esophagus have also been used in some patients.

Clinical Features

Esophageal injury caused by prolonged direct mucosal contact with ingested, particularly large-sized, tablets or capsules occurs frequently. Commonly implicated agents include antibiotics (particularly tetracyclines and clindamycin), nonsteroidal antiinflammatory drugs (NSAIDs), potassium chloride, ascorbic acid, iron supplements, quinidine, and bisphosphonates. Symptoms include odynophagia, continuous retrosternal pain, and dysphagia. Elderly patients and women are affected most frequently. Affected patients often report having ingested a pill with very little or no fluid before nighttime sleep. Most affected individuals do not have an abnormality of esophageal transit. However, in some reports, patients with quinidine- or potassium chloride–induced injury were shown to have a history of external esophageal compression, such as valvular heart disease with left atrial enlargement, or esophageal entrapment by fixed mediastinal structures and adhesions after thoracic surgery.

Pathology

Pill esophagitis often results in discrete ulcers with normal or only mildly inflamed esophageal mucosa. Ulcers may be shallow or, more commonly, deep with extension into the muscularis mucosae. They are usually located at the junction of the proximal and middle thirds of the esophagus, the area where the aortic arch compresses the esophagus and peristaltic amplitude is relatively low. Patients with left atrial enlargement are especially susceptible to pill-induced esophageal injury.

The histologic appearance of pill-induced esophagitis is typically nonspecific. However, prominent eosinophilic infiltration, spongiosis, and necrosis of squamous epithelium should always raise the possibility of pill-induced injury, particularly if located in the upper esophagus. Crystalline stainable iron may be identified in cases of ferrous sulphate–induced disease, and polarizable crystalline material may be evident in cases of alendronate-induced injury ( Fig. 14.12 ). Some cases of pill esophagitis are severe and lead to perforation.

A, Severe active pill (ferrous sulfate) esophagitis shows marked acute inflammation, ulceration containing pigmented material, and reactive epithelial changes. B and C, Inflammatory exudate of the base of the esophageal ulcer shows brown crystalline material ( B ), identified as stainable iron by Perls stain ( C ).

Differential Diagnosis

A variety of conditions can cause histologic features similar to those found in pill esophagitis. Herpes esophagitis is often a major consideration; a clinical history of immu­nosuppression and identification of characteristic viral cytopathic inclusions is useful in this differential diagnosis. Other causes of infectious esophagitis, including CMV and Candida, may mimic pill esophagitis, both clinically and pathologically. Identification of CMV cytopathic effect or fungal elements is diagnostic. GERD is more common than pill esophagitis; however, it usually is not possible to distinguish these conditions on histologic grounds in an isolated esophageal biopsy specimen and in the absence of clinical information.

Clinical Features

Corrosive or caustic esophageal injury occurs in children and adults, most commonly as a result of the ingestion of alkaline (lye) or acid (nitric). Gastroduodenal lesions also are common after ingestion of caustic agents. Coughing, crying, and vomiting after ingestion are typical presenting symptoms. Dysphagia, refusal to drink, and mouth or chest pain, with drooling and salivation, may ensue. Airway obstruction and glottic edema can result in respiratory distress and stridor.

Pathology

The endoscopic appearance of the esophageal mucosa varies according to the type, physical state, concentration, and volume of the ingested substance. Typically, one encounters mucosal edema, erythema, hemorrhage, and necrosis, sometimes with the formation of circumferential ulcers and mucosal sloughing.

The pathologic features are nonspecific and are related to tissue necrosis and subsequent inflammation. Acid injury often produces coagulative necrosis, with the depth of injury limited by the eschar formation. Alkaline injury typically causes liquefactive necrosis with fat and protein digestion. Because a protective eschar does not develop in cases of alkaline injury, the depth of penetration is often greater than with acid injury, and perforation secondary to corrosive esophagitis develops in some patients. Initially, the esophagitis may reveal a dense neutrophilic infiltrate, vessel thrombosis, bacterial invasion, and abundant granulation tissue. Long-term complications include stricture formation, which may require endoscopic or surgical treatment, and, rarely, squamous cell carcinoma.

Clinical Features and Pathogenesis

Esophagitis dissecans superficialis (EDS) is the term coined by Rosenberg in 1892 to describe a lesion characterized by extensive dissection of the squamous epithelial lining of the esophagus from its underlying corium in the form of a tubular cast. Dramatic presentations of EDS, with vomiting of esophageal casts, were documented before the endoscopic era. In less dramatic cases, the condition varies from sloughing of large fragments of the esophageal squamous mucosa, which may be coughed up or vomited, to a condition that is not even suspected until the endoscopist notices whitish strips or streaks (pseudomembranes) of peeling esophageal mucosa during an endoscopic examination performed for reasons that may be unrelated to the esophagus. The usual symptoms are dysphagia, odynophagia, and heartburn. In a series of 12 patients with documented endoscopic and histologic features of EDS, the most common symptoms or signs leading to upper endoscopy were dysphagia, occult or overt GI bleeding unrelated to EDS, weight loss, epigastric pain, and heartburn. Although EDS has been reported in association with several types of medications (bisphosphonates, NSAIDs, and potassium chloride), hot beverages, chemical irritants, heavy smoking, physical trauma, celiac disease, collagen vascular disorders, and autoimmune bullous dermatoses (pemphigus and pemphigoid), the pathogenesis remains poorly understood. A recent report of 31 patients described a similar pattern of injury. In that study, the term sloughing esophagitis was used to describe patients whose biopsies showed prominent parakeratosis and superficial sloughing of necrotic squamous epithelium. Endoscopy revealed plaques or membranes. The affected patients were predominantly older (range, 32 to 85 years), were chronically debilitated, and consumed multiple medications.

Pathology

Endoscopic features of EDS may include single or multiple white patches of peeling mucosa, extending from the middle to the distal esophagus, or even diffuse sloughing of the entire esophageal mucosa. In addition, long linear mucosal breaks, vertical fissures, and circumferential cracks with peeling mucosa, with or without bleeding, have been described. Histologically, at low power, the biopsy samples consist of long, detached fragments of superficial squamous epithelium with some degree of intraepithelial splitting at varying levels above the basal layer of the squamous epithelium, occasionally associated with separation of the epithelial layers to form bullae. Other common findings include prominent parakeratosis, orthokeratosis, and fragments of necrotic epithelium with minimal or no inflammation, often associated with bacterial or fungal colonization ( Fig. 14.13 ). Neutrophils and eosinophils may be present within the epithelium, but these inflammatory cells are not a prominent feature of this condition.

A, Esophagitis dissecans superficialis characterized by prominent parakeratosis and detached superficial strips of squamous epithelium with parakeratosis, flaking debris, and bacterial colonies in the absence of active inflammation. B, Intraepithelial splitting of parakeratotic squamous epithelium with minimal or no inflammation.

Differential Diagnosis

The differential diagnosis of EDS includes mechanical trauma related to esophagoscopy, infectious esophagitis (fungal or herpetic), and chronic bullous diseases that involve the esophagus. Repeated attempts to obtain a biopsy, combined with endoscopic trauma, causes layers of squamous epithelium to detach from the mucosa, simulating bullae. Several cases have been reported to occur after traumatic esophagoscopy. However, epithelial detachment induced by endoscopic trauma does not reveal necrosis, inflammation, or bacterial colonies on histologic examination.

Inflammation and necrosis are common features of infectious esophagitis, but prominent orthokeratosis and parakeratosis are not. Vesiculobullous dermatoses such as Stevens-Johnson syndrome, pemphigus, and pemphigoid may mimic EDS. However, chronic bullous diseases can be excluded by demonstration of an absence of complement and immunoglobulin deposits by direct immunofluorescence (DIF), lack of anti-desmoglein antibodies by enzyme-linked immunosorbent assay (ELISA), and lack of corresponding cutaneous and oropharyngeal lesions. Clinically, patients with EDS show a poor response to steroid therapy.

Treatment

Despite its sometimes dramatic presentation, EDS in most patients has a positive outcome. A combination of acid suppression, topical analgesics, and discontinuation of any potential precipitating medications results in healing of EDS without sequelae in most cases. Because of the superficial nature of the epithelial injury in this disease, it is presumed that stricture development is rare.

Clinical Features

EOE is an allergic disorder that involves the esophagus. During the past 10 to 15 years, this disease has gained considerable recognition and has shown an increasing prevalence. The current definition of this disease is “chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.” This condition affects both children and adults. Infants and toddlers often are brought in because of feeding difficulties, whereas school-aged children typically have nausea, vomiting, and pain. Dysphagia is the predominant symptom in young adults. Other symptoms in adult patients include solid-food dysphagia, chest pain, food impaction, and upper abdominal pain. By definition, patients have normal or near-normal pH monitoring levels and fail to respond to antireflux therapy, although a subgroup of patients do respond to PPIs, so the association with reflux is controversial. EOE tends to occur in children and young adults, with a strong male predominance (male-to-female ratio, 3 : 1), but cases are being increasingly diagnosed across the entire age spectrum. Many affected patients have a history of concurrent allergic diatheses (food allergy, asthma, eczema, chronic rhinitis, and environmental allergies). Between 28% and 86% of adults and between 42% and 92% of pediatric patients have been shown to have other allergic diseases. Several studies have documented peripheral blood eosinophilia in adults and pediatric patients with EOE.

Pathogenesis

The pathogenesis of EOE is poorly understood and is the subject of intense ongoing research. The prevailing belief is that EOE represents a disease of type 2 (Th2) helper T cells in which genetic predisposition, environmental exposures, allergic background (including inhaled aeroallergens and ingested food allergens), and probably other factors may act as triggers. Basic murine studies and studies of human samples have proposed important roles for mast cells, lymphocytes, eotaxin 3, IL13, IL15, and thymic stromal lymphopoietin (TSLP) in the pathogenesis of EOE. TSLP is located on the 5q22 locus and is overexpressed in the mucosa of patients with EOE. TSLP is an epithelial-derived IL7-like cytokine that can activate a number of immune cells, in particular dendritic and mast cells, and plays a role in other allergic diseases such as asthma. Eotaxin – 3 (now called CCL26 ), a gene that encodes a component of the immunologic cascade, has been shown to be highly induced in patients with EOE compared with healthy controls. Eosinophils are recruited to the esophagus in response to injurious stimuli. Eosinophil activation by IL5, IL13, and eotaxin 3 results in extracellular release of cytotoxic granules. The resulting inflammatory response leads to the pathologic changes observed in the mucosa, submucosal fibrosis, remodelling, and esophageal strictures.

Pathology

Gross (Endoscopic) Features

Endoscopically, patients with EOE often exhibit characteristic fixed esophageal rings, also referred to as trachealization or ringed esophagus . Other endoscopic findings include transient esophageal rings (also known as feline folds or felinization), mucosal plaques or exudates, longitudinal furrows, edema, diffuse esophageal narrowing, narrow-caliber esophagus, and mucosal tears readily induced by passage of the endoscope ( Table 14.3 and Fig. 14.14, A ). In some cases, the esophagus appears entirely normal, but more than 90% of affected patients display one or more of these endoscopic abnormalities. However, these endoscopic features have been described in other conditions and are not pathognomonic of EOE.

Table 14.3

Diagnostic Approach to Patients with Suspected Eosinophilic Esophagitis

Clinical	Food impaction/dysphagia in adults Feeding intolerance/GERD symptoms in young children High-dose PPI therapy × 2 mo to exclude GERD
Endoscopic	Rings, pinpoint white mucosal exudates, furrows, strictures Obtain multiple biopsies from proximal and distal esophagus Biopsy normal and abnormal areas Biopsy stomach and duodenum if eosinophilic gastroenteritis is in the differential diagnosis
Pathologic	Avoid Bouin fixative Evaluate for eosinophilic microabscesses, surface layering and slough, eosinophil degranulation Count eosinophils per HPF in the peak (most dense) areas to obtain a mean count

 

GERD , Gastroesophageal reflux disease; HPF , high-power field; PPI , proton pump inhibitor.

Data from Furuta GT. Eosinophilic esophagitis: update on clinicopathological manifestations and pathophysiology. Curr Opin Gastroenterol. 2011;27:383-388.

A, Endoscopic photograph of the esophagus in a patient with primary eosinophilic esophagitis (EOE). The esophageal mucosa shows furrows and concentric rings and is studded with whitish-gray nodular plaques and exudates. B, Medium-power view of primary EOE shows marked reactive squamous hyperplasia, numerous intraepithelial eosinophils (peak eosinophilic count, >15 per high-power field), and accumulation of eosinophils in the superficial portions of the epithelium. C, Medium-power view shows eosinophilic microabscesses in the superficial portion of the squamous mucosa. Some eosinophils are degranulated. D, High-power view of another eosinophilic microabscess shows aggregation of mainly intact eosinophils in an area of mucosa associated with epithelial cell degeneration. E, Accumulation of eosinophils within the superficial necroinflammatory debris and forming a membrane.

Differential Diagnosis

Mucosal infiltration by eosinophils is a component of a variety of esophageal inflammatory conditions ( Box 14.1 ), including GERD, EOE, eosinophilic gastroenteritis, Crohn’s disease, collagen vascular diseases, infectious esophagitis (secondary to herpes, Candida, or parasites), drug-induced esophagitis, and hypereosinophilic syndrome. The histologic features of GERD and EOE overlap (see Table 14.4 ). Biopsy sampling of the proximal, middle, and distal esophagus is important to help separate these two disorders: GERD involves the distal esophagus more severely than the proximal esophagus, and the lesions are not usually patchy or segmental in distribution. In parasitic and fungal infections, eosinophils aggregate intensively in areas of infection, even forming abscesses in the lamina propria, and are often associated with neutrophils. The plaques and exudates observed in patients with EOE may suggest Candida esophagitis endoscopically, but on microscopy, the plaques in EOE consist of sloughed squamous cells admixed with eosinophils, which are easily distinguished from the fungal elements characteristic of Candida esophagitis.

Eosinophilic gastroenteritis is characterized by tissue eosinophilia that is often patchy in distribution and may involve any portion, and any layer, of the GI tract (i.e., mucosa, muscularis propria, and serosa). Mucosal biopsies in patients with eosinophilic gastroenteritis often show numerous eosinophils, frequently degranulated, infiltrating the lamina propria, muscularis mucosae, and epithelium and usually involve one or more anatomic locations such as the esophagus, stomach, and duodenum. Therefore, obtaining biopsy specimens from the stomach and duodenum and correlating the findings with clinical symptoms such as nausea, vomiting, and diarrhea is helpful in establishing a correct diagnosis. Unlike patients with EOE, most of those with eosinophilic gastroenteritis have increased serum total and food-specific immunoglobulin E (IgE) levels and positive skin test responses to a variety of food antigens.

Esophageal involvement by Crohn’s disease can reveal nonspecific esophagitis, sometimes associated with increased numbers of eosinophils. The presence of non-necrotizing granulomas is a helpful diagnostic feature, but granulomas are relatively uncommon, observed in only 7% to 9% of patients with esophageal Crohn’s disease. Crohn’s disease never involves the esophagus in the absence of stomach, small intestine, or colon involvement, and other features such as erosions, sinuses, fistulas, neutrophils, and increased lymphoid tissue are often present in addition to increased eosinophils.

Drug-induced esophagitis can manifest with eosinophilia. It is helpful to establish a temporal clinicopathologic association between use of the drug, onset of symptoms, and tissue eosinophilia in determining that diagnosis. Resolution is often demonstrated when the drug is withdrawn from use.

Vasculitides, including Churg-Strauss syndrome and polyarteritis nodosa, affect the GI tract in approximately 20% to 30% of cases. Eosinophil-rich granulomas, with necrosis, involving medium to small-sized vessels, are typically found in Churg-Strauss syndrome, whereas arteritis in a background of eosinophilic inflammation is typical of polyarteritis nodosa.

Natural History

There are limited data regarding the natural history of EOE. However, EOE often leads to persistent dysphagia if left untreated. In one study of 30 untreated patients who were observed for an average of 7.2 years, dysphagia persisted in 29 patients (97%). Successfully treated patients experience relapse in 25% to 40% of cases. The long-term outcome for patients with EOE who receive treatment, and the proportion of patients who require multiple courses of treatment, are unknown. To date, no malignant potential has been associated with this disease. Few reports have suggested an association with BE, but a recent study of a national pathology database suggests that there is a strong inverse relationship between Barrett’s metaplasia and eosinophilic infiltrates in the esophageal mucosa. In that study, the observed prevalence rate of the simultaneous occurrence of these two conditions was one third of what would be expected if they occurred independently (odds ratio, 0.29; 95% confidence interval, 0.27 to 0.33; P < .0001).

Treatment

Several types of therapeutic modalities are available for patients with EOE. The efficacy of any particular treatment is best evaluated clinically by showing relief of symptoms, or a reduction in the degree of eosinophilic infiltration, or both. Currently, therapy for esophageal inflammation is based on antigen elimination trials, antiinflammatory medications, and physical dilatation if strictures are present. Dietary elimination is a treatment modality frequently used in children, but it is often not well tolerated by adults. Corticosteroids, either systemic or topical, have been effective in the treatment of this disorder in both children and adults. Systemic steroids are used for acute exacerbations, such as severe dysphagia, hospitalization, and weight loss. Topical glucocorticoids are used to provide long-term control. Glucocorticoids show a significant positive effect in reducing esophageal eosinophilia. Before 2007, swallowed fluticasone was primarily used. Since then, oral bude­sonide has also been shown to be effective. Treatment of EOE with cromolyn sodium, leukotriene receptor antagonists, or immunosuppressive agents is not recommended. Humanized antibody therapy directed to block IL5 and IL13 is currently being tested in clinical trials. Esophageal dilatation is performed for adult patients whose presenting symptoms include symptomatic esophageal narrowing resulting from fixed strictures. However, this procedure usually needs to be repeated regularly and does not reduce the degree of inflammation.

Clinical Features

Achalasia is a chronic esophageal motility disorder that is characterized by an inability of the LES to relax after swallowing, which results in periodic esophageal obstruction. The symptoms of achalasia may appear gradually. Patients present initially with a history of dysphagia to solid foods, and later on with difficulty swallowing liquids. Often there is a history of weight loss, regurgitation of undigested food, and avoidance of certain solid or bulky foods. Half of the patients complain of chest pain or heartburn. Discomfort or fullness under the breastbone and a history of aspiration or aspiration pneumonia may be elicited as well.

As much as 95% of the patients with achalasia have a positive result on esophagography with barium contrast. A positive study shows characteristic tapering of the distal esophagus and the so-called “bird’s beak” sign at the level of the esophageal hiatus. Esophageal endoscopy is typically performed to evaluate for other causes of esophageal obstruction.

Pathogenesis

The pathophysiology of achalasia is linked to destruction of ganglion cells present in the esophageal wall and LES, which leads to an impairment of relaxation of the LES. Destruction of ganglion cells is associated with an inflammatory (particularly lymphocytic) response, which seems to suggest an autoimmune, viral, or chronic degenerative process. In a minority of patients with Allgrove syndrome, a mutation on chromosome 12 is implicated in the development of achalasia. Secondary achalasia (or pseudoachalasia) may develop as a result of obstructing lesions, such as GEJ tumors, Chagas disease, or amyloidosis, and closely mimics primary achalasia clinically. In addition, functional obstruction of the LES may be induced by a fundoplication or by gastric banding procedures.

Pathology

The primary histologic abnormality in achalasia is a marked reduction, or complete absence, of myenteric ganglion cells ( Fig. 14.16 ). Myenteric nerve inflammation, with a predominance of T lymphocytes, and myenteric neural fibrosis are present. Other alterations include diffuse squamous hyperplasia, florid lymphocytic esophagitis, lymphocytic inflammation of the lamina propria and submucosa, and submucosal glandular atrophy with periductal and glandular inflammation. Mucosal changes in patients with achalasia are variable. In a series of 48 untreated patients, 10 had changes suggestive of GERD, whereas others had normal mucosa. The principal role of pretherapy biopsies is to rule out all potential causes of pseudoachalasia, including neoplastic alterations or infections.

Histopathology of achalasia. A, Normal myenteric plexus shows multiple ganglion cells and no significant inflammation. B, Mild myenteric plexus infiltrate of lymphocytes exhibits few intact ganglion cells. C and D, Severe inflammation of the myenteric plexus is characterized by a dense infiltrate of mononuclear cells. Ganglion cells are not identified.

Treatment

Management of achalasia includes several therapeutic modalities. Pharmacologic management with sublingual nitrates and calcium channel blockers has a high failure rate and is poorly tolerated. Injection of the LES with botulinum toxin is effective for short-term relief of dysphagia. Dilatation remains a valuable option for nonsurgical candidates. Minimally invasive Heller myotomy has low rates of morbidity and mortality; both it and laparoscopic Heller myotomy with partial fundoplication are durable, safe, and effective treatment options for patients with achalasia.

Definition and Classification of Barrett’s Esophagus

Definition

The American College of Gastroenterology (ACG), defines BE as endoscopically recognizable columnar metaplasia of the esophageal mucosa that is confirmed pathologically to contain intestinal metaplasia, the latter defined by the presence of goblet cells. Based on this definition, both the endoscopic and the pathologic component must be present to establish a diagnosis of BE ( Fig. 14.23 ). By definition, this disease does not include patients who have intestinal metaplasia (goblet cells) of the gastric cardia. Columnar mucosa is recognized endoscopically by the presence of salmon-pink, “gastric-type” mucosa in the distal esophagus. As much as one third of GERD patients who lack columnar mucosa within the distal esophagus show intestinal metaplasia (goblet cells) in their otherwise anatomically normal GEJ, and these patients do not qualify as having BE based on the ACG definition. This position is based on the assumption that the presence of a few intestinalized glands in the GEJ region of patients without endoscopically apparent columnar metaplasia of the distal esophagus does not confer the same increased risk of malignancy as endoscopically visible BE.

A, Endoscopic appearance of Barrett’s esophagus (BE). Tongues of gastric-appearing columnar mucosa extend proximal to the gastroesophageal junction in an irregular circumferential fashion. Notice the presence of squamous islands within the columnar mucosa. B, Histologic appearance of BE is characterized by the presence of incomplete intestinal metaplasia, mucous columnar cells, scattered goblet cells, and reactive changes in the bases of the crypts. Notice the presence of splayed fibers of muscularis mucosae at the bottom of the field. Nondysplastic BE shows mildly distorted crypt architecture characterized by increased crowding, branching, and budding. C, A high-power view of the surface epithelium shows slight pseudostratification, a serrated (or hyperplastic) luminal contour, and reactive changes characterized by cells with prominent nucleoli. Several pseudogoblet cells are also present in the top portion of the surface epithelium. The lamina propria shows a mild lymphoplasmacytic infiltrate.

However, there is not worldwide agreement that intestinal metaplasia (goblet cells) should be required for a diagnosis of BE. The British Society of Gastroenterology does not require intestinal metaplasia to establish this diagnosis. Similarly, in Japan, the GERD Society Study Committee does not require histologic confirmation of goblet cells in esophageal columnar epithelium. There are data to suggest that most patients with at least 2 cm of columnar-lined esophagus are found to have intestinal metaplasia if enough biopsy samples are obtained from the columnar-lined segment. Therefore, sampling error is a confounding factor. Some patients with significant lengths of columnar-lined esophagus do not have documented intestinal metaplasia despite analysis of many biopsy specimens, but this is exceedingly rare. Several studies have found a similar risk of progression to dysplasia or cancer in patients with and without goblets cells in columnar-lined eso­phagus. Furthermore, some data indicate that the immunohistochemical and molecular characteristics of columnar-lined esophagus with and without goblet cells are similar, so the significance of goblet cells, and their density, are controversial at this time.

Defining BE by pathologic confirmation of intestinal metaplasia (goblet cells) is problematic for a few other reasons as well. This definition is based primarily on the fact that intestinal-type esophageal epithelium is at highest risk for neoplastic progression. However, it is now well recognized that the background nongoblet columnar epithelium in BE shows physiologic properties of “intestinal” differentiation, such as expression of CDX2, HepPar-1, villin, DAS-1, and MUC3. Moreover, cancer may uncommonly develop in goblet cell–poor or even nongoblet esophageal columnar epithelium. There is also some evidence to suggest that neoplastic progression in BE is associated with loss of goblet cell differentiation. In fact, the true relationship between the density of goblet cell metaplasia and cancer risk has never been defined specifically.

The chance of detecting goblet cells in mucosal biopsy specimens of the esophagus from patients with suspected BE is proportional to the length of BE and the site of the biopsy and, of course, is subject to sampling error. In one study, 30.5% of patients with 1 to 2 cm of columnar-lined esophagus had goblet cells in their biopsy specimens, compared with 90% of patients with more than 6 cm of esophageal columnar mucosa. The likelihood of detecting goblet cells increases proportionally with the number of specimens obtained and depends on their location as well. For instance, biopsies obtained from the neo-SCJ show a higher rate of detection of goblet cells than distal biopsies. In one study, goblet cells were detected in 68% of endoscopies in which eight biopsies were obtained, compared with only 35% of those in which four biopsies were analyzed. Finally, detection of goblet cells has been shown to be dependent on patient age in pediatric studies. Goblet cells are rare in patients younger than 10 years of age but increase in number progressively with age.

Based on these limitations, some authors have proposed an alternative classification system that would use the term Barrett’s esophagus regardless of the presence or absence of goblet cells. In this system, patients would be classified as having BE (or simply columnar metaplasia of the esophagus) and then subclassified as to whether they have or do not have goblet cells ( Fig. 14.24 ).

Columnar mucosa from the distal esophagus of a patient without histologic evidence of goblet cells. Both of these biopsy specimens were obtained from mucosa located proximal to the gastroesophageal junction (GEJ). A, The mucosa shows mucinous columnar epithelium with underlying mucous glands and a cross section of a gland duct. The lamina propria shows a mild degree of lymphoplasmacytic inflammation. B, The mucosa shows oxyntic-type mucosa similar to that seen in the normal gastric corpus. Patients who have ultrashort segments of columnar mucosa in the distal esophagus without goblet cells are considered to be at little risk of subsequent neoplastic development and are not regarded as having Barrett’s esophagus, based on the absence of goblet cells. Nevertheless, the fact that these specimen was obtained from above the GEJ, in the distal esophagus, indicates that it is metaplastic in origin.

Classification

Traditionally, BE has been separated into long-segment, short-segment, and ultrashort-segment types, depending on the length of involved esophageal mucosa (>3 cm, 1 to 3 cm, or <1 cm, respectively). However, the biologic significance of this classification system remains unclear. Several studies have evaluated the risk of dysplasia and cancer in relation to the length of BE. A recent multicenter cohort study suggests an 11% increased risk of high-grade dysplasia and EAC for every 1 cm increase in BE length. The increased risk associated with longer lengths of BE has been attributed to a larger surface area at risk for neoplastic progression. The Prague C & M criteria were developed to standardize the endoscopic grading of BE. Endoscopic criteria are based on anatomic landmarks, with the GEJ defined as the proximal margin of the gastric mucosal folds. The extent of Barrett’s mucosa is then calculated by measuring (in centimeters) the most proximal extent of circumferential columnar mucosa (C value) and the maximal extent of noncircumferential columnar mucosa (M value) above the GEJ. For example, if Barrett’s mucosa is circumferential for 2 cm above the GEJ and the maximal extent of noncircumferential Barrett’s mucosa is 6 cm above the GEJ, the BE would be graded C2M6. This scoring system has been shown to be reliable in assessing the extent of endoscopic BE ( Fig. 14.25 ).

Schematic depiction of the Prague C & M criteria for grade C2M5 Barrett’s esophagus. The circumferential extent of columnar metaplasia is 2 cm above the gastroesophageal junction (GEJ), and the maximal extent is 5 cm (tallest tongue of columnar metaplasia extending above the GEJ).

(Courtesy of Dr. Michael Huba, Cleveland Clinic.)

Endoscopic Landmarks of Barrett’s Esophagus

Several landmarks are important for endoscopists to identify when evaluating patients with possible BE. The GEJ, which is the junction between the tubular esophagus and the proximal stomach, is defined in North America as the most proximal aspect of the gastric folds. Endoscopists in Asia often use the distal extent of the palisade vessels, which are fine longitudinal veins located in the lamina propria of the distal esophagus, as their landmark for the GEJ. The SCJ, also known as the Z-line, is the junction of squamous and columnar mucosa. It does not necessarily correspond to the location of the GEJ, and is irregular in many apparently normal individuals with and without GERD symptoms. The endoscopist should provide the pathologist with knowledge about the relationship of the SCJ to the GEJ (i.e., whether it is located at or above the GEJ) and the precise location of the biopsy relative to these anatomic landmarks. The distal 2 to 3 cm of the tubular esophagus corresponds to the LES ( Fig. 14.26 ) and is an anatomic region of increased intraluminal pressure. However, there are no anatomic landmarks demarcating the beginning and end of this physiologic sphincter. Therefore, if the SCJ is observed to be proximally displaced relative to the GEJ, biopsies of the GEJ, the SCJ, and the intervening (salmon-pink colored) columnar mucosa should be obtained to help establish a diagnosis of BE.

A, Schematic depiction of a normal gastroesophageal junction ( GEJ ). The squamocolumnar junction ( SCJ ) lies directly at the GEJ, which is located at the most proximal point of the gastric folds. The cardia represents the most proximal aspect of the gastric mucosa, which is composed of either mucous glands or mixed mucous and oxyntic glands. B, Schematic depiction of an ultrashort segment of Barrett’s esophagus. A short segment of gastric columnar-appearing mucosa (<1.0 cm in length) extends into the distal esophagus, proximal to the level of the GEJ. In this case, the SCJ is irregular in outline and located proximal to the GEJ.

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