Inflammatory Disorders of the Esophagus

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Chapter 14

Inflammatory Disorders of the Esophagus

Ana E. Bennett

John R. Goldblum

Robert D. Odze


Inflammatory disorders of the esophagus are extremely common. Gastroesophageal reflux disease (GERD) is among the most common chronic conditions, affecting as much as 40% of people in the Western world.1 Because of the ease and frequency of use of upper endoscopy for diagnosing gastrointestinal (GI) illnesses, biopsy specimens procured from esophageal mucosa to evaluate the presence or absence of inflammatory diseases—particularly GERD and its attendant complication, Barrett’s esophagus (BE)—are commonly encountered by surgical pathologists. This chapter focuses on inflammatory conditions that affect the esophagus.


Gastroesophageal Reflux Disease

Clinical Features

GERD is an extremely common chronic condition, particularly in Western countries.1 Estimates based on an assumption that reflux-like symptoms are an indicator of the disease suggest a prevalence rate of 20% to 40%.2,3 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.


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.46 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.2,3,79 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.1013 Likewise, there is evidence to suggest that Helicobacter pylori infection may actually protect against the development of GERD and its complications.14 Specifically, corpus gastritis is associated with decreased acid secretion, and GERD is less common in patients with severe corpus gastritis.7,15 When acid secretion returns to normal after the eradication of H. pylori, there is an increased risk of developing GERD.16,17

Recent studies of the pathogenesis of GERD in animal models 15,18,19 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.15


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.20 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.4,20 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 endoscopy21; 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. 22 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,22,23 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.24

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.25,26

Squamous Hyperplasia

For many years, it was believed that the only true diagnostic criterion for esophagitis was the presence of intraepithelial inflammation. However, in 1970, Ismail-Beigi and co-workers found that some patients who had clinical symptoms of GERD but a normal or only minimally abnormal endoscopic appearance showed hyperplasia of the squamous epithelium, a finding that they postulated was an early histologic manifestation of reflux-induced injury.27 Squamous hyperplasia was defined by (1) lengthening of the subepithelial lamina propria to more than two thirds of the thickness of the squamous epithelium and (2) expansion of the basal zone of the squamous epithelium to more than 15% of the thickness of the epithelium (see Fig. 14.1). Subsequent studies confirmed these initial observations and also demonstrated a significant positive correlation between the severity of reflux, as measured by 24-hour pH score (a composite quantitative evaluation of acid reflux) and the length of the lamina propria papillae.28 These correlations also occur in infants and children with GERD.29 Increased mitoses, slight enlargement of basal and suprabasal nuclei, and prominent nucleoli and hyperchromatism are features often associated with true basal cell hyperplasia. True basal cell hyperplasia is best evaluated in well-oriented tissue sections that include at least three consecutive papillae. Unfortunately, this is rare in small pinch biopsy samples. Therefore, one should be cautious not to overinterpret “mild” changes as evidence in favor of esophagitis.


The principal inflammatory cells in patients with reflux esophagitis include neutrophils, eosinophils, and lymphocytes (see Fig. 14.2).30 However, depending on the phase of disease and the treatment status, none, one, or all of these inflammatory cells may be present in a single biopsy specimen. Therefore, a diagnosis of (reflux) esophagitis can be established in the absence of inflammation if the basal cell and lamina propria papillae changes are present, particularly in a patient who has begun treatment with antireflux agents.


Within the esophageal squamous epithelium, intraepithelial neutrophils always indicate a pathologic process. However, intraepithelial neutrophils are not a sensitive indicator of reflux esophagitis, because they are present in fewer than 30% of GERD patients with documented reflux. They also are not specific for GERD. Nevertheless, the presence of a significant number of neutrophils, particularly in association with a surface erosion or ulcer, should prompt the pathologist to search for a viral or fungal (Candida) infection.


Increased numbers of eosinophils often are present in patients with esophagitis.31 However, because rare, isolated eosinophils may be found in the mucosa of normal adults, particularly in the distal 1 to 2 cm of the esophagus, they are not considered diagnostic of esophagitis if sparse in number and not associated with other features of esophagitis, such as those discussed previously. On the other hand, the presence of even rare intraepithelial eosinophils is a valuable diagnostic aid in evaluating reflux esophagitis in children, because they are not normally present in this age group.3234 In addition, eosinophils in the lamina propria are considered an even more sensitive indicator of GERD in infants.24

Occasionally, large numbers of eosinophils are present in esophageal biopsy specimens of adult patients with putative reflux.28,35 In this circumstance, causes of esoph­ageal eosinophilia other than reflux, such as primary eosinophilic esophagitis (EOE), drug reaction (including Stevens-Johnson syndrome), pill-induced esophagitis, collagen vascular disease, and, very rarely, parasitic infection,36 should be excluded. Children with apparent GERD who have prominent eosinophilia may improve clinically when given an elemental diet, which suggests that certain protein sensitivities may lead to reflux-like symptoms37,38 (see Primary Eosinophilic Esophagitis).


Lymphocytes are considered a normal intraepithelial component of the esophageal squamous mucosa.30,39,40 These are largely T lymphocytes and have either a round or an irregular nuclear contour, particularly when deformed by adjacent squamous epithelial cells. Because of their “squiggly” appearance, intraepithelial lymphocytes may resemble granulocytes. These cells have been identified as CD8+ and TIA-1+ T lymphocytes and tend to be more prominent in the peripapillary epithelium.41 Normal esophageal mucosa contains roughly 10 to 12 lymphocytes per high-power field (HPF).40,41 Although lymphocytes are present in increased numbers in patients with GERD, this finding in isolation has no independent diagnostic significance, because normal control subjects may also have increased numbers.40 In addition, other disorders, such as achalasia and Crohn’s disease, may be associated with increased numbers of intraepithelial lymphocytes.42,43

Other Microscopic Features of GERD

Dilation and congestion of lamina propria capillaries are additional characteristic features of reflux esophagitis,44 but this finding may also occur in specimens from normal controls, albeit in a mild fashion, possibly as a traumatic biopsy artefact.45 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.46

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.

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 fibroblasts47,48 (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).

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.

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.4951 Some researchers have proposed that NERD is a discrete entity because of its unique physiologic characteristics, which include a more competent antireflux barrier.52 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,5356 but it is unknown whether NERD can progress directly to BE without an erosive phase.57 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.5860 Erosive esophagitis is a risk factor for BE.61,62 Barrett’s esophagus develops in between 1% to 13% of patients with erosive esophagitis annually.63 In a recent prospective, follow-up endoscopic study64 to evaluate the risk of BE in a Swedish general population (the Kalixanda study database),65 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.55,66

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.67 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.67 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.68 Surgical treatment is considered an option for patients with chronic GERD who are not responsive to medical therapy or have a defective LES.69,70

Infectious Esophagitis

Infections remain an important cause of esophagitis and can have significant implications in the immunocompromised host. Viruses and fungi cause most forms of acute infectious esophagitis.71 Bacterial esophagitis occurs in some patients with systemic or upper respiratory infection, but this condition is rarely sampled histologically.

Viral Esophagitis—Herpes

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.7274 Symptoms of herpetic esophagitis include odynophagia, dysphagia, epigastric pain, fever, and upper GI bleeding, but some patients are asymptomatic.75 Coexistent herpes labialis and oropharyngeal ulcers are seen in approximately one fourth of patients.71,74 Herpetic ulcers in the esophagus may serve as a portal of entry for other pathogens and can be associated with herpetic pneumonitis.72 Endoscopically, herpetic ulcers are typically shallow, sharply punched-out lesions and are often surrounded by relatively normal-appearing mucosa.


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).72,73 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.76 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.

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.



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