Context.—Esophagitis is a common cause of symptoms for which patients seek the advice of a physician. Esophagitis of differing etiologies often demonstrate overlapping histopathologic features, making their distinction difficult. This is especially true in esophageal disorders associated with increased numbers of intraepithelial eosinophils, some of which have just recently been recognized.
Objective.—This review discusses the important clinical and pathologic features of the 2 most common disorders associated with esophageal eosinophilic infiltrates—reflux esophagitis and eosinophilic esophagitis—with special emphasis on features that allow the surgical pathologist to distinguish between these disorders. The various forms of drug-induced esophagitis are also discussed because these are frequently underrecognized by pathologists.
Data Sources.—Data were extracted from articles identified through PubMed-based research. Histologic figures have been taken from the personal case collection of the author.
Conclusions.—Reflux and eosinophilic esophagitis demonstrate overlapping histologic features, which may make their distinction difficult. Drug-induced esophagitis is probably a common phenomenon but is underrecognized by pathologists.
The term gastroesophageal reflux disease (GERD) describes a spectrum of clinical conditions and histologic alterations resulting from gastroesophageal reflux. Reflux esophagitis describes a subset of GERD patients with histopathologic evidence of esophageal injury. The prevalence of symptoms associated with GERD ranges from 40% to 45% in the United States and Canada.1,2 Frequent symptoms (occurring at least once per week) are reported by 20% of the general population in these countries. Endoscopic evidence of esophagitis, esophageal erosion, or ulceration is present in one-third to one-half of those patients with GERD symptoms.3–5 Gastroesophageal reflux disease affects men more commonly than women, and men are more likely to develop histologically identifiable esophagitis.6 In adults, predisposing conditions include increased intra-abdominal or intragastric pressure as a result of pregnancy, ascites, obesity, or motility disorders.7 Gastroesophageal reflux disease also complicates acquired structural abnormalities, including hiatal hernias. Patients who undergo prolonged periods of recumbency (eg, ventilator-dependent patients, patients who have had a stroke, and immobile nursing home residents) are also prone to reflux esophagitis. Gastroesophageal reflux disease is also common in children, especially those with neurologic disorders or those with congenital esophageal or gastric abnormalities.
Gastroesophageal reflux disease is a multifactorial process, with different abnormalities predominating in different patients. Factors predisposing individuals to GERD include (1) decreased esophageal sphincter pressure, (2) diminished esophageal clearance resulting from defective peristalsis, (3) delayed gastric emptying or abnormal gastric contractility, (4) decreased salivary flow, and (5) increased gastric acid production. Esophageal dysmotility contributes to poor clearance of the refluxed material, thereby leading to an increased mucosal contact time. With persistent reflux, esophageal motor function becomes increasingly abnormal, leading to further deterioration of lower esophageal sphincter competence.
The nature and amount of refluxed material, as well as the length of time the refluxate remains in contact with the esophageal mucosa, determine whether disease develops. Acid alone causes relatively few changes. However, when combined with pepsin, bile acids, or trypsin, more severe damage results.
Adult patients with GERD present with diverse symptoms, including epigastric pain, pharyngeal burning, nausea, vomiting, heartburn, regurgitation of gastric contents resulting in a bitter-tasting fluid into the mouth, dysphagia, hypersalivation, atypical intermittent chest pain, hiccups, odynophagia, and globus sensation. Occasional patients may present to the cardiologist with angina-like chest pain.8 Others may present with pulmonary or pharyngeal symptoms, including hoarseness, coughing, asthma, or recurrent pulmonary complaints.9 These symptoms may be experienced daily, weekly, or only several times a month. The frequency and severity of symptoms from gastroesophageal reflux do not correlate with morphologic changes seen in the esophageal mucosa.10,11
Some patients develop complications, including erosions or ulcers, strictures, Barrett esophagus, and cancer. The symptoms associated with esophageal peptic ulcers resemble those associated with gastric or duodenal peptic ulcers, except that the pain usually localizes to the xiphoid or high substernal region. Peptic stricture or peristaltic dysfunction causes progressive dysphagia. Esophagitis may cause massive, but usually limited, hemorrhage.
In children, the classic adult history of heartburn often cannot be elicited. Gastroesophageal reflux is common in infants, and it is probably physiologic, usually resolving spontaneously.12 General symptoms in this group of children include regurgitation, prolonged crying and irritability, vomiting, apnea, asthma, choking, stridor, and respiratory distress. Older children may experience heartburn, dysphagia, odynophagia, night walking, hoarseness, chronic cough, and asthma.13 The most frequent complication of recurrent GERD is failure to thrive resulting from caloric deprivation and recurrent bronchitis or pneumonia caused by repeated episodes of pulmonary aspiration. Severe dental caries also are common.
Gross and Endoscopic Findings
The gross appearance of the esophagus varies with disease severity. Areas of erythema and longitudinal red streaks in the distal esophagus are the first endoscopic abnormalities. In severe reflux, the esophagus appears friable, diffusely reddened, and hemorrhagic. Mucosal erosions, ulcerations, intramural thickening, strictures, or Barrett esophagus are characteristic of severe chronic disease. Most erosions and ulcers occur distally, tapering off proximally. Inflammatory polyps may be present at the squamocolumnar junction. Strictures develop close to the gastroesophageal junction or immediately proximal to a hiatal hernia.
Repetitive episodes of tissue damage and healing produce histologic features that reflect disease activity at the time of examination superimposed on those from previous injury. Biopsies are performed to confirm the presence of esophagitis, to determine its nature (eg, peptic vs drug-induced) and severity, and to rule out the presence of a coexisting infection, such as Candida, cytomegalovirus, herpes (particularly in immunosuppressed patients), Barrett esophagus, or a neoplastic process. Esophagitis can heal completely, or it may progress on to any of the complications discussed below.
Because the histologic features of GERD are not specific, a number of histologic features must be assessed before a presumptive diagnosis of reflux esophagitis can be made. In addition, it is important to be aware of the clinical and drug history of the patient.
Balloon cells are swollen, pale, periodic acid-Schiff-negative cells with irregular pyknotic nuclei developing in the epithelial midzone (Figure 1, A). They are present in approximately two-thirds of GERD patients. Balloon cells develop in any damaged mucosa, but in the absence of other more characteristic features of GERD, they may be the only clue that a chemical injury has occurred.
Capillary ectasia consisting of dilated and congested venules located high in the lengthened esophageal papillae is a common finding in reflux esophagitis, affecting up to 83% of affected patients. In contrast, this finding is present in only 10% of patients without GERD.14,15 This change is often present in the absence of any inflammation and corresponds to the endoscopically identified red mucosal streaks.
Intercellular Edema (Spongiosis)
Intercellular edema often results from acid reflux. It is usually most prominent in the basal layers, often in the absence of inflammation. The intercellular fluid accumulation may make the intercellular bridges unusually prominent.
Normally, the basal layer is only 1 to 4 cells thick and occupies less than 15% of the squamous epithelial thickness. Prolonged bathing of the esophageal mucosa with acid accelerates mucosal cell shedding and results in compensatory basal cell hyperplasia. Because individuals without GERD show mild epithelial hyperplasia 2 to 3 cm proximal to the lower esophageal sphincter, this feature is not useful in diagnosing GERD if the biopsies are taken in the distal 3 cm. Basal cell hyperplasia is most easily appreciated when this layer exceeds 25% of the mucosal thickness (Figure 1, B). Stromal papillae also lengthen. Extension of the lamina propria papillae into more than two-thirds of the mucosal thickness often occurs in GERD. Regenerating basal epithelium is characterized by nuclear enlargement, hyperchromasia, and mitotic figures in the basal cell layers. Nucleoli may also be prominent.
Very small or poorly oriented biopsies, especially those with significant inflammation and associated reactive atypia, may be impossible to interpret. In this situation, repeat biopsies may be necessary once the reflux has been treated.
Small numbers of lymphocytes, plasma cells, and eosinophils typically populate the normal esophageal lamina propria, so their presence does not establish a diagnosis of esophagitis. However, one usually has the impression that mucosal lymphocyte numbers (intraepithelial and in the lamina propria) are conspicuously increased in patients with GERD. Intraepithelial lymphocytes have been referred to as “squiggle cells” or “cells with irregular nuclear contours” because of their curved nuclei that appear to fit between the epithelial cells. They have almost no visible cytoplasm. Intraepithelial lymphocytes are present in esophagitis of diverse etiologies16,17 and are not specific for any specific form of esophageal injury.
Intraepithelial eosinophils are considered by many to be the single most specific diagnostic feature of reflux esophagitis (Figure 2, A), as shown by esophageal pH monitoring,18–20 but they are not sensitive, being present in only 40% to 50% of symptomatic individuals. Intraepithelial eosinophils, however, are not pathogenomonic for reflux esophagitis, because they can be found in control patients, and an occasional eosinophil can also be encountered in any of the entities listed in Table 1. Intraepithelial eosinophils may be focal, necessitating a search for them on serial sections and on multiple levels.
Neutrophils, either in the squamous epithelium or in the lamina propria, serve as evidence for acute erosive or ulcerative esophagitis (Figure 2, B). Large collections of neutrophils suggest that a biopsy comes from an ulcer or erosion. Although neutrophils provide evidence of erosions or ulcers, they are not specific for reflux esophagitis. The presence of neutrophils in an esophageal biopsy should prompt a search for evidence of fungal or viral infection.
Multinucleated Epithelial Cells
Multinucleated squamous epithelial cells with histologic features simulating a viral cytopathic effect or dysplasia develop in patients with many forms of esophagitis, including reflux (Figure 3). The nuclei may contain single or multiple eosinophilic nucleoli with a perinuclear halo, but the cells lack inclusions, hyperchromasia, or atypical mitoses. The giant cells are generally confined to the basal epithelium, although occasionally they occur more superficially. Following treatment, these cells disappear.21
Biopsies obtained from the cardiac mucosa immediately distal to the Z line in patients with GERD often contain large numbers of acute or chronic inflammatory cells, even in areas appearing endoscopically normal. The inflammation is limited to the gastric cardia in the absence of similar changes in the remaining stomach.4 Carditis may be a more sensitive marker of GERD than inflammation involving the squamous mucosa, as judged by pH monitoring studies.
The histologic features discussed above suggest the diagnosis of GERD, especially in the distal esophagus, but none are specific for this entity. Other disorders to be considered in the differential diagnosis of GERD include infection, eosinophilic esophagitis, drug-induced injury, and involvement by systemic diseases, such as progressive systemic sclerosis or Crohn disease. Reactive changes in biopsies from patients with GERD may appear so atypical that the differential diagnosis may also include malignancy. When extensive pseudoepitheliomatous hyperplasia is present, the question of an invasive carcinoma may also arise. Additionally, the base of ulcers may contain bizarre cells that may mimic an invasive carcinoma. Immunohistochemical stains using antibodies directed against endothelial and epithelial cells distinguish between the reparative reactions and malignancy. The presence of isolated cytokeratin-positive cells strongly suggests the presence of an invasive cancer, especially if the cytokeratin-positive cells demonstrate significant nuclear atypia and lie within a desmoplastic stroma. However, it is important to note that reactive mesenchymal cells are sometimes cytokeratin immunoreactive.
Eosinophilic esophagitis (EE) is most commonly a disease of childhood, but adults also may be affected. Affected individuals are typically young white males, but the disease may affect all races, both sexes, and all ages. Males comprise approximately two-thirds of affected children and adults.22–28 During the past decade, the frequency with which the diagnosis of EE has been made has increased dramatically.29,30 Whether the apparent increasing incidence of the disease is related to a true increase in the number of individuals with the disorder or is due to increased recognition of the disease by pathologists and clinicians is still unclear.
The presenting symptoms of EE vary depending on patient age. Children younger than 2 years typically present with feeding refusal, food intolerance, vomiting, abdominal pain, or other symptoms often thought secondary to GERD.22,31 Children also may present with failure to thrive, growth retardation, and developmental delay.32,33 Adults frequently present with solid food dysphagia or food impaction.28,34,35 Many patients have a history of atopic dermatitis, eczema, allergic rhinitis, asthma, or other food allergies.22–24,35–38 Approximately 50% of EE patients have peripheral eosinophilia.35,36 There also may be an association between EE and celiac disease or other autoimmune diseases.39,40
The cause of eosinophilic esophagitis is poorly understood, but it is most likely associated with allergy. Most affected patients demonstrate clinical evidence of food and airborne allergen hypersensitivity.41 In addition, many patients report seasonal variation in their symptoms.42 One recent study43 suggests that at least in children, eosinophilic esophagitis is associated with increased expression of eotaxin-3, an eosinophil-specific chemoattractant. In addition, a single nucleotide polymorphism in the gene encoding this protein was also associated with susceptibility to EE.43
Endoscopically, esophageal furrows, strictures, and rings (trachealization) are characteristic of EE.22,23,35,36,44,45 In addition, white patches or plaques are commonly identified. A narrow esophagus with a fixed internal diameter may also be an endoscopic finding.46 Up to one-third of EE patients, however, demonstrate no endoscopic abnormalities.23
Histologically, esophageal biopsies demonstrate often marked epithelial basal hyperplasia and extensive infiltration of the epithelium by eosinophils (Figure 4, A and B). The changes occur not just in the distal esophagus, as in GERD, but also in the mid and upper esophageal mucosa, a feature that is often useful in the differentiation of EE from reflux esophagitis. Eosinophils generally number in excess of 20 to 24 per high-power field.22,47 Eosinophils in EE are typically more numerous in the superficial portion of the squamous epithelium, and they frequently occur in small aggregates of 4 or more cells to form eosinophilic microabscesses (Figure 4, C). It is important to note that the histologic changes are commonly patchy in this disorder, and therefore multiple biopsies should be taken and examined before the diagnosis is excluded (Figure 5).
Recent consensus recommendations for the diagnosis of EE state that intraepithelial eosinophils should be counted in the most intensely inflamed portion of the biopsy specimen and that at least 15 eosinophils per high-power field should be present before the diagnosis is suggested.48 It is important to note that these consensus recommendations also state that the diagnosis of EE should only be made in the proper clinical context, and therefore close communication between the pathologist and gastroenterologist is necessary to establish the diagnosis.
In contrast, GERD is usually characterized by lower numbers of intramucosal eosinophils, usually 7 or fewer per high-power field.47,49 It should be emphasized, however, that large numbers of eosinophils (>20 per high-power field) may occasionally be present in adult patients with GERD50,51 and in patients with other esophageal disorders.50 Therefore, absolute eosinophil counts cannot be used to establish a definitive diagnosis of EE. In addition, many patients appear to have features of both EE and GERD, making definite distinction between the 2 entities difficult.
Some have speculated that GERD may in some way predispose an individual to the development of EE, making true separation of these 2 diseases impossible.52 Alternatively, EE may induce changes in the esophageal lining predisposing individuals to the development of GERD. This may be particularly true in adult patients. Acid peptic injury to the squamous epithelium of the esophagus may affect tight junctions, making the epithelium permeable to allergens. In addition, GERD could cause recruitment of inflammatory cells into the esophageal mucosa, which could contribute to the local development of allergic reactions. Eosinophilic esophagitis could predispose to GERD as a result of the release of eosinophil secretory products. Vasoactive intestinal peptide and platelet-activating factor, 2 eosinophil secretory products, have been shown to cause lower esophageal sphincter relaxation.53,54 Eosinophilic esophagitis also induces fibrosis in the lamina propria of the esophagus,44 a factor that could result in impaired peristalsis and acid clearance. The features that may be helpful in distinguishing EE and GERD are summarized in Table 2.
Eosinophilic infiltrates of the esophageal wall commonly pose diagnostic dilemmas, with the differential diagnosis usually centering around reflux esophagitis, parasitic infection, drug reactions, or eosinophilic esophagitis. The esophagus normally does not contain any eosinophils, and therefore their identification represents a pathologic accumulation in this site.41,47 Esophageal eosinophilic disorders can be classified as primary or secondary. Primary disorders are further categorized into those that are associated with atopy, those that are unassociated with atopy, and those that are familial. Secondary disorders may occur with or without a coexisting systemic eosinophilic disease.
Treatment and Prognosis
The treatment of eosinophilic esophagitis includes avoidance of known specific food and airborne allergens in atopic patients. In cases where dietary changes are ineffective, an elemental diet may provide improvement in symptoms.55 Administration of systemic or topical steroids may also be of benefit.56,57 In addition, gastric acid should be neutralized, even in patients without gastroesophageal reflux disease.42 If left untreated, eosinophilic esophagitis may progress, resulting in chronic scarring and esophageal stricture formation. The risk for the development of Barrett esophagus in this condition is unknown.
No characteristic pathologic findings exist for drug-induced esophagitis, because different drugs damage the esophagus via different mechanisms. Drugs commonly implicated in drug-induced esophagitis include those listed in Table 3. Age, posture, volume of a fluid chaser, and dissolution pH of the medication all influence drug-mediated esophageal injury. Hiatal hernia, esophageal dysmotility, or stricture predispose individuals to prolonged esophageal medication retention and enhance the ability of drugs to damage the mucosa.
Some injuries result from physical entrapment of undigested medicines, especially those that contain a hydrophilic swelling agent or fiber that ensures rapid disintegration when the pills contact water.58 These medicines act as foreign bodies impacting in the esophageal lumen, especially if they are taken with a minimum of liquid. As the medication dissolves, localized esophageal damage, ranging from inflammation to severe hemorrhage and even perforation, develops (Figure 6).59
Other mechanisms of drug-induced esophagitis are allergic in nature, and these may be suspected based on the history or the presence of eosinophilia in the absence of reflux esophagitis. Still other drugs, such as chemotherapeutic agents, directly damage replicating cells. Basal cell hyperplasia, mild atypia, and numerous mitoses, some of which may appear atypical, characterize recovery from chemotherapeutic injury. Antibiotics account for at least half of the reported cases of drug-associated esophagitis, with tetracyclines, especially doxycycline, being the most common offenders.59
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs in the Western world; the world market now exceeds $6 billion per year. Nonsteroidal anti-inflammatory drugs also are the drugs most frequently causing complications necessitating hospitalization.60,61 Nonsteroidal anti-inflammatory drugs are primarily used to treat rheumatoid arthritis and other degenerative joint diseases and to reduce the incidence of cancer. Aspirin is used to prevent cardiovascular and cerebrovascular thrombotic events. Its antithrombotic effects are largely mediated by its ability to acetylate, and thus irreversibly inactivate, platelet cyclooxygenase-1, the rate-limiting enzyme in thromboxane A2 synthesis. A linear dose relationship exists between NSAID ingestion and gastrointestinal damage. These relationships are modified by host responses, concomitant drug or alcohol use, route of administration, the specific drug used, and the presence of Helicobacter pylori infections.62 Different preparations tend to affect different portions of the gastrointestinal tract.
Esophagitis develops in patients on NSAIDs of all sorts, and in part it relates to the development of reflux esophagitis due to a reduction of lower esophageal sphincter pressure and impairment of cholinergic control of lower esophageal sphincter contraction.63,64 Esophagitis, esophageal ulcers, and esophageal strictures all complicate NSAID therapy.65 Nonsteroidal anti-inflammatory drug– induced ulcers are characteristically large, shallow, discrete, midesophageal ulcers surrounded by a normal mucosa. Patients on long-term NSAID therapy may have an endoscopically normal–appearing esophagus, but histologically nonspecific esophagitis may be seen. Alternatively, the esophageal mucosa may appear inflamed, eroded, or ulcerated. Patients also may develop reflux esophagitis. Basal cell hyperplasia may not be present, because proliferation is inhibited by the prostaglandin inhibitors.66
Many chemotherapeutic agents damage the gastrointestinal tract. Systemic chemotherapeutic agents primarily target mitotically active cells inducing massive cell death,67 causing crypt epithelial apoptosis and mucosal ulceration and inflammation. The degree of mucosal toxicity varies depending on the number of drugs used, their dosage, complicating effects of surgery, extent of tumor involvement, and the presence of concomitant radiotherapy or secondary infection. Some chemotherapeutic agents also damage the myenteric plexus, leading to motility problems.
Chemotherapy leads to a high incidence of mucositis affecting the oral, esophageal, gastric, and intestinal mucosa. Patients with mucositis experience considerable pain and discomfort. Symptoms associated with chemotherapy treatment include nausea, vomiting, stomatitis, anorexia, diarrhea, abdominal pain, and ileus. Chemotherapy-related diarrhea is a common problem. Chemotherapy-induced vomiting can lead to Mallory-Weiss tears, intramural hematomas, and esophageal perforation. Chemotherapy also predisposes patients to mucosal infections, neutropenic enterocolitis, ischemia, hemolytic uremia syndrome, pseudomembranous colitis, and opportunistic infections with organisms such as Candida, herpes, and cytomegalovirus. Patients most likely to develop complications often have late-stage cancers with the compounding effects of malnutrition, ischemia, sepsis, or shock.
Chemotherapeutic agents cause mucositis, ulcers, erosions, strictures, and fistulas anywhere in the gut. The incidence of esophageal injury is high because of the frequent combination of chemotherapy and radiation therapy in attempts to aggressively treat tumors arising in the chest. Cytotoxic agents damage the esophageal mucosa directly. Nonspecific areas of necrosis, inflammation, and granulation tissue occur in severe injury. In less severe injury, one may see an intact squamous epithelium containing enlarged, atypical squamous cells. The regenerative basal squamous epithelium may appear atypical, sometimes with atypical mitoses. Underlying stromal cells and submucosal glands also often appear atypical. Chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil may cause Barrett esophagus.
Bisphosphonate injury tends to affect older individuals, especially women treated for osteoporosis. Only a fraction of individuals develop severe adverse esophageal reactions to the drug. Patients with serious injury from bisphosphonates are usually individuals taking other medications in addition to the alendronate.68
Alendronate damages the esophagus both by its toxicity and from nonspecific irritation secondary to pill contact with the esophageal mucosa in a manner similar to that seen in other forms of “pill esophagitis.” The esophagitis results from swallowing the medication with little or no water, lying down during or after ingestion of the tablet(s), and continuation of the drug after symptom onset. Because the patients are elderly, many have reduced esophageal motility, predisposing them to the drug injury.
Alendronate also can cause visible gastric mucosal injury in most patients studied, and it is severe in 50% of patients. Gastric ulcers may be present in 8% of cases.69–71 Because most patients who take alendronate are elderly, it is quite conceivable that coexisting H pylori infections or the use of NSAIDs to treat arthritis may add to the mucosal toxicity.69
Alendronate is well tolerated in most patients, but it causes severe upper gastrointestinal symptoms in approximately 1.5% of patients receiving the medication.72 Patients typically present with dysphagia secondary to midesophageal inflammation or stricture.72,73 In some patients, the ulceration is severe enough to necessitate hospitalization.74,75 Bleeding is rare.
Endoscopy shows an erosive esophagitis with erythema, ulcerations, an inflammatory exudate, and thickening of the esophageal wall.75,76 The esophageal erosions and ulcers may become confluent, developing into multiple deep, large ulcers. The histologic features of the esophageal changes are those common to many severe ulcerating esophageal disorders. Neutrophilic infiltrates are often present, as is intraepithelial eosinophilia. The squamous epithelium appears reactive, as evidenced by the presence of enlarged and hyperchromatic nuclei. There also may be small intraepithelial vesicles. Clear, refractile, crystalline foreign material is often present in the fibroinflammatory exudate, and it is seen easily with polarizing light. The crystals resemble those of crushed alendronate tablets. Scattered multinucleated giant cells may associate with the crystals.77 The histologic features of gastric injury resemble NSAID injury. The changes resolve with drug cessation. The development of late-onset strictures is uncommon.
The most dangerous drug-related esophagitis results from potassium chloride. Several patients have died of esophagitis directly related to its ingestion. Histologically one sees subepithelial edema, thickening of the stratum corneum, and the presence of balloon cells. The presence of balloon cells serves as an early esophageal mucosal marker of chemical injury but is not specific for it.
Presented in part at the Latest Advances in Esophageal Pathology course, CAP '08 meeting, September 2008, San Diego, California.
The author has no relevant financial interest in the products or companies described in this article.
Reprints: Amy E. Noffsinger, MD, Department of Pathology, University of Chicago Medical Center, MC6101, 5841 S Maryland Ave, Chicago, IL 60637 (email@example.com)