Inflammatory Disorders of the Esophagus

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%. ^, GERD is associated with considerable healthcare costs; in the United States in 2015 esophageal disorders accounted for $18.1 billion in health care expenditures, including $12.4 billion for acid-inhibition therapies. Clinically, GERD is often classified as erosive or nonerosive based on endoscopic or pathological features, and currently includes the concepts of proven and unproven GERD in clinical decision-making. One recent review defines GERD as “a family of syndromes attributable to, or exacerbated by, gastroesophageal reflux, evident symptomatically, endoscopically, or by physiological testing, which impart morbidity through troublesome symptoms and/or risk.” Using this definition, GERD phenotypes emerge including nonerosive reflux disease, GERD hypersensitivity, low- or high-grade esophagitis, Barrett’s esophagus, reflux chest pain syndrome, laryngopharyngeal reflux, and regurgitation dominant reflux. Risk factors associated with GERD include advanced age (especially after age 40 years), 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. Compared to females, males are at increased risk for erosive esophagitis, Barrett’s esophagus, and especially esophageal adenocarcinoma. The symptoms most often associated with GERD are heartburn, acid regurgitation, and dysphagia. Reflux symptoms are common in runners. 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, GERD may also be defined as “a condition in which a normal physiological event is affected by an imbalance between aggressive and defensive factors.” Aggressive factors include hiatus hernia, found in patients who have moderate to marked GERD; transient relaxation of the lower esophageal sphincter in GERD patients who do not have hiatus hernia; acid; pepsin; bile acids; alcohol; and acidic foods. Defensive factors include lower and upper esophageal sphincters, esophageal peristalsis, and restoration of normal esophageal pH following a reflux episode by salivary bicarbonate secretion, impaired in patients who have xerostomia or Sjogren’s syndrome. Expressed as the “burn hypothesis,” reflux esophagitis is caused by reflux of gastric or duodenal fluid into the esophagus, and refluxed gastric acid, bile, pepsin, and duodenal contents cause injury to the esophageal mucosa. Esophageal epithelial injury is greater if pepsin is present in addition to acid in refluxate. 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 in addition to those already stated above include delayed gastric emptying, 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 inflammation hypothesis asserting that the inflammatory response, not the direct effect of acid, is the initial factor responsible for damaging esophageal mucosa. Evidence supporting the role of inflammation in GERD includes antiinflammatory symptoms reduction, reported by many patients affected by GERD, after commencing proton pump inhibitors (PPI) therapy, because PPI recently have been shown to have antiinflammatory effects on esophageal epithelium. Histological 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.

The diagnosis of GERD has rested on the clinical impression of symptoms consistent with pathological reflux and the demonstration of excessive acid reflux. However, the association of symptoms with reflux is generally weak, and the use of additional modalities may add to the diagnostic accuracy. A schema to increase diagnostic accuracy for GERD is shown in Table 14.1 .

The role of esophageal biopsy in the diagnosis of GERD is debated. In the schema in Table 14.1 , for example, histomorphology is considered adjunctive, to be obtained only in cases not confirmed endoscopically or by pH or pH impedance. Other strategies suggest more liberal use of biopsy including to rule out eosinophilic esophagitis (see Eosinophilic Esophagitis section). However, a recent study concluded that in patients who have refractory GERD symptoms but do not have dysphagia, the prevalence of eosinophilic esophagitis is so low that obtaining biopsies may be considered unnecessary.

Pathology

On endoscopic examination, patients with erosive esophagitis exhibit erosions, ulcers, strictures, or some combination of these. However, as many 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/pathological discrepancies, biopsies are always warranted in symptomatic patients to document the presence of tissue injury and to exclude other entities such as infections, eosinophilic esophagitis (EoE) especially in patients who have dysphagia, 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 histological 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 histological diagnosis. Use of jumbo forceps does not increase the rate of complications related to endoscopy ; rather, it greatly improves the quality of the histological 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 histological 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) to diagnose esophagitis reliably, and submitted specimens should state the esophageal site from which the biopsies were obtained. Furthermore, because of a high level of discordance between endoscopic and histological 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. ^, Scoring several histological features of esophageal biopsies (elongated papillae, basal zone hyperplasia, dilated intercellular spaces, intraepithelial inflammatory cells, necrosis, and erosions) may be useful to distinguish nonerosive reflux disease biopsies from reflux hypersensitivity, functional heartburn, and control biopsies. ^{, ,}

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.

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, trauma, and systemic diseases such as collagen vascular disease, Crohn’s disease, Stevens-Johnson syndrome, various bullous diseases, lichen planus, and graft-versus-host disease. Many of these conditions share overlapping morphological features with GERD. Therefore, an accurate diagnosis of “reflux” esophagitis requires correlation with the patient’s clinical, endoscopic, manometric, and histological data. In the absence of clinical information, a diagnosis of reflux esophagitis cannot be established on the basis of biopsy findings alone. The histological 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 14.2 ; see also Chapter 24 for details).

Table 14.2

Differential Diagnosis of Reactive Hyperplasia versus Dysplasia of Squamous Epithelium

Feature	Hyperplasia	Dysplasia
Papillae	Regular	Absent or irregular
Nuclear enlargement	++	+→+++
Nuclear pleomorphism	+/−	+→+++
Nuclear overlapping	−	+→+++
Nuclear hyperchromasia	+/−	+→+++
Nuclear membrane	Smooth	Irregular

+, Mild degree; ++, moderate degree; +++, marked degree.

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).

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 multiple phenotypic presentations, and nonerosive reflux disease (NERD), erosive esophagitis, and BE may form a continuum. 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. ^, Interestingly, patients who have GERD have reduced risk of developing microscopic colitis, ulcerative colitis, or Crohn’s disease, especially GERD patients who have erosive esophagitis or Barrett’s metaplasia. 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 PPI and other acid inhibitors, are highly effective at relieving symptoms and repeat biopsies may show histological improvement or resolution of pre-therapy pathology. However, progressive disease develops in some patients despite ongoing therapy. In one study, as many 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. ^, Esophageal biopsy is indicated for patients who become refractory to therapy or who develop new symptoms to evaluate for emergence of complications such as neoplasms.

Although PPI are the current mainstay for GERD treatment, approximately 30% of GERD patients continue to experience symptoms while receiving once daily label-dose PPI. Use of a bile sequestrant along with a daily label-dose PPI significantly reduced heartburn symptoms compared to a placebo, and regurgitation symptoms were also reduced. A US expert panel of foregut surgeons and therapeutic gastroenterologists recently agreed that surgery was a viable option for GERD patients for whom PPI discontinuation becomes necessary or who want to discontinue PPI therapy. Laparoscopic fundoplication and magnetic sphincter augmentation were considered acceptable options for such patients, and transoral incisionless fundoplication was considered an option for such patients who do not have a hiatal hernia. For PPI-nonresponders, laparoscopic fundoplication was recommended as an appropriate surgical option if a hiatal hernia was present. Magnetic sphincter augmentation was considered appropriate for PPI-nonresponders with regurgitation-predominant disease who had or did not have a hiatal hernia, and transoral incisionless fundoplication was appropriate for PPI-nonresponders who did not have a clinically significant hiatal hernia. Laparoscopic fundoplication and magnetic sphincter augmentation were not considered appropriate surgical options for PPI-nonresponders whose impedance-pH study was negative.

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. In a recent analysis of 46 patients with herpes esophagitis, 72% were immunocompromised and those with longer symptom duration were more likely to require treatment extension; in addition, 37% of patients had underlying esophageal disease and were more likely to have concomitant Candida esophagitis. 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 morphological 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 14.3 ). 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 histological 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. However, a recent retrospective study of endoscopic appearances of patients with herpes or CMV esophagitis identified a scoring system with 97% sensitivity and 89% specificity to discriminate CMV from herpes esophagitis. 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.

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 . 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 or swallowed 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.

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. This is in contrast to the white patches seen in eosinophilic esophagitis that cannot easily be dislodged from esophageal epithelium (see Eosinophilic Esophagitis).

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 ( Fig. 14.10 ). 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. C. auris , first described in 2009 causing an ear infection, has been isolated from the oral cavity, oropharynx and nares, but has not yet been reported in the esophagus.

Differential Diagnosis

On occasion, the endoscopist may identify small white plaques that, although they resemble Candida esophagitis, represent glycogenic acanthosis, ectopic sebaceous glands or inflammatory exudate in EoE. 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. White plaques in EoE tend to be smaller than those associated with Candida and are composed of exudate containing eosinophils and squamous epithelial cells. EoE plaques are typically more difficult to dislodge than are Candida -associated plaques.

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, such as patients who are infected with glabrata species of Candida which is more commonly azole-resistant than albicans species. 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. ^, Lack of symptomatic response in patients with Candida esophagitis should prompt search for a co-infecting agent such as herpes virus.

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 and occurs in 98% of patients. 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. The 2018 achalasia guidelines include a statement that there are only minor differences in the clinical presentation of idiopathic achalasia and achalasia caused by Chagas disease.

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. In idiopathic achalasia, inhibitory neurons are lost selectively, whereas in Chagas disease both inhibitory and excitatory neurons are lost. This neuronal loss 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-positive and glial fibrillary acidic protein (GFAP)-positive enteroglial cells when compared with seronegative controls and asymptomatic seropositive patients. A 2013 immunohistochemical study identified increased substance P, which has proinflammatory effects, and decreased vasoactive intestinal peptide, which has antiinflammatory effects, in sections of chagasic megaesophagus, suggesting that these alterations contribute to inflammation that ultimately leads to denervation. With disease progression, there is intense neuronal destruction and denervation of the organ, with loss of function.

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, dilation 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 but appear to be more effective in idiopathic achalasia than Chagas disease. ^{, ,}

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-induced or potassium chloride–induced injury had 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 histological appearance of pill-induced esophagitis is typically nonspecific. However, prominent eosinophilic infiltration, spongiosis (dilated intercellular spaces), 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 sulfate–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.

Differential Diagnosis

A variety of conditions can cause histological 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 histological grounds in an isolated esophageal biopsy specimen and in the absence of clinical information. Features potentially helpful in the differential diagnosis are diffusely dilated intercellular spaces that were found more commonly in a study of 22 cases of pill esophagitis compared to 20 cases of reflux esophagitis, and reactive epithelial changes and papillary elongation that were more common in reflux compared to pill esophagitis.