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Available online at www.sciencedirect.com

www.elsevier.com/locate/semdp

Non-reflux esophagitis: A review of inflammatory diseases of the esophagus exclusive of reflux esophagitis Salwan J. Almashat, MDa,b,1, Lei Duan, MDa,b,1, Jeffrey D. Goldsmith, MDa,b,c,n a

Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 Harvard Medical School, Boston, MA 02215 c Department of Pathology, Children's Hospital Boston, Boston, MA b

article info

abstra ct

Keywords:

Esophagitis is a frequent cause of clinical symptoms and is often an indication for upper

Allergic/eosinophilic esophagitis

endoscopy. Mucosal biopsies are procured for diagnostic purposes and may be used to

Infectious esophagitis

assess the efficacy of treatment, as in patients with eosinophilic esophagitis. This article

Drug-induced esophagitis

outlines salient clinical and pathologic features of diseases that cause esophagitis

Sloughing esophagitis

exclusive of reflux esophagitis.

Crohn's disease

& 2014 Elsevier Inc. All rights reserved.

Graft-versus-host disease

Introduction The esophagus is a frequent site of biopsy during upper endoscopy primarily due to the fact the esophagus-related symptomatology is a common indication for endoscopic evaluation. This review summarizes salient clinicopathologic entities, exclusive of reflux esophagitis, that result in pathologic findings appreciable in endoscopically obtained mucosal biopsies.

Allergic/eosinophilic esophagitis Eosinophilic esophagitis is a chronic inflammatory condition of the esophagus characterized by symptomatic esophageal dysfunction and prominent intraepithelial eosinophilic infiltration, which is thought to have an allergic etiology.1 It was first described in a handful of case reports and small series in the 1970s and 1980s but was not defined as a distinct n

1

clinicopathologic entity until 1993.2 Since then, eosinophilic esophagitis has become an increasingly recognized cause of dysphagia and esophageal dysfunction, particularly among patients refractory to medical treatment of gastroesophageal reflux disease.1,3 A considerable increase in prevalence has been reported in recent years, with eosinophilic esophagitis accounting for 1.9% of patients undergoing esophageal biopsy for symptoms of dysphagia.4,5 A Swedish population-based study of 1000 adults estimated the prevalence of eosinophilic esophagitis to be 1% based on histologic criteria,6 whereas a Canadian report cited an incidence of 11 per 10,000 adults with a 39% annual increase in incidence from 2004 to 2008.7 Whether these reports describe a true increase in disease incidence or simply improved recognition of the entity remains unclear. A 17-year retrospective review of biopsies with “reflux esophagitis” taken between 1982 and 1999 revealed no change in incidence of eosinophilic esophagitis when histologic criteria were applied, despite a 40-fold increase in endoscopic procedures during the same time

Corresponding author at: Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail address: [email protected] (J.D. Goldsmith). Drs. Almashat and Duan contributed equally to the creation of this manuscript.

http://dx.doi.org/10.1053/j.semdp.2014.02.002 0740-2570/& 2014 Elsevier Inc. All rights reserved.

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period.8 On the other hand, population-based studies report increases in incidence and prevalence that seem to be independent of increased awareness alone.3,9 Eosinophilic esophagitis typically occurs in children or adolescents, although it is increasingly recognized in adults. Males outnumber females by a ratio of 3–4:1.1 Patients often have co-existing, or a history of, allergic conditions, including asthma and atopic dermatitis, as well as peripheral eosinophilia, all of which are more common in children.10–12 In the adult population, dysphagia, particularly with solid foods, is the most common presenting symptom, but other symptoms include chest and upper abdominal pain.1 Children with eosinophilic esophagitis typically present with heartburn and/or regurgitation, abdominal pain, emesis, and solid food impaction.10 Dysphagia has been described in children, but is relatively uncommon. Complications of eosinophilic esophagitis include stricture formation and chronic scarring; Barrett esophagus has not been clearly associated with this disease and rare reports may be fortuitous.10 The endoscopic appearance of eosinophilic esophagitis includes esophageal narrowing (“small caliber” esophagus), multiple, concentric “corrugated” rings (“trachealization” or “feline esophagus”), white plaques, and linear furrows. Esophageal rings are commonly seen in eosinophilic esophagitis and appear to be somewhat specific. In one study, 72% of endoscopically evaluated patients with eosinophilic esophagitis exhibited esophageal rings, and in another study, they were more than twice as common in patients with eosinophilic esophagitis compared to those with gastroesophageal reflux disease.11,12 In general, however, endoscopic findings correlate poorly with histologic severity and are not diagnostic of eosinophilic esophagitis.13 The histologic diagnosis of eosinophilic esophagitis rests, in part, on the number of eosinophils present within the squamous epithelium. The original histopathologic description of eosinophilic esophagitis reported a mean number of 56 eosinophils per high-power field (HPF) and used 20 eosinophils/HPF as a diagnostic threshold.2 Since then, the numerical cutoff used to diagnose and study eosinophilic esophagitis has ranged from 15 to 30 eosinophils/HPF.10–12 In order to standardize diagnostic criteria for eosinophilic esophagitis, consensus guidelines were published in 2007 by the American Gastroenterological Association Institute and North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition10 and were subsequently updated in 2011.1 Fifteen to 20 eosinophils/HPF was established as the minimum for the histologic diagnosis of eosinophilic esophagitis in the appropriate clinical context for most cases (Fig. 1A). However, biopsies of eosinophilic esophagitis frequently contain greater numbers of eosinophils, sometimes exceeding 250 eosinophils/HPF.14 As noted in the guidelines mentioned above and elsewhere, significantly increased intraepithelial eosinophils may be seen in conditions other than eosinophilic esophagitis, including gastroesophageal reflux disease, parasitic infection, and drug-associated injury and, thus, cannot be used alone to diagnose the disease. Increased eosinophils may also be present in a patchy distribution, necessitating multiple tissue samples to document disease. In one study, diagnostic numbers of

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Fig. 1 – Typical examples of eosinophilic esophagitis show markedly increased numbers of intraepithelial eosinophils (A; H&E, 100
). Superficial layering of eosinophils sometimes results in surface exudates consisting of necrotic squamous epithelial cells and degranulated eosinophils (B; H&E, 400
). Eosinophilic microabscesses appear as superficial, intraepithelial clusters of eosinophils and are more common in eosinophilic esophagitis than gastroesophageal reflux disease (C; H&E, 400
).

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eosinophils were present in less than half of sampled tissues in 34% of eosinophilic esophagitis cases.11 Another helpful feature in the diagnosis of eosinophilic esophagitis is the anatomic location of the eosinophilia. Biopsies taken from the upper and mid-portions of the esophagi from patients with eosinophilic esophagitis more often contain increased eosinophils than do samples from patients with gastroesophageal reflux disease.1,15,16 Thus, multiple biopsies taken throughout the esophagus are recommended for best diagnostic yield.1,14 Apart from the number of intraepithelial eosinophils, certain qualitative aspects related to eosinophils may be helpful in establishing a diagnosis of eosinophilic esophagitis. These include superficial layering of eosinophils, eosinophilic microabscesses, and eosinophil degranulation (Fig. 1B).8,11,14,17,18 A heavy burden of superficial eosinophils and luminal eosinophilic microabscesses imparts a “motheaten” appearance to the squamous epithelium due to associated intercellular edema and acantholysis.11 Eosinophilic microabscesses, generally defined as superficial aggregates of 4 or more eosinophils, may be found in 40–50% of cases of eosinophilic esophagitis (Fig. 1C). Degranulated eosinophils are more likely to be encountered when high numbers of eosinophils are present and may correlate with symptoms.19 It is important to note that these qualitative features tend to be more common in cases eosinophilic esophagitis compared with gastroesophageal reflux disease, but none are entirely specific.11,17 Eosinophilic microabscesses, superficial eosinophil layering, and degranulation have all been described in gastroesophageal reflux disease, especially when high numbers of intraepithelial eosinophils are present. Degranulated eosinophils may be seen in nearly 50% of cases of gastroesophageal reflux disease that show more than 20 eosinophils/HPF and microabscesses are detected in 20% of such cases.20 In addition, biopsies from gastroesophageal reflux disease patients with high intraepithelial eosinophil counts contain superficial eosinophilic layering in one-half to two-thirds of cases.21,22 Thus, while relatively specific, these qualitative features are not pathognomonic for eosinophilic esophagitis. As noted above, there is a significant histologic overlap between eosinophilic esophagitis and gastroesophageal reflux disease. For example, one study comparing the histologic features of eosinophilic esophagitis and gastroesophageal reflux disease found that, while the mean eosinophil counts in eosinophilic esophagitis biopsies were five times greater than those of gastroesophageal reflux disease patients, 17% of biopsies from the gastroesophageal reflux disease population had at least 15 eosinophils/HPF.17 Given the overlapping histologic features of eosinophilic esophagitis and gastroesophageal reflux disease, pathologists should be wary of making a definitive diagnosis of either entity in the absence of appropriate clinical and endoscopic data, including either a positive esophageal pH probe test or, more commonly, response to proton pump inhibitor therapy. Indeed, a proportion of patients with suspected eosinophilic esophagitis do respond to a trial of acid suppression, indicating that the clinical features of these entities show substantial overlap. A recent prospective study examining a cohort of patients with greater than 15 eosinophils/HPF found that

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approximately one-third of patients showed clinical and histologic improvement of injury following proton pump inhibitor therapy.20 In another study, 26 of 35 (75%) patients with proximal biopsies exhibiting greater than 15 eosinophils/HPF showed complete clinicopathologic remission following acid-suppression therapy. These findings further complicate the clinicopathologic boundary between gastroesophageal reflux disease and eosinophilic esophagitis and suggest a more complex relationship between the two entities. The diagnostic value of ancillary studies in distinguishing eosinophilic esophagitis from gastroesophageal reflux disease has been extensively studied and, to date, no single marker has proven superior to correlation of histology and clinical findings. Immunohistochemical stains targeting eosinophil peroxidase and eosinophilic major basic protein enhance detection of eosinophils compared to evaluation of hematoxylin and eosin stained sections, but their clinical relevance remains unproven.17,23 Gene expression analysis of chemokines shows promise in distinguishing eosinophilic esophagitis from gastroesophageal reflux disease, although these techniques are not widely available.21 Management of eosinophilic esophagitis typically consists of corticosteroid administration and/or dietary modification.24 Symptom resolution is achieved in up to two-thirds of patients with corticosteroid treatment, and a majority of treated patients demonstrate histologic resolution.25,26 However, it must be emphasized that eosinophils may have a patchy distribution in the mucosa and their density often does not correlate with symptom severity. Thus, while it is necessary to report an eosinophil count in the initial diagnosis of eosinophilic esophagitis, it is not recommended that the number of eosinophils/HPF alone be used in assessing treatment response in follow-up biopsies. Treatment response is best assessed using a combination of eosinophil counts and clinical findings, as well as comparison with prior biopsies.

Infectious esophagitis Candida species Candidal esophagitis is the most commonly encountered fungal infection of the esophagus. It predominantly affects immunocompromised patients but can be seen in immunocompetent patients, as well as other conditions including malignancy, corticosteroid use, diabetes mellitus, pregnancy, human immunodeficiency virus infection, organ transplant, esophageal dysmotility, and antibiotic use. Patients typically present with dysphagia and odynophagia and may have concurrent oral thrush. Candidal esophagitis can often be suspected at the time of endoscopy owing to the presence of characteristic white or yellow mucosal plaques. Fungal forms are usually present in desquamated keratin debris. Occasional yeast can be detected in superficial squamous epithelium where they elicit a mixed inflammatory infiltrate of neutrophils, lymphocytes, and eosinophils (Fig 2A). Yeast forms and pseudohyphae with refractile cell walls are the key diagnostic findings. Yeasts are oval, measure 3– 5 μm in diameter, and tend to be more basophilic than the pseudohyphae. The non-septate pseudohyphae are 3–5 μm in

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width, sausage-like in appearance, and are arranged perpendicular to the long axes of keratinocytes in the superficial epithelium (Fig. 2B). In most cases, fungal forms are conspicuous in routinely stained sections, although their appearance is enhanced with a periodic acid-Schiff or Grocott methenamine silver stain (Fig. 2C). Neutrophils are often present in small, superficially located clusters that may be a helpful diagnostic clue, whereas lymphocytes are more evenly distributed in the epithelium. Occasionally, crushed intraepithelial lymphocytes may simulate Candida pseudohyphae. The evenness of the smudged chromatin and lack of refractory cell wall help distinguish crushed inflammatory cells from fungal elements. The distribution and extent of Candida is variable. Most infections are characterized as superficial isolated, intraepithelial fungal forms, and organisms in detached squamous cells, whereas others may show tissue invasion, ulcers, and erosions. The latter occurs exclusively in immunocompromised hosts. Candida may also superinfect fibrinopurulent exudate of pre-existing ulcers, in which case, it is generally insignificant. When Candida forms are present only in desquamated keratin unassociated with epithelial inflammation or endoscopic findings, carryover from an oral infection should be suspected.

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immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients, transplant patients receiving long-term immunosuppressant therapy, and patients receiving chemotherapy or high-dose steroids. In fact, CMV is the most common cause of ulcerative esophagitis in the HIV

Herpes simplex virus (HSV) esophagitis Herpes esophagitis is typically seen in the immunocompromised population, although it may occasionally occur in healthy adults, children, and pregnant women.27,28 Both HSV types 1 and 2 can infect the esophagus with type 1 being far more common.29 Patients with herpes esophagitis typically present with odynophagia and dysphagia. Herpetic lesions predominantly occur in the middle to lower esophagus, where they appear as multiple vesicles or punched-out ulcers with discrete edges. The histologic appearance of herpes esophagitis is similar to that of herpesvirus infection at other sites. The virus infects squamous cells of intact or denuded epithelium, and, thus, optimal histologic diagnosis requires sampling of the ulcer edge rather than the ulcer bed. Infected cells may be acantholytic and degenerated with hard, brightly eosinophilic cytoplasm, and they are immunopositive with antibodies to HSV (Fig. 3). Infection is associated with a mixed inflammatory infiltrate of intraepithelial neutrophils, eosinophils, and lymphocytes, as well as a dense macrophage-rich infiltrate that can be a helpful diagnostic clue. Viral infection elicits several cytopathic effects. Infected cells are often enlarged and multinucleated with marginated chromatin and nuclear molding. Intranuclear inclusions may be the more common large eosinophilic glassy inclusions (Cowdry type A) or powdery, homogeneous inclusions (Cowdry type B). Concomitant infection by another microorganism such as Candida, cytomegalovirus, or bacteria can co-exist, particularly in immunocompromised patients.

Cytomegalovirus (CMV) esophagitis Cytomegalovirus-induced esophagitis typically occurs in the immunosuppressed population, although it may rarely cause esophagitis in immunocompetent patients, especially in the elderly.30 Infection is well documented in human

Fig. 2 – Most immunocompetent patients with candidal esophagitis have biopsies that contain neutrophilic inflammation. Fungal pseudohyphae and yeast forms are visible on routine H&E stain within superficial desquamated epithelial cells. Both pseudohyphae and yeast are basophilic, although pseudohyphae are slightly refractile in H&E stained sections (B; H&E, 400
). Ancillary stains such as PAS can be used to visualize fungal elements (C; periodic acid-Schiff, 400
).

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Mycobacteria species Mycobacterial infection is a rare cause of esophagitis. Most cases occur in the context of advanced AIDS or other immunosuppressive conditions,33 though it may also occur in HIV uninfected patients.34 The inflammatory reaction of tuberculous esophagitis often imparts a mass-like appearance that is radiographically visible, whereas mucosal changes include linear ulcers and induration that preferentially affect the mid-portion of the esophagus.34 Typical histologic features include mural necrotic and non-necrotic granulomas in combination with scarring and chronic inflammation. Acid-fast bacilli can be recognized on Ziehl–Neelsen

Fig. 3 – Herpes simplex virus directly infects squamous epithelial cells, producing several characteristic changes. Infected cells are multinucleated and show glassy, eosinophilic central inclusions (Cowdry A nuclear inclusions) with margination of chromatin (A; H&E, 400
). Immunohistochemistry may be used to confirm the diagnosis (B; HSV 1 and 2 immunohistochemistry, 200
). population.31 Ulcers tend to be solitary or relatively few in number; large ulcers, spanning more than 1 cm, have also been reported. In contrast to HSV esophagitis, the squamous epithelium is rarely infected by CMV, although endothelial cells and glandular epithelium are particularly vulnerable to CMV infection.31 Therefore, the ulcer bed should preferentially be biopsied whenever CMV esophagitis is suspected. Virally infected cells may show a range of cytopathic features that include nuclear enlargement with small “atypical” intranuclear inclusions, classic “owl eye” large intranuclear inclusions, and granular, eosinophilic inclusions in the cytoplasm.32 Fully developed CMV intranuclear inclusions are single, large, and deeply amphophilic with a pale rim of nuclear chromatin (Fig. 4). Atypical intranuclear inclusions are more subtle and may simulate activated fibroblasts. They are smaller and lack a surrounding clear halo.31 Ulceration and granulation tissue formation with associated acute inflammation are common. Ancillary immunohistochemical stains against CMV are widely available and may be used to facilitate viral detection in difficult cases.

Fig. 4 – Cytomegalovirus elicits mixed acute and chronic inflammation in this case of infection at the squamocolumnar junction with rare enlarged endothelial cells (A; 100
). Higher power examination reveals characteristic cytomegalovirus inclusions with nucleomegaly and cytomegaly. The nucleus contains a typical cherry-red “owl's eye” inclusion with margination of the chromatin to the nuclear membrane, resembling the Cowdry A inclusion of herpes simplex virus. Additional punctuate, lightly eosinophilic cytoplasmic inclusions are seen here (B; 400X).

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stain in approximately two-thirds of cases.34 Potential complications include fistula formation and perforation.35

Bacterial esophagitis Clinically significant bacterial esophagitis occurs almost exclusively in immunocompromised patients.36 Secondary bacterial colonization of areas of prior esophageal injury is common, and thus, bacterial invasion of squamous mucosa or the deeper wall must be present without co-existent viral or fungal infection, neoplastic process or prior surgery, in order to establish a diagnosis of primary bacterial esophagitis.36,37 Gram-positive bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, viridans streptococci, and betahemolytic streptococci are the most commonly implicated organisms.37,38 Sheets of bacteria, best visualized on tissue Gram stain, are typically present with associated necrosis and mucosal erosion. Notably, inflammation may be scant or absent in neutropenic patients.37 Some patients develop subsequent bacteremia with no identifiable extraesophageal source.36,37

Corrosive esophagitis Corrosive esophagitis due to ingestion of caustic substances is traditionally divided into acid- and alkaline-based injury, and may lead to significant esophageal damage. Corrosive esophagitis constitutes a considerable public health burden in the pediatric population, in which 80% of cases occur.39 It is particularly problematic in underdeveloped countries, whereas the prevalence in the United States appears to be declining due to preventive education measures.39,40 Most cases are due to ingestion of sodium or potassium hydroxide, both of which are commonly found in household cleaning products. Substances containing sulfuric or hydrochloric acid represent the second major cause of corrosive esophagitis. The severity of injury depends on the amount and type of material ingested, as well as duration of exposure. Acids tend to cause coagulative necrosis and scar formation, while alkaline-based materials produce more severe injury due to liquefactive necrosis and penetration of caustic material into the esophageal wall.39 A temporal progression of injury follows initial exposure, beginning with mucosal necrosis, hemorrhage, and edema within minutes of ingestion; mucosal sloughing, bacterial invasion, and granulation tissue formation at 4–7 days; and scar formation with reepithelialization after 3–4 weeks.39 Arteriolar thrombosis and ischemia may also play a role in esophageal injury.41 The histologic features are fairly non-specific, and correlation with clinical history and presentation is essential to diagnosis. Complications of corrosive esophagitis include strictures, disturbances in motility, and gastroesophageal reflux disease. Lye ingestion is thought to confer a 1000–3000-fold increased risk for squamous cell carcinoma compared with the general population with a latent period as long as 40–60 years.42

Drug-induced esophagitis Drug-induced, or “pill esophagitis,” refers to cases in which an ingested drug causes direct injury to the esophageal

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mucosa.43 The areas of esophageal narrowing overlying the aortic arch and left atrium are particularly vulnerable to druginduced injury and patients with decreased esophageal motility or cardiomegaly are at an increased risk.43 The most commonly implicated drugs are antibiotics, including doxycycline, tetracyclines, clarithromycin, clindamycin, ampicillin, and rifampin, ferrous sulfate, and ascorbic acid. These agents tend to produce localized ulcers that improve upon withdrawal of the offending medication; the risk for stricture or other complications is low.43,44 The other major category of offending drugs consists of the non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin. These commonly produce severe reactions with a significant risk of stricture formation and hemorrhage. NSAIDs account for less than 10% of all pill-induced esophageal injuries but are the causative agents in nearly 50% of drug-associated hemorrhagic complications of the esophagus. Bisphosphanate drugs, particularly alendronate, are especially caustic and are frequently associated with severe esophageal injury.43,45 Histologic features of pill-induced esophagitis are generally non-specific. Findings range from small, punctuate erosions to large circumferential ulcers surmounted by fibrinopurulent exudate and granulation tissue. More specific histologic features include perivascular edema and inflammatory mural degeneration of submucosal vessels in doxycycline-induced injury, polarizable crystalline foreign material with or without a foreign-body histiocytic giant-cell reaction in alendronate-induced injury, and Prussian blue positive, extracellular, brown, crystalline material in iron-pill esophagitis (Fig. 5).46–48

Lymphocytic esophagitis Lymphocytic esophagitis is a poorly characterized histologic finding that may be associated with a variety of clinical entities. Biopsies show increased numbers of intraepithelial lymphocytes both surrounding and distant from papillae, often in association with intraepithelial edema. Increased intraepithelial lymphocytes of the esophagus are most commonly observed in patients with gastroesophageal reflux disease and, in fact, their numbers correlate with the presence of reflux-like symptoms and decrease upon initiation of acid suppressive therapy.49,50 Rubio et al.51 defined lymphocytic esophagitis as a high number of intraepithelial lymphocytes, particularly in peripapillary regions (mean ¼ 55/HPF), without neutrophilic inflammation. Such cases were more common among pediatric patients and those with Crohn disease or celiac disease. Subsequent data suggest that lymphocytic esophagitis may be a marker of Crohn disease, particularly in children.52,53 To date, however, lymphocytic esophagitis remains a poorly characterized entity without standardized criteria. In our practice, we have seen a lymphocytic esophagitis pattern of injury in biopsies from patients with scleroderma and achalasia, as well as those with immune-mediated disorders. It may be that this pattern is not specific for any single entity, but rather, represents a type of injury that may result from a variety of causes including motility disorders, medications, and immunemediated diseases.

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and edema may be present between the upper and lower zones of squamous epithelium, but these findings are usually mild. The differential diagnosis includes other entities that may produce white mucosal plaques, such as corrosive esophagitis, pill-induced esophagitis, and invasive fungal infection, although most of these are readily distinguished owing to the presence of more intense inflammatory changes and divergent histologic features. The clinical differential diagnosis of sloughing esophagitis also includes vesiculobullous diseases involving the esophagitis, although these can usually be distinguished histologically. Cases of sloughing esophagitis show intraepithelial clefting, whereas pemphigus vulgaris, the most common vesiculobullous disorder that involves the esophagus, shows suprabasilar bullous formation.

Crohn disease Crohn disease can affect any portion of the digestive tract, including the esophagus. When Crohn disease manifests in the esophagus, it typically has other sites of coincident activity elsewhere in the luminal gastrointestinal tract.

Fig. 5 – Drug-induced (pill) esophagitis often appears as ulcerated mucosa with neutrophilic inflammation (A; H&E, 100
). Some examples contain polarizable pill fragments or pigmented material in the exudate. This case of iron-pill esophagitis contains refractile, golden-brown deposits (B; H&E, 400
).

Sloughing esophagitis Sloughing esophagitis, also known as “esophagitis dissecans superficialis,” is a poorly understood clinicopathologic entity that tends to affect the middle and distal esophagus of adults in their sixth and seventh decades of life. Virtually all patients suffer from multiple co-morbidities, chronic debilitation, or receive multiple medications.54–56 Patients typically present with reflux-like symptoms or dysphagia. The endoscopic features of this disorder are striking. One may encounter white plaques, membranes, or sloughed epithelium that forms a cast of the esophageal lumen.54 Longitudinal tears in the membranes are common. The most notable histologic features include the presence of a sharply demarcated superficial layer of necrotic squamous epithelium overlying viable, mature, and uninflamed squamous epithelium (Fig. 6A). The juxtaposition of a superficial hyper-eosinophilic layer of necrosis overlying a more intact basal zone creates a “two-toned” appearance (Fig. 6B). A variable amount of neutrophilic inflammation

Fig. 6 – A “two-tone” epithelial appearance is characteristic of sloughing esophagitis, in which the superficial portion of the epithelium is necrotic (A; H&E, 200
). Classic cases show an intraepithelial cleft between separated layers of epithelium (B; H&E, 100
). (Photomicrographs courtesy of Dr. H. Appelman, University of Michigan, Ann Arbor, MI, USA.)

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Isolated esophageal Crohn disease is exceptionally rare in the adult population.57,58 However, there is a higher incidence of upper gastrointestinal tract Crohn disease, including esophageal involvement, in the pediatric population.59–61 Crohn disease almost always affects the distal two-thirds of the esophagus.62 Features include fissuring ulcers with fibrosis and prominent transmural lymphoplasmocytic infiltrates. Non-necrotizing granulomata are reported in approximately 60% of the esophageal Crohn disease cases.63 Many characteristic features of Crohn disease are not amenable to endoscopic biopsy assessment. Transmural inflammation and fibrosis cannot be evaluated. Superficial biopsies of non-ulcerated areas often show non-specific findings such as active esophagitis with a brisk lymphocytic and neutrophilic infiltrate (Fig. 7).64 The specificity of intraepithelial lymphocytes is low in the adult population, as reflux esophagitis and other entities can also present with increased intraepithelial lymphocytes. However, lymphocytic esophagitis is reported to have a more significant association with Crohn disease in the pediatric population.52,60,65 Lamina propria, if present in biopsy specimens, typically shows fibrosis and increased lymphoplasmacytic inflammation.65

Graft-versus-host disease (GVHD) The luminal gastrointestinal tract is a common target for graft-versus-host disease, although esophageal involvement is uncommon. Typical symptoms of esophageal include dyphagia and non-cardiac chest pain. Endoscopic findings may include friability, mucosal fragility, vesicles, and ulceration. The histologic features of esophageal graft-versus-host disease resemble those of disease in the skin and typically involve the upper portion of the esophagus. Necrotic and/or apoptotic basal squamous cells with lichenoid interface inflammation are key diagnostic features (Fig. 8). Intraepithelial acute inflammation, erosions, ulcers, and rarely sloughing necrosis can be seen in the acute setting.66,67 Chronic graftversus-host disease is associated with a pauci-inflammatory

Fig. 7 – Crohn disease of the esophagus produces nonspecific inflammatory changes. This patient has erosive esophagitis with an associated inflammatory infiltrate composed predominantly of lymphocytes, although other cell types, such as neutrophils and eosinophils may be seen (H&E, 100
).

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Fig. 8 – Graft-versus-host disease elicits a modest intraepithelial lymphocytosis that tends to be more dense in the basilar portion of the epithelium. Scattered dyskeratotic squamous cells are present (H&E, 100
). lamina propria fibrosis, which may be difficult, or impossible, to recognize on endoscopic biopsies.68 Of note, mycophenolic acid, an immunosuppressive drug used in solid organ transplant patients, has been reported to induce mild changes in the esophagus at toxic levels that mimic graft-versus-host disease.69 This finding poses a diagnostic dilemma for pathologists. Correlation with the patients' clinical history is the key to differentiate mycophenolate toxicity from graft-versus-host disease. This topic is discussed in further detail in a subsequent article in this issue.

Radiation-induced esophagitis Radiation esophagitis is often seen in patients receiving radiation therapy of the thorax and head/neck region. Endoscopic features include a granular mucosal appearance with edema and luminal narrowing. Acute and subacute radiation esophagitis can present as single cell or confluent epithelial cell necrosis, edema, and mucosal denudation. Ectatic vessels with endothelial damage and fibrin thrombi are common findings that begin to develop in the subacute stages of disease. Karyorrhectic nuclear debris of stromal cells may be seen.70 Chronic radiation esophagitis manifests as marked atypia of the squamous epithelium characterized by combined cyto- and nucleomegaly with open to smudgy chromatin and preserved nuclear to cytoplasmic ratios. Multinucleation of both the epithelial and stromal cells may be seen. The lamina propria in chronic radiation esophagitis is diffusely fibrotic with thickened hyalinized vessel walls, and large bizarre stromal cells (Fig. 9). These histologic changes can last for decades after the exposure.

Vesicobullous diseases Various autoimmune bullous dermatidides can involve the esophageal mucosa, with pemphigus vulgaris being the most

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common. More than 50% of patients with vesicobullous disease have esophageal symptoms and endoscopic esophageal abnormalities.71. Identification of esophageal involvement by pemphigus vulgaris may be the first step to diagnosing asymptomatic pemphigus vulgaris in some patients.72–74 Esophageal findings in pemphigus vulgaris are similar to that of other sites. Biopsies show suprabasilar clefting with a “tombstone” appearance of basal squamous cells with associated acantholysis (Fig. 10).75 A mild intraepithelial and lamina propria mixed inflammatory infiltrate including lymphocytes and eosinophils often accompanies the blister. Pemphigus vulgaris may occasionally cause epithelial sloughing.76 Direct immunofluorescence studies of esophageal biopsy specimens almost always show characteristic intercellular deposition of IgG and C3 in the squamous epithelium, even in the absence of histologic features of pemphigus vulgaris.77,78 In contrast to pemphigus vulgaris, which can affect the esophagus in up to 50% of patients, esophageal involvement is rare among patients with bullous pemphigoid.79 The histologic features of bullous pemphigoid include subepithelial clefting, characteristically with associated eosinophils. Linear IgG and C3 deposition on the upper portion of blisters is the typical direct immunofluorescence finding.

Summary and conclusions Esophagitis is a frequent indication for endoscopy and mucosal biopsy and causes of esophagitis, exclusive of reflux esophagitis, are increasingly recognized. Some of these, including infections and drug-related injury, may produce pathognomic changes that lead to a specific diagnosis,

Fig. 10 – Pemphigus vulgaris produces suprabasilar bullae without substantial inflammation (A; H&E 100
). Higher power shows the characteristic tombstone appearance of basal squamous cells (B; H&E, 400
).

whereas others create non-specific patterns of injury that require clinical context for appropriate classification. Thus, knowledge of these diverse pathologic entities is critical for accurate diagnosis and treatment.

refere nces

Fig. 9 – Radiation therapy results in esophageal ulcers. The lamina propria contains scattered enlarged fibroblasts with smudgy chromatin (H&E, 100
).

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