Dig Dis Sci DOI 10.1007/s10620-015-3590-3
ORIGINAL ARTICLE
Esophagitis Dissecans Superficialis: Clinical, Endoscopic, and Histologic Features Phil A. Hart • Ryan C. Romano • Roger K. Moreira Karthik Ravi • Seth Sweetser
•
Received: 17 November 2014 / Accepted: 13 February 2015 Ó Springer Science+Business Media New York 2015
Abstract Background Esophagitis dissecans superficialis (EDS) is a desquamative disorder of the esophagus, but there is a paucity of the literature regarding this condition. Aim We examined our institution’s experience to further characterize clinical outcomes, and endoscopic and histopathologic features. Methods Endoscopy and pathology databases were retrospectively reviewed from 2000 to 2013 at Mayo Clinic Rochester to identify potential cases of EDS. Medical records and endoscopic images were reviewed to identify cases, and original pathologic specimens were also reviewed. Clinical, endoscopic, and histologic characteristics of EDS were defined. Results Forty-one subjects were identified with a median age at diagnosis of 65.0 years (IQR 52.8–76.1) and a female preponderance (63.4 %). Many patients were taking a
psychoactive agent (73.1 %) or acid-suppressive therapy (58.5 %) preceding the index endoscopy. Strips of sloughed membranes had a predilection for the distal and/ or middle esophagus and resolved in 85.7 % of subjects at endoscopic follow-up. Parakeratosis and intraepithelial splitting were histologic features seen in all patients, while splitting of the connective tissue and intraepithelial bullae were seen in 46.2 and 11.1 %, respectively. There were no disease-related complications at a median follow-up of 10.4 months (IQR 1.2–17.2). Conclusions EDS is likely under-recognized. A distinct endoscopic feature of EDS is ‘‘sloughing’’ strips of mucosa with parakeratosis and intraepithelial splitting being sine qua non histologic findings. The use of psychoactive agents (particularly a SSRI or SNRI) was prevalent at endoscopic diagnosis, although the clinical relevance of this is uncertain. EDS appears to be a benign, incidental finding without complications. Keywords Sloughing esophagitis Intraepithelial splitting Parakeratosis Esophageal membrane
Electronic supplementary material The online version of this article (doi:10.1007/s10620-015-3590-3) contains supplementary material, which is available to authorized users. P. A. Hart K. Ravi S. Sweetser (&) Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected] P. A. Hart Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA R. C. Romano R. K. Moreira Department of Pathology, Mayo Clinic, Rochester, MN, USA
JEL Classification 6.7: non-reflux esophageal disorders 6.5: EGD: NSAIDs, clinical studies 22.1: EGD; upper endoscopy Abbreviations EDS Esophagitis dissecans superficialis ELP Esophageal lichen planus EoE Eosinophilic esophagitis NSAID Non-steroidal anti-inflammatory drug SNRI Serotonin and norepinephrine reuptake inhibitor SSRI Serotonin receptor uptake inhibitor TCA Tricyclic antidepressant
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Introduction Esophagitis dissecans superficialis (EDS) is a desquamative disorder of the esophagus, in which there is sloughing of the superficial mucosa. Endoscopically, EDS is characterized by sheets of sloughed squamous tissue with normal underlying mucosa. Rarely, patients can develop esophageal casts that can obliterate the esophageal lumen and cause obstructive symptoms [1–3]. Previous reports have also used terminology including ‘‘chronic esophagitis dissecans’’ or simply ‘‘esophagitis dissecans’’ to describe EDS. A recent description of a series of 31 patients with ‘‘sloughing esophagitis’’ attempted to differentiate this entity from EDS; however, these terms have been used interchangeably [4]. A variety of systemic diseases, including pemphigus vulgaris [5, 6], celiac disease [7], coronary artery disease [4], and chronic kidney disease [4], have been associated with EDS. Likewise, medications known to cause topical injury have been implicated as potential causative agents including NSAIDs [4, 8, 9], bisphosphonates [2, 10, 11], and other agents including potassium chloride [4] and iron [4]. However, to date, there are less than 100 reported cases of EDS (and sloughing esophagitis) in the published literature. Consequently, accurate characterizations regarding the clinical presentation, etiology, and clinical outcomes are lacking. We set out to more fully define EDS by detailing patient characteristics, disease associations, and subsequent clinical outcomes for patients with this condition. Anticipating a high frequency of overlooked diagnoses, considering its relatively recent description, we systematically reviewed both our endoscopy and pathology databases to identify all potential cases. Herein, we describe our institution’s experience with diagnosis and follow-up of EDS.
Methods This study protocol was approved by the Mayo Clinic Institutional Review Board. Case Identification We sought to identify all patients with EDS who underwent endoscopic evaluation at Mayo Clinic Rochester from January 1, 2000, to December 31, 2013. Since many cases were anticipated to be retrospective diagnoses, we attempted to identify cases through several methods (Fig. 1). First, clinical notes were electronically searched for a final diagnosis of EDS (i.e., prospectively diagnosed). Next, an institutional endoscopy database containing all reports and
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captured images was searched. The database was queried for all upper endoscopies (i.e., esophagogastroduodenoscopies) performed during the study period with one of the following keywords in the procedural report: slough*, esophagitis dissecans, esophagitis dissecans superficialis, or sloughing esophagitis. Endoscopy reports and images were then independently reviewed by two investigators (PAH and SRS) and selected if they were potentially consistent with EDS. Discrepancies were reconciled by mutual discussion and, if needed, discussion with a third investigator (KR). Finally, the Mayo Clinic Rochester pathology database was queried for a final diagnosis of ‘‘esophagitis dissecans,’’ ‘‘esophagitis dissecans superficialis,’’ or ‘‘sloughing esophagitis.’’ In the absence of diagnostic criteria for EDS, we generated an a priori list of diagnostic endoscopic features based on our review of existing case series [4, 8, 9, 12]. All three of the following criteria were required for inclusion in the study: (1) strip(s) of sloughed esophageal mucosa [2 cm in length; (2) normal underlying esophageal mucosa; and (3) lack of ulcerations or friability of immediately adjacent esophageal mucosa. Endoscopy reports and clinical records were reviewed to determine alternate explanations for the findings. For example, sloughed mucosa not observed during esophageal intubation, but apparent following small bowel enteroscopy, was felt to be iatrogenic and not included. There were no cases that occurred following a caustic or thermal ingestion. Similarly, the histologic diagnostic criteria for EDS are not established. Consequently, histologic features previously described as consistent with EDS, including (1) parakeratosis [4, 8, 9], (2) intraepithelial splitting at varying degrees above the basal layer, occasionally associated with distinct intraepithelial bullae [4, 8, 9, 12], (3) minimal to no inflammation [4, 9, 12], and/or (4) unusually long, detached fragments of superficial epithelium [9], were evaluated (Fig. 2 and supplemental figure). Data Collection Data were retrospectively obtained through review of the patient’s medical records, endoscopy reports/images, and review of original pathology specimens. The indication(s) for the procedure was identified through review of clinical documentation of patient symptoms at the time of the index endoscopy. Medications used in the 30 days prior to the date of endoscopy were obtained from review of the clinical notes and often from a medication review performed by an endoscopy nurse on the date of endoscopy. Records were reviewed through December 31, 2013, for endoscopic follow-up.
Dig Dis Sci Fig. 1 Study participant flow diagram
Fig. 2 Prominent parakeratosis is noted in the upper 1/3 of the epithelium, characterized by retained keratinocyte nuclei oriented parallel to the surface (a). A transition in color between the parakeratotic layer and the underlying epithelium is also seen. Long detached fragments of superficial epithelium lacking a basal layer, some with a necrotic edge, are characteristic of EDS (b).
Parakeratosis with early degenerative change in the superficial epithelium and longitudinal intraepithelial splitting (c). A clear transition between the areas of cystic degeneration and eventual detached epithelium is sometimes evident (d) (hematoxylin and eosin stain, a–d; original magnification: a, d, 940; b, 910; c, 920)
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For the purposes of this study, diabetes mellitus was diagnosed according to the American Diabetes Association definition (hemoglobin A1c C 6.5 % or fasting blood glucose C126 mg/dL on two occasions). Subjects were considered to have coronary artery disease if they had disease that previously necessitated revascularization with either percutaneous coronary intervention or coronary artery bypass grafting.
Results Baseline Study Characteristics and Disease Associations
Table 1 Frequency of medication use in subjects with esophagitis dissecans superficialis during the 30 days preceding the index upper endoscopy Medications
Psychoactive (any)
Concurrent Medication Usage Selected medications used preceding diagnosis are displayed in Table 1 (A comprehensive list of medications used prior to the index endoscopy is provided in the Supplemental Table). Twenty-four (58.5 %) patients were taking either an H2-receptor antagonist and/or a proton pump inhibitor (PPI) prior to the endoscopy. Initiation of a PPI was recommended for 6/17 of subjects not taking this at the time of endoscopy. The use of a medication strongly associated with pill-induced esophagitis (e.g., potassium chloride, iron, or a bisphosphonate) was found in 12 subjects (one subject was using both potassium chloride and iron). More than one-third of patients were taking aspirin (81 or 325 mg daily), and an additional three subjects used an NSAID other than aspirin. The most commonly used medications were psychoactive drugs with usage in 73.1 % of subjects; more than half of the study population was using a selective serotonin receptor uptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI). Lastly, antibiotics were used in 22.0 % of subjects, with penicillin-based medications constituting the vast majority.
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% of total study population (n = 41)
30
73.2
21
51.2
TCA
9
22.0
Gaba-oid (gabapentin or pregabalin)
7
17.1
Antiepileptic
2
4.9
Atypical antipsychotic
2
4.9
Serotonin 5-HT1B, 1D receptor agonist (rizatriptan)
1
2.4
SSRI or SNRI
Other
We identified a total of 41 cases of EDS during the study period. The median age of patients at the time of the index endoscopy was 65.0 years (IQR 52.8–76.1), and only 7 (17.1 %) patients were younger than 40 years of age. Nearly two-thirds of subjects were female, and most subjects (97.2 %) were white, which reflects the racial demographics of the study site. Evaluation for celiac disease with either serologies (n = 10) or duodenal biopsies (n = 15) was positive in a single patient who was already known to have celiac disease prior to their index endoscopy. Coronary artery disease (7, 17.1 %) and diabetes mellitus (6, 14.6 %) were rarely identified. One patient was undergoing chemotherapy for metastatic sarcoma. No patients had a bullous skin or chronic kidney disease.
n
4
9.8
25
61.0
Potassium chloride (KCl)
7
17.1
Iron (any form)
4
9.8
Vitamin C
4
9.8
Vitamin (any)
Magnesium Non-selective NSAIDs, antiplatelets, and anticoagulants (any) Aspirin (81 or 325 mg)
1
2.4
25
61.0
15
36.6
Non-ASA NSAIDa
7
17.1
Prednisone
4
9.8
Clopidogrel
1
2.4
Other—heparin, coumadin, dabigatran
6
14.6
Gastric acid protective (any)
24
58.5
Proton pump inhibitor
24
58.5
H2 blocker
4
9.8
Sucralfate
1
2.4
24
58.5
Beta-blocker
14
34.1
Diuretic (loop or thiazide)
14
34.1
Calcium channel blocker
12
29.3
ACE inhibitor/angiotensinogen receptor blocker
10
24.4
Antiarrhythmic
5
12.2
Nitrate
3
7.3
2 17
4.9 41.5
Opioid agonist
9
22.0
Benzodiazepine
8
19.5
Muscle relaxant (baclofen or cyclobenzaprine)
3
7.3
Cardiac and antihypertensive (any)
Other antihypertensive Analgesic/sedative (any)
Hypnotic (eszopiclone or zolpidem)
3
7.3
13
31.7
Statin
9
22.0
Fibrate
3
7.3
Ezetimibe
1
2.4
Antihyperlipemic (any)
Dig Dis Sci Table 1 continued Medications
Antimicrobial (any)
n
% of total study population (n = 41)
Table 2 Endoscopic features for 41 subjects diagnosed with esophagitis dissecans superficialis n Indication(s) for EGDa
9
22.0
Abdominal pain/dyspepsia
20
48.8
Penicillin derivative
4
9.8
Heartburn
17
41.5
Antiviral
2
4.9
Dysphagia
15
36.7
Fluconazole
1
2.4
Regurgitation
8
19.5
Other antibiotic
4
9.8
Anemia/melena
5
12.5
6
14.6
Metformin
4
9.8
Diarrhea Chest pain
4 3
9.8 7.3
Insulin
2
4.9
Otherb
10
24.4
2
4.9
Outpatient status
33
80.4
Antidiabetic medication (any)
Bisphosphonate
Bold values indicate the cumulative number/% of patients taking any medication from the respective drug classes
Endoscopic findings
Selected medications are listed according to major drug categories. Only medications of potential interest are displayed, so the sums do not equal drug category subtotals NSAID non-steroidal anti-inflammatory drug, SNRI serotonin and norepinephrine reuptake inhibitor, SSRI serotonin receptor uptake inhibitor, TCA tricyclic antidepressant a
%
Distribution of sloughed membranes
41
Proximal third
12/37
100 32.4
Middle third
30/38
78.9
Distal third
28/38
73.4
2–5 cm long
5
12.2
[5 cm long
1
2.4
Hiatal hernia
Includes diclofenac, etodolac, ibuprofen, meloxicam, and piroxicam a
Endoscopy Features and Diagnostic Testing Upper endoscopies were performed for a variety of indications, with abdominal pain/dyspepsia, heartburn, and dysphagia being the most common (Table 2). The majority of procedures revealing a diagnosis of EDS were performed in the outpatient setting. Vertical strips of mucosal sloughing were a requisite for study inclusion and, therefore, identified in all patients in this series. The underlying mucosa was normal appearing without suggestion of esophagitis, although two subjects had LA grade A reflux esophagitis. When the location of EDS was detailed (n = 38), the middle and/or distal one-third of the esophagus was most common; only one subject had membranes isolated to the proximal esophagus. Diagnostic evaluation for Candida sp. with either brushings or biopsies was performed in 31 (75.6 %) subjects and was positive in four patients. Each of these four subjects with Candida esophagitis had the typical white exudates in addition to the classic endoscopic feature of sloughed strips of mucosa of EDS. Otherwise, the presence of a hiatal hernia (14.6 %) was uncommon, and Barrett’s esophagus and esophageal strictures were not observed. At the time of endoscopy, EDS was entertained as a potential etiology by the performing endoscopist for 17 (41.5 %) of subjects. Eosinophilic esophagitis, esophageal lichen planus, Candida esophagitis, and an ‘‘unknown’’ etiology were the postprocedural diagnoses in 4, 1, 2, and 17 cases, respectively. Fungal testing was negative for both of the cases with Candida esophagitis listed as the postprocedural endoscopic diagnosis.
19 subjects had [1 indication for their EGD Other indications listed in \3 subjects included vomiting, nausea, cough, and weight loss b
None of the seven subjects who underwent a diagnostic barium esophagram either immediately prior to or following their index endoscopy had an esophageal stricture. Esophageal manometry testing was performed in six patients and demonstrated a major motor abnormality (i.e., achalasia) in only one subject while the remaining studies were normal or showed non-specific esophageal dysmotility. Histologic Features of Esophagitis Dissecans Esophageal biopsies were available for review from 36 subjects. Parakeratosis was observed in all cases, and basal cell hyperplasia was seen in 18 (50.0 %) cases. Long strips of surface epithelium were frequently identified (26/36, 72.2 %), including many which showed a distinct necrotic edge (18/36, 50.0 %). Despite the lack of inflammatory changes of the mucosa endoscopically, an inflammatory infiltrate (typically focal) was seen in 18 subjects. The focal infiltrates included 4 (11.1 %) cases of chronic inflammation, 5 (13.9 %) cases with focal activity (neutrophilic infiltrate), 6 (16.7 %) cases with scattered eosinophils (\15 per high-power field), and 3 (8.3 %) cases with a mixed active and eosinophilic inflammation. An eosinophilic infiltration ([15 eosinophils per high-power field) was only seen in one subject (who had a maximum of
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20 eosinophils per high-power field) despite the absence of endoscopic features consistent with EoE. Intraepithelial splitting was observed in 31 (86.1 %) cases with distinct bullae or cystic degeneration seen in 9 (25.0 %) cases. Clinical Follow-up A total of 14 (34.1 %) subjects underwent a follow-up endoscopy a median 4.6 months (IQR 1.8–13.4) following the index endoscopy. The sloughing membranes resolved in most subjects (12/14, 85.7 %) at follow-up. None of the patients in our study developed an esophageal stricture or malignancy during a median 10.4 months (IQR 1.2–17.2) of clinical follow-up.
Discussion We further characterized the clinical, endoscopic, and histologic features of EDS in a relatively large cohort of 41 subjects. EDS was most common in middle-aged women. Patients underwent endoscopy for a variety of symptoms, so it is uncertain whether these symptoms are truly related to the esophageal pathology, or whether the esophageal findings are purely incidental. Despite previous reports, the rates of exposure to bisphosphonates and NSAIDs (other than aspirin) were low. Conversely, there was high usage of psychoactive medications (primarily SSRI or SNRI’s) preceding diagnosis. Endoscopic abnormalities resolved in the vast majority of those undergoing endoscopic followup, and there were no immediate complications such as esophageal stricture or cancer. In this series, EDS was considered at the time of endoscopy in a minority of patients (41.5 %) despite characteristic findings, suggesting poor clinical recognition even in a tertiary care center. The sloughed sheets often typically appear as multiple columns of strips (Fig. 3). The strips were most commonly seen in the distal and/or middle third of the esophagus and less commonly involved the proximal portion of the esophagus. Sheets typically peeled off (prior to esophageal intubation) in the proximal to distal direction, with persistent attachment at the distal-most aspect of the tissue sheet. We did not observe the presence of rings (such as seen in eosinophilic esophagitis), but there were a small number of instances in which the sloughed mucosa crumpled giving the suggestion of a ring-like appearance. Although prior case reports have described esophageal casts and esophageal strictures at the time of presentation, we did not observe these findings. In a few cases, EDS was misdiagnosed, resulting in unnecessary treatment. The differential diagnosis of EDS is important to consider (Fig. 4), and if there is diagnostic doubt, then biopsies (and/or brushings) should be obtained.
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EDS was most commonly confused with Candida esophagitis. The isolated white exudates of Candida esophagitis are endoscopically distinct from EDS, but with more severe Candida infection, the exudates become confluent and can potentially mimic EDS. However, careful endoscopic inspection will reveal a rough surface appearance of the Candida exudates with absence of ‘‘sloughing’’ as characteristically seen in EDS. It is important to note that Candida can occur concurrently with EDS (12.9 % in our series), further emphasizing the need to obtain samples if the diagnosis is in question. The white plaques seen in esophageal lichen planus (ELP) have a plaque-like appearance, rather than the normal-appearing thin sheets of epithelium in EDS. In addition, the presence of a proximal esophageal stricture, narrow-caliber esophagus, or extraesophageal manifestations of lichen planus would strongly favor ELP. Other entities that should not be confused with EDS due to the consequences of delayed diagnosis include graft-versus-host disease and squamous cell carcinoma, particularly verrucous carcinoma. The histopathologic features of EDS (also interchangeably referred to as ‘‘sloughing esophagitis’’ in the pathology literature) are relatively non-specific when considered individually, but the constellation of microscopic findings seen in typical cases is quite characteristic of this entity. Parakeratosis was the most common histologic finding in this series. Although this is a relatively common feature (it is also seen in cases of chemical or thermal injury, medication-induced mucosal damage, gastroesophageal reflux disease, esophageal lichen planus, prolonged intubation, achalasia, and fungal infections), it is usually associated with histologic evidence of pauci-inflammatory intraepithelial sloughing in cases of EDS. The main histologic challenge in suspected cases of EDS is distinguishing true intraepithelial splitting occurring in vivo from artifactual epithelial disruption that is commonly seen as a result of mucosal instrumentation during the endoscopic procedure, tissue handling during gross examination, or tissue sectioning during processing. Several cases showed a spectrum of changes that unequivocally indicated ‘‘true’’ intraepithelial splitting rather than various forms of artifact. In some cases, numerous small intraepithelial clefts (generally within the mid-portion to upper third of the epithelial layer, filled with either proteinaceous fluid or various amounts of inflammatory cells and cellular debris) (Supplemental figure) were present adjacent to larger cystic areas that were often contiguous with sloughing, long strips of epithelium (usually relatively uniform in thickness and devoid of a basal layer) (Fig. 2b). Tissue necrosis of the epithelial strips, with or without associated bacterial or fungal colonies, was also frequently observed, indicating unequivocal evidence of epithelial injury (Fig. 2b) [9]. In the majority of cases in
Dig Dis Sci
Fig. 3 Representative endoscopic images of esophagitis dissecans superficialis. Typical features include long sheets of denuded, or ‘‘sloughed,’’ mucosa with normal underlying mucosa. Strips typically occur in multiple vertical columns, but may also occur with a more intact appearance
which necrosis was identified and histologic orientation was sufficiently preserved, the necrosis appeared to be confined primarily to the basal aspect of the fragment of the epithelium (along the cleavage plane), whereas colonization by microorganisms occurred primarily along the luminal aspect. In several cases, a clear transition from viable squamous epithelium to necrotic epithelium was also evident (Fig. 2d). Finally, both epithelial strips and cystic areas showed, in several cases, evidence of a ‘‘necrotic edge’’ (i.e., a thin border of necrotic-appearing tissue
occurring along the plane of epithelial cleavage)—also indicative of previous injury. We recommend the term ‘‘intraepithelial cystic degeneration’’ to describe the above spectrum of histologic changes that are characteristic of EDS in the appropriate clinical context. Since previous series describing EDS have been relatively small (only one series had [20 subjects), the accuracy of associated conditions and medication usage is not validated. Despite careful searching for the previously reported disease associations, these conditions (coronary
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Fig. 4 Diseases with a similar endoscopic appearance to esophagitis dissecans superficialis include esophageal lichen planus (a), eosinophilic esophagitis with microabscesses (b), Candida esophagitis (c),
graft-versus-host disease (d), squamous cell carcinoma in situ (e), and verrucous squamous cell carcinoma of the esophagus (f)
artery disease and celiac disease) were seen in a minority of subjects. Likewise, many previous reports have associated EDS with medication ingestion, with proposed mechanisms of disease, including topical injury and a medicationinduced defect of mucosal adhesion [13]. We found that almost three-fourths of individuals were using some form of psychoactive agent, with over one-half using an SSRI or SNRI. A biologically plausible explanation for how this would contribute to esophageal mucosal injury is not available, suggesting that this may simply reflect underlying functional bowel disorders, which frequently prompt endoscopic evaluation. Conversely, medications known to
cause pill-induced esophagitis were used by a minority of subjects, and, even in these cases, there was no evidence of focal esophagitis suggesting topical injury. Previous associations with NSAID use (other than aspirin), bisphosphonates, and antibiotics were not observed in our series. EDS is assumed to have a benign natural history. Aside from coexisting esophageal strictures in a small number of patients, there have been no other esophageal complications reported. None of our patients had an esophageal stricture at presentation or during follow-up. Moreover, in the majority with a follow-up endoscopy, there was
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complete resolution of the endoscopic sloughing. Unfortunately, due to the retrospective nature of the study, repeat endoscopies were not available for all patients. Likewise, barium esophagram and esophageal manometries were only performed in a small number of subjects, so we are unable to make any definitive conclusions regarding the potential role of underlying esophageal dysmotility. Notably, manometry studies demonstrated underlying achalasia and scleroderma esophagus in three patients, so further systematic evaluation of motility abnormalities as a potential contributing factor to the development of EDS may be warranted. Diagnostic criteria for EDS have not been established, although its various features have been described. Based on our review of published case series and the current study, we propose that EDS is a clinicopathologic diagnosis. Since the most common histologic features (parakeratosis and intraepithelial splitting) are non-specific, we believe the major diagnostic criterion should be the endoscopic appearance of the esophageal mucosa. Fulfillment of the three following endoscopic criteria is consistent with EDS: (1) strip(s) of sloughed esophageal mucosa [2 cm in length; (2) normal underlying esophageal mucosa; and (3) lack of ulcerations or friability of immediately adjacent esophageal mucosa. Biopsies may not be necessary for all patients, particularly when endoscopic features are classic and no esophageal symptoms are present. However, biopsies (and potentially brushings) are indicated for those in which the endoscopic features are not typical, esophageal symptoms are present (especially to evaluate for esophageal eosinophilia), or there is a question regarding a coexisting diagnosis. In conclusion, the prevalence of EDS is likely underestimated and it is frequently misdiagnosed. However, with increased diagnostic awareness, it can easily be identified and discriminated from other esophageal mucosal abnormalities. Recognition of EDS is important, as misdiagnosis can lead to unwarranted and expensive investigations and unnecessary therapy. When there is doubt or question of coexisting diseases, histology can provide supportive evidence and rule out other conditions. Medication use may or
may not play a pathogenic role, but if it does, the mechanism is not readily apparent. EDS appears to have a benign natural history, with frequent resolution of endoscopic abnormalities, suggesting that EDS is often an incidental finding. Conflict of interest
None.
References 1. Beck RN. Oesophagitis dissecans superficialis. Br Med J. 1954;1:501–502. 2. Cameron RB. Esophagitis dissecans superficialis and alendronate: case report. Gastrointest Endosc. 1997;46:562–563. 3. Perez-Carreras M, Castellano G, Colina F, et al. Esophagitis dissecans superficialis (esophageal cast) complicating esophageal sclerotherapy. Am J Gastroenterol. 1998;93:655–656. 4. Purdy JK, Appelman HD, McKenna BJ. Sloughing esophagitis is associated with chronic debilitation and medications that injure the esophageal mucosa. Mod Pathol. 2012;25:767–775. 5. Kaplan RP, Touloukian J, Ahmed AR, Newcomer VD. Esophagitis dissecans superficialis associated with pemphigus vulgaris. J Am Acad Dermatol. 1981;4:682–687. 6. Cesar WG, Barrios MM, Maruta CW, et al. Oesophagitis dissecans superficialis: an acute, benign phenomenon associated with pemphigus vulgaris. Clin Exp Dermatol. 2009;34:e614–e616. 7. Hage-Nassar G, Rotterdam H, Frank D, Green PH. Esophagitis dissecans superficialis associated with celiac disease. Gastrointest Endosc. 2003;57:140–141. 8. Albert DM, Ally MR, Moawad FJ. The sloughing esophagus: a report of five cases. Am J Gastroenterol. 2013;108:1816–1817. 9. Carmack SW, Vemulapalli R, Spechler SJ, Genta RM. Esophagitis dissecans superficialis (‘‘sloughing esophagitis’’): a clinicopathologic study of 12 cases. Am J Surg Pathol. 2009;33:1789–1794. 10. Hokama A, Ihama Y, Nakamoto M, et al. Esophagitis dissecans superficialis associated with bisphosphonates. Endoscopy. 2007;39(Suppl 1):E91. 11. Longman RS, Remotti H, Green PH. Esophagitis dissecans superficialis. Gastrointest Endosc. 2011;74:403–404. 12. Ponsot P, Molas G, Scoazec JY, et al. Chronic esophagitis dissecans: an unrecognized clinicopathologic entity? Gastrointest Endosc. 1997;45:38–45. 13. Coppola D, Lu L, Boyce HW Jr. Chronic esophagitis dissecans presenting with esophageal strictures: a case report. Hum Pathol. 2000;31:1313–1317.
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ORIGINAL ARTICLE
Esophagitis Dissecans Superficialis: Clinical, Endoscopic, and Histologic Features Phil A. Hart • Ryan C. Romano • Roger K. Moreira Karthik Ravi • Seth Sweetser
•
Received: 17 November 2014 / Accepted: 13 February 2015 Ó Springer Science+Business Media New York 2015
Abstract Background Esophagitis dissecans superficialis (EDS) is a desquamative disorder of the esophagus, but there is a paucity of the literature regarding this condition. Aim We examined our institution’s experience to further characterize clinical outcomes, and endoscopic and histopathologic features. Methods Endoscopy and pathology databases were retrospectively reviewed from 2000 to 2013 at Mayo Clinic Rochester to identify potential cases of EDS. Medical records and endoscopic images were reviewed to identify cases, and original pathologic specimens were also reviewed. Clinical, endoscopic, and histologic characteristics of EDS were defined. Results Forty-one subjects were identified with a median age at diagnosis of 65.0 years (IQR 52.8–76.1) and a female preponderance (63.4 %). Many patients were taking a
psychoactive agent (73.1 %) or acid-suppressive therapy (58.5 %) preceding the index endoscopy. Strips of sloughed membranes had a predilection for the distal and/ or middle esophagus and resolved in 85.7 % of subjects at endoscopic follow-up. Parakeratosis and intraepithelial splitting were histologic features seen in all patients, while splitting of the connective tissue and intraepithelial bullae were seen in 46.2 and 11.1 %, respectively. There were no disease-related complications at a median follow-up of 10.4 months (IQR 1.2–17.2). Conclusions EDS is likely under-recognized. A distinct endoscopic feature of EDS is ‘‘sloughing’’ strips of mucosa with parakeratosis and intraepithelial splitting being sine qua non histologic findings. The use of psychoactive agents (particularly a SSRI or SNRI) was prevalent at endoscopic diagnosis, although the clinical relevance of this is uncertain. EDS appears to be a benign, incidental finding without complications. Keywords Sloughing esophagitis Intraepithelial splitting Parakeratosis Esophageal membrane
Electronic supplementary material The online version of this article (doi:10.1007/s10620-015-3590-3) contains supplementary material, which is available to authorized users. P. A. Hart K. Ravi S. Sweetser (&) Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected] P. A. Hart Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA R. C. Romano R. K. Moreira Department of Pathology, Mayo Clinic, Rochester, MN, USA
JEL Classification 6.7: non-reflux esophageal disorders 6.5: EGD: NSAIDs, clinical studies 22.1: EGD; upper endoscopy Abbreviations EDS Esophagitis dissecans superficialis ELP Esophageal lichen planus EoE Eosinophilic esophagitis NSAID Non-steroidal anti-inflammatory drug SNRI Serotonin and norepinephrine reuptake inhibitor SSRI Serotonin receptor uptake inhibitor TCA Tricyclic antidepressant
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Introduction Esophagitis dissecans superficialis (EDS) is a desquamative disorder of the esophagus, in which there is sloughing of the superficial mucosa. Endoscopically, EDS is characterized by sheets of sloughed squamous tissue with normal underlying mucosa. Rarely, patients can develop esophageal casts that can obliterate the esophageal lumen and cause obstructive symptoms [1–3]. Previous reports have also used terminology including ‘‘chronic esophagitis dissecans’’ or simply ‘‘esophagitis dissecans’’ to describe EDS. A recent description of a series of 31 patients with ‘‘sloughing esophagitis’’ attempted to differentiate this entity from EDS; however, these terms have been used interchangeably [4]. A variety of systemic diseases, including pemphigus vulgaris [5, 6], celiac disease [7], coronary artery disease [4], and chronic kidney disease [4], have been associated with EDS. Likewise, medications known to cause topical injury have been implicated as potential causative agents including NSAIDs [4, 8, 9], bisphosphonates [2, 10, 11], and other agents including potassium chloride [4] and iron [4]. However, to date, there are less than 100 reported cases of EDS (and sloughing esophagitis) in the published literature. Consequently, accurate characterizations regarding the clinical presentation, etiology, and clinical outcomes are lacking. We set out to more fully define EDS by detailing patient characteristics, disease associations, and subsequent clinical outcomes for patients with this condition. Anticipating a high frequency of overlooked diagnoses, considering its relatively recent description, we systematically reviewed both our endoscopy and pathology databases to identify all potential cases. Herein, we describe our institution’s experience with diagnosis and follow-up of EDS.
Methods This study protocol was approved by the Mayo Clinic Institutional Review Board. Case Identification We sought to identify all patients with EDS who underwent endoscopic evaluation at Mayo Clinic Rochester from January 1, 2000, to December 31, 2013. Since many cases were anticipated to be retrospective diagnoses, we attempted to identify cases through several methods (Fig. 1). First, clinical notes were electronically searched for a final diagnosis of EDS (i.e., prospectively diagnosed). Next, an institutional endoscopy database containing all reports and
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captured images was searched. The database was queried for all upper endoscopies (i.e., esophagogastroduodenoscopies) performed during the study period with one of the following keywords in the procedural report: slough*, esophagitis dissecans, esophagitis dissecans superficialis, or sloughing esophagitis. Endoscopy reports and images were then independently reviewed by two investigators (PAH and SRS) and selected if they were potentially consistent with EDS. Discrepancies were reconciled by mutual discussion and, if needed, discussion with a third investigator (KR). Finally, the Mayo Clinic Rochester pathology database was queried for a final diagnosis of ‘‘esophagitis dissecans,’’ ‘‘esophagitis dissecans superficialis,’’ or ‘‘sloughing esophagitis.’’ In the absence of diagnostic criteria for EDS, we generated an a priori list of diagnostic endoscopic features based on our review of existing case series [4, 8, 9, 12]. All three of the following criteria were required for inclusion in the study: (1) strip(s) of sloughed esophageal mucosa [2 cm in length; (2) normal underlying esophageal mucosa; and (3) lack of ulcerations or friability of immediately adjacent esophageal mucosa. Endoscopy reports and clinical records were reviewed to determine alternate explanations for the findings. For example, sloughed mucosa not observed during esophageal intubation, but apparent following small bowel enteroscopy, was felt to be iatrogenic and not included. There were no cases that occurred following a caustic or thermal ingestion. Similarly, the histologic diagnostic criteria for EDS are not established. Consequently, histologic features previously described as consistent with EDS, including (1) parakeratosis [4, 8, 9], (2) intraepithelial splitting at varying degrees above the basal layer, occasionally associated with distinct intraepithelial bullae [4, 8, 9, 12], (3) minimal to no inflammation [4, 9, 12], and/or (4) unusually long, detached fragments of superficial epithelium [9], were evaluated (Fig. 2 and supplemental figure). Data Collection Data were retrospectively obtained through review of the patient’s medical records, endoscopy reports/images, and review of original pathology specimens. The indication(s) for the procedure was identified through review of clinical documentation of patient symptoms at the time of the index endoscopy. Medications used in the 30 days prior to the date of endoscopy were obtained from review of the clinical notes and often from a medication review performed by an endoscopy nurse on the date of endoscopy. Records were reviewed through December 31, 2013, for endoscopic follow-up.
Dig Dis Sci Fig. 1 Study participant flow diagram
Fig. 2 Prominent parakeratosis is noted in the upper 1/3 of the epithelium, characterized by retained keratinocyte nuclei oriented parallel to the surface (a). A transition in color between the parakeratotic layer and the underlying epithelium is also seen. Long detached fragments of superficial epithelium lacking a basal layer, some with a necrotic edge, are characteristic of EDS (b).
Parakeratosis with early degenerative change in the superficial epithelium and longitudinal intraepithelial splitting (c). A clear transition between the areas of cystic degeneration and eventual detached epithelium is sometimes evident (d) (hematoxylin and eosin stain, a–d; original magnification: a, d, 940; b, 910; c, 920)
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For the purposes of this study, diabetes mellitus was diagnosed according to the American Diabetes Association definition (hemoglobin A1c C 6.5 % or fasting blood glucose C126 mg/dL on two occasions). Subjects were considered to have coronary artery disease if they had disease that previously necessitated revascularization with either percutaneous coronary intervention or coronary artery bypass grafting.
Results Baseline Study Characteristics and Disease Associations
Table 1 Frequency of medication use in subjects with esophagitis dissecans superficialis during the 30 days preceding the index upper endoscopy Medications
Psychoactive (any)
Concurrent Medication Usage Selected medications used preceding diagnosis are displayed in Table 1 (A comprehensive list of medications used prior to the index endoscopy is provided in the Supplemental Table). Twenty-four (58.5 %) patients were taking either an H2-receptor antagonist and/or a proton pump inhibitor (PPI) prior to the endoscopy. Initiation of a PPI was recommended for 6/17 of subjects not taking this at the time of endoscopy. The use of a medication strongly associated with pill-induced esophagitis (e.g., potassium chloride, iron, or a bisphosphonate) was found in 12 subjects (one subject was using both potassium chloride and iron). More than one-third of patients were taking aspirin (81 or 325 mg daily), and an additional three subjects used an NSAID other than aspirin. The most commonly used medications were psychoactive drugs with usage in 73.1 % of subjects; more than half of the study population was using a selective serotonin receptor uptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI). Lastly, antibiotics were used in 22.0 % of subjects, with penicillin-based medications constituting the vast majority.
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% of total study population (n = 41)
30
73.2
21
51.2
TCA
9
22.0
Gaba-oid (gabapentin or pregabalin)
7
17.1
Antiepileptic
2
4.9
Atypical antipsychotic
2
4.9
Serotonin 5-HT1B, 1D receptor agonist (rizatriptan)
1
2.4
SSRI or SNRI
Other
We identified a total of 41 cases of EDS during the study period. The median age of patients at the time of the index endoscopy was 65.0 years (IQR 52.8–76.1), and only 7 (17.1 %) patients were younger than 40 years of age. Nearly two-thirds of subjects were female, and most subjects (97.2 %) were white, which reflects the racial demographics of the study site. Evaluation for celiac disease with either serologies (n = 10) or duodenal biopsies (n = 15) was positive in a single patient who was already known to have celiac disease prior to their index endoscopy. Coronary artery disease (7, 17.1 %) and diabetes mellitus (6, 14.6 %) were rarely identified. One patient was undergoing chemotherapy for metastatic sarcoma. No patients had a bullous skin or chronic kidney disease.
n
4
9.8
25
61.0
Potassium chloride (KCl)
7
17.1
Iron (any form)
4
9.8
Vitamin C
4
9.8
Vitamin (any)
Magnesium Non-selective NSAIDs, antiplatelets, and anticoagulants (any) Aspirin (81 or 325 mg)
1
2.4
25
61.0
15
36.6
Non-ASA NSAIDa
7
17.1
Prednisone
4
9.8
Clopidogrel
1
2.4
Other—heparin, coumadin, dabigatran
6
14.6
Gastric acid protective (any)
24
58.5
Proton pump inhibitor
24
58.5
H2 blocker
4
9.8
Sucralfate
1
2.4
24
58.5
Beta-blocker
14
34.1
Diuretic (loop or thiazide)
14
34.1
Calcium channel blocker
12
29.3
ACE inhibitor/angiotensinogen receptor blocker
10
24.4
Antiarrhythmic
5
12.2
Nitrate
3
7.3
2 17
4.9 41.5
Opioid agonist
9
22.0
Benzodiazepine
8
19.5
Muscle relaxant (baclofen or cyclobenzaprine)
3
7.3
Cardiac and antihypertensive (any)
Other antihypertensive Analgesic/sedative (any)
Hypnotic (eszopiclone or zolpidem)
3
7.3
13
31.7
Statin
9
22.0
Fibrate
3
7.3
Ezetimibe
1
2.4
Antihyperlipemic (any)
Dig Dis Sci Table 1 continued Medications
Antimicrobial (any)
n
% of total study population (n = 41)
Table 2 Endoscopic features for 41 subjects diagnosed with esophagitis dissecans superficialis n Indication(s) for EGDa
9
22.0
Abdominal pain/dyspepsia
20
48.8
Penicillin derivative
4
9.8
Heartburn
17
41.5
Antiviral
2
4.9
Dysphagia
15
36.7
Fluconazole
1
2.4
Regurgitation
8
19.5
Other antibiotic
4
9.8
Anemia/melena
5
12.5
6
14.6
Metformin
4
9.8
Diarrhea Chest pain
4 3
9.8 7.3
Insulin
2
4.9
Otherb
10
24.4
2
4.9
Outpatient status
33
80.4
Antidiabetic medication (any)
Bisphosphonate
Bold values indicate the cumulative number/% of patients taking any medication from the respective drug classes
Endoscopic findings
Selected medications are listed according to major drug categories. Only medications of potential interest are displayed, so the sums do not equal drug category subtotals NSAID non-steroidal anti-inflammatory drug, SNRI serotonin and norepinephrine reuptake inhibitor, SSRI serotonin receptor uptake inhibitor, TCA tricyclic antidepressant a
%
Distribution of sloughed membranes
41
Proximal third
12/37
100 32.4
Middle third
30/38
78.9
Distal third
28/38
73.4
2–5 cm long
5
12.2
[5 cm long
1
2.4
Hiatal hernia
Includes diclofenac, etodolac, ibuprofen, meloxicam, and piroxicam a
Endoscopy Features and Diagnostic Testing Upper endoscopies were performed for a variety of indications, with abdominal pain/dyspepsia, heartburn, and dysphagia being the most common (Table 2). The majority of procedures revealing a diagnosis of EDS were performed in the outpatient setting. Vertical strips of mucosal sloughing were a requisite for study inclusion and, therefore, identified in all patients in this series. The underlying mucosa was normal appearing without suggestion of esophagitis, although two subjects had LA grade A reflux esophagitis. When the location of EDS was detailed (n = 38), the middle and/or distal one-third of the esophagus was most common; only one subject had membranes isolated to the proximal esophagus. Diagnostic evaluation for Candida sp. with either brushings or biopsies was performed in 31 (75.6 %) subjects and was positive in four patients. Each of these four subjects with Candida esophagitis had the typical white exudates in addition to the classic endoscopic feature of sloughed strips of mucosa of EDS. Otherwise, the presence of a hiatal hernia (14.6 %) was uncommon, and Barrett’s esophagus and esophageal strictures were not observed. At the time of endoscopy, EDS was entertained as a potential etiology by the performing endoscopist for 17 (41.5 %) of subjects. Eosinophilic esophagitis, esophageal lichen planus, Candida esophagitis, and an ‘‘unknown’’ etiology were the postprocedural diagnoses in 4, 1, 2, and 17 cases, respectively. Fungal testing was negative for both of the cases with Candida esophagitis listed as the postprocedural endoscopic diagnosis.
19 subjects had [1 indication for their EGD Other indications listed in \3 subjects included vomiting, nausea, cough, and weight loss b
None of the seven subjects who underwent a diagnostic barium esophagram either immediately prior to or following their index endoscopy had an esophageal stricture. Esophageal manometry testing was performed in six patients and demonstrated a major motor abnormality (i.e., achalasia) in only one subject while the remaining studies were normal or showed non-specific esophageal dysmotility. Histologic Features of Esophagitis Dissecans Esophageal biopsies were available for review from 36 subjects. Parakeratosis was observed in all cases, and basal cell hyperplasia was seen in 18 (50.0 %) cases. Long strips of surface epithelium were frequently identified (26/36, 72.2 %), including many which showed a distinct necrotic edge (18/36, 50.0 %). Despite the lack of inflammatory changes of the mucosa endoscopically, an inflammatory infiltrate (typically focal) was seen in 18 subjects. The focal infiltrates included 4 (11.1 %) cases of chronic inflammation, 5 (13.9 %) cases with focal activity (neutrophilic infiltrate), 6 (16.7 %) cases with scattered eosinophils (\15 per high-power field), and 3 (8.3 %) cases with a mixed active and eosinophilic inflammation. An eosinophilic infiltration ([15 eosinophils per high-power field) was only seen in one subject (who had a maximum of
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20 eosinophils per high-power field) despite the absence of endoscopic features consistent with EoE. Intraepithelial splitting was observed in 31 (86.1 %) cases with distinct bullae or cystic degeneration seen in 9 (25.0 %) cases. Clinical Follow-up A total of 14 (34.1 %) subjects underwent a follow-up endoscopy a median 4.6 months (IQR 1.8–13.4) following the index endoscopy. The sloughing membranes resolved in most subjects (12/14, 85.7 %) at follow-up. None of the patients in our study developed an esophageal stricture or malignancy during a median 10.4 months (IQR 1.2–17.2) of clinical follow-up.
Discussion We further characterized the clinical, endoscopic, and histologic features of EDS in a relatively large cohort of 41 subjects. EDS was most common in middle-aged women. Patients underwent endoscopy for a variety of symptoms, so it is uncertain whether these symptoms are truly related to the esophageal pathology, or whether the esophageal findings are purely incidental. Despite previous reports, the rates of exposure to bisphosphonates and NSAIDs (other than aspirin) were low. Conversely, there was high usage of psychoactive medications (primarily SSRI or SNRI’s) preceding diagnosis. Endoscopic abnormalities resolved in the vast majority of those undergoing endoscopic followup, and there were no immediate complications such as esophageal stricture or cancer. In this series, EDS was considered at the time of endoscopy in a minority of patients (41.5 %) despite characteristic findings, suggesting poor clinical recognition even in a tertiary care center. The sloughed sheets often typically appear as multiple columns of strips (Fig. 3). The strips were most commonly seen in the distal and/or middle third of the esophagus and less commonly involved the proximal portion of the esophagus. Sheets typically peeled off (prior to esophageal intubation) in the proximal to distal direction, with persistent attachment at the distal-most aspect of the tissue sheet. We did not observe the presence of rings (such as seen in eosinophilic esophagitis), but there were a small number of instances in which the sloughed mucosa crumpled giving the suggestion of a ring-like appearance. Although prior case reports have described esophageal casts and esophageal strictures at the time of presentation, we did not observe these findings. In a few cases, EDS was misdiagnosed, resulting in unnecessary treatment. The differential diagnosis of EDS is important to consider (Fig. 4), and if there is diagnostic doubt, then biopsies (and/or brushings) should be obtained.
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EDS was most commonly confused with Candida esophagitis. The isolated white exudates of Candida esophagitis are endoscopically distinct from EDS, but with more severe Candida infection, the exudates become confluent and can potentially mimic EDS. However, careful endoscopic inspection will reveal a rough surface appearance of the Candida exudates with absence of ‘‘sloughing’’ as characteristically seen in EDS. It is important to note that Candida can occur concurrently with EDS (12.9 % in our series), further emphasizing the need to obtain samples if the diagnosis is in question. The white plaques seen in esophageal lichen planus (ELP) have a plaque-like appearance, rather than the normal-appearing thin sheets of epithelium in EDS. In addition, the presence of a proximal esophageal stricture, narrow-caliber esophagus, or extraesophageal manifestations of lichen planus would strongly favor ELP. Other entities that should not be confused with EDS due to the consequences of delayed diagnosis include graft-versus-host disease and squamous cell carcinoma, particularly verrucous carcinoma. The histopathologic features of EDS (also interchangeably referred to as ‘‘sloughing esophagitis’’ in the pathology literature) are relatively non-specific when considered individually, but the constellation of microscopic findings seen in typical cases is quite characteristic of this entity. Parakeratosis was the most common histologic finding in this series. Although this is a relatively common feature (it is also seen in cases of chemical or thermal injury, medication-induced mucosal damage, gastroesophageal reflux disease, esophageal lichen planus, prolonged intubation, achalasia, and fungal infections), it is usually associated with histologic evidence of pauci-inflammatory intraepithelial sloughing in cases of EDS. The main histologic challenge in suspected cases of EDS is distinguishing true intraepithelial splitting occurring in vivo from artifactual epithelial disruption that is commonly seen as a result of mucosal instrumentation during the endoscopic procedure, tissue handling during gross examination, or tissue sectioning during processing. Several cases showed a spectrum of changes that unequivocally indicated ‘‘true’’ intraepithelial splitting rather than various forms of artifact. In some cases, numerous small intraepithelial clefts (generally within the mid-portion to upper third of the epithelial layer, filled with either proteinaceous fluid or various amounts of inflammatory cells and cellular debris) (Supplemental figure) were present adjacent to larger cystic areas that were often contiguous with sloughing, long strips of epithelium (usually relatively uniform in thickness and devoid of a basal layer) (Fig. 2b). Tissue necrosis of the epithelial strips, with or without associated bacterial or fungal colonies, was also frequently observed, indicating unequivocal evidence of epithelial injury (Fig. 2b) [9]. In the majority of cases in
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Fig. 3 Representative endoscopic images of esophagitis dissecans superficialis. Typical features include long sheets of denuded, or ‘‘sloughed,’’ mucosa with normal underlying mucosa. Strips typically occur in multiple vertical columns, but may also occur with a more intact appearance
which necrosis was identified and histologic orientation was sufficiently preserved, the necrosis appeared to be confined primarily to the basal aspect of the fragment of the epithelium (along the cleavage plane), whereas colonization by microorganisms occurred primarily along the luminal aspect. In several cases, a clear transition from viable squamous epithelium to necrotic epithelium was also evident (Fig. 2d). Finally, both epithelial strips and cystic areas showed, in several cases, evidence of a ‘‘necrotic edge’’ (i.e., a thin border of necrotic-appearing tissue
occurring along the plane of epithelial cleavage)—also indicative of previous injury. We recommend the term ‘‘intraepithelial cystic degeneration’’ to describe the above spectrum of histologic changes that are characteristic of EDS in the appropriate clinical context. Since previous series describing EDS have been relatively small (only one series had [20 subjects), the accuracy of associated conditions and medication usage is not validated. Despite careful searching for the previously reported disease associations, these conditions (coronary
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Fig. 4 Diseases with a similar endoscopic appearance to esophagitis dissecans superficialis include esophageal lichen planus (a), eosinophilic esophagitis with microabscesses (b), Candida esophagitis (c),
graft-versus-host disease (d), squamous cell carcinoma in situ (e), and verrucous squamous cell carcinoma of the esophagus (f)
artery disease and celiac disease) were seen in a minority of subjects. Likewise, many previous reports have associated EDS with medication ingestion, with proposed mechanisms of disease, including topical injury and a medicationinduced defect of mucosal adhesion [13]. We found that almost three-fourths of individuals were using some form of psychoactive agent, with over one-half using an SSRI or SNRI. A biologically plausible explanation for how this would contribute to esophageal mucosal injury is not available, suggesting that this may simply reflect underlying functional bowel disorders, which frequently prompt endoscopic evaluation. Conversely, medications known to
cause pill-induced esophagitis were used by a minority of subjects, and, even in these cases, there was no evidence of focal esophagitis suggesting topical injury. Previous associations with NSAID use (other than aspirin), bisphosphonates, and antibiotics were not observed in our series. EDS is assumed to have a benign natural history. Aside from coexisting esophageal strictures in a small number of patients, there have been no other esophageal complications reported. None of our patients had an esophageal stricture at presentation or during follow-up. Moreover, in the majority with a follow-up endoscopy, there was
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complete resolution of the endoscopic sloughing. Unfortunately, due to the retrospective nature of the study, repeat endoscopies were not available for all patients. Likewise, barium esophagram and esophageal manometries were only performed in a small number of subjects, so we are unable to make any definitive conclusions regarding the potential role of underlying esophageal dysmotility. Notably, manometry studies demonstrated underlying achalasia and scleroderma esophagus in three patients, so further systematic evaluation of motility abnormalities as a potential contributing factor to the development of EDS may be warranted. Diagnostic criteria for EDS have not been established, although its various features have been described. Based on our review of published case series and the current study, we propose that EDS is a clinicopathologic diagnosis. Since the most common histologic features (parakeratosis and intraepithelial splitting) are non-specific, we believe the major diagnostic criterion should be the endoscopic appearance of the esophageal mucosa. Fulfillment of the three following endoscopic criteria is consistent with EDS: (1) strip(s) of sloughed esophageal mucosa [2 cm in length; (2) normal underlying esophageal mucosa; and (3) lack of ulcerations or friability of immediately adjacent esophageal mucosa. Biopsies may not be necessary for all patients, particularly when endoscopic features are classic and no esophageal symptoms are present. However, biopsies (and potentially brushings) are indicated for those in which the endoscopic features are not typical, esophageal symptoms are present (especially to evaluate for esophageal eosinophilia), or there is a question regarding a coexisting diagnosis. In conclusion, the prevalence of EDS is likely underestimated and it is frequently misdiagnosed. However, with increased diagnostic awareness, it can easily be identified and discriminated from other esophageal mucosal abnormalities. Recognition of EDS is important, as misdiagnosis can lead to unwarranted and expensive investigations and unnecessary therapy. When there is doubt or question of coexisting diseases, histology can provide supportive evidence and rule out other conditions. Medication use may or
may not play a pathogenic role, but if it does, the mechanism is not readily apparent. EDS appears to have a benign natural history, with frequent resolution of endoscopic abnormalities, suggesting that EDS is often an incidental finding. Conflict of interest
None.
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