Inflammatory lesions of the esophagus are a diverse group, often with nonspecific histologic findings. These benign changes can produce diagnostic difficulties for pathologists.
To discuss the typical histologic findings of a variety of the most common causes of esophagitis (reflux, eosinophilic esophagitis, infections, medications) along with less common issues such as sloughing esophagitis and skin disorders involving the squamous mucosa.
The literature has been reviewed to discuss histologic definitions of current and developing issues in the area of esophagitis.
Histologic features are not entirely sensitive and specific for inflammatory esophageal disorders. Awareness of these problems is essential; clinical and endoscopic information can be very useful in distinguishing among the various lesions.
Forms of esophagitis have been recognized for millennia; there is apparently a word for “heartburn” in Sumerian. The Greek physician Galen described the malady as kardialgia (heart pain), and the Romans developed antacids for treatment, consisting of powdered coral containing calcium carbonate. In the early 20th century, Bertram Sippy1 developed a bland diet of milk, cream, and pureed food taken with antacids to manage gastric acid, though his aim was to manage peptic ulcers. This was used to treat heartburn until the 1970s, when medical treatments, such as histamine blockers and eventually proton pump inhibitors, became available. These are now widely used; up to 30% of the North American population may suffer from weekly episodes of reflux.2 As suction biopsies and then endoscopic biopsies became more widespread starting in the 1970s, reflux-induced changes, including both damage to the squamous mucosa and the development of Barrett esophagus, were recognized. Since that time, we have become aware of a spectrum of inflammatory diseases of the esophagus, well beyond pure reflux esophagitis. Eosinophilic esophagitis (EoE), once thought to be purely a pediatric disorder, is now recognized in adults as an allergic, possibly diet-induced reaction. Lymphocytic esophagitis is now being singled out as a separate entity. A number of inflammatory disorders of the skin can involve the squamous mucosa of the esophagus, and we should always consider the possibility of inflammatory bowel disease and iatrogenic damage, that is, pill-induced esophagitis. In this review, the various etiologies and pathologies of esophagitis are considered.
The diagnosis of gastroesophageal reflux disease (GERD) is predominantly based on “troublesome” symptoms—when the classic symptoms of heartburn, retrosternal chest pain and dysphagia are no longer simply occasional physiologic issues but become detrimental to patient well-being.3 The diagnosis is empirically confirmed by response to lifestyle modifications and/or acid-suppression therapies. Patients may not undergo further clinical investigations (pH monitoring, manometry), endoscopy, or biopsy unless their symptoms persist, or if there are concerns about misdiagnosis or complications of reflux disease. On endoscopy, only a moderate proportion of patients with symptomatic reflux will show signs of mucosal damage by normal endoscopic methods (Figure 1, A), although those promoting newer methods of high-definition endoscopy have developed the term minimal change esophagitis for the slight mucosal changes seen in some cases of nonerosive reflux disease, including vascular injection and mild irregularities of the gastroesophageal junction and villous mucosal surface.4
Histology, in comparison with clinical evaluation techniques, has a relatively low sensitivity and specificity for GERD.5 The histologic diagnosis of GERD is based on papers written in the early days of endoscopic biopsies,6 and the parameters described are still in use today. The typical features of GERD are increased thickness of the basal cell layer; increased length of the papillae; intraepithelial inflammation, including eosinophils; and intercellular edema (spongiosis) (Figure 1, B).7 Although these findings may correlate with usual white-light endoscopy changes, the degree of histologic damage may not predict symptomatology.
Dilated intercellular spaces (DIS) may be the only histologic change seen in early or minimal GERD, defined as spaces larger than 2.5 μm, present diffusely in the basal and parabasal areas.8 Fiocca et al9 defined DIS as either “bubbles” or “ladder” patterns: bubbles were irregular round dilatations whereas ladders showed more diffuse widening crossed by the intercellular bridges; in the final analysis, these 2 criteria were collapsed into 1 DIS criterion. This study demonstrated reasonable interobserver correlation, though difficulties were noted in mild cases. Krugmann et al7 note that artifacts must be considered in the evaluation of DIS, and separated DIS into small intracellular spaces, less than the diameter of 1 lymphocyte, versus large spaces, larger than 1 lymphocyte in diameter.
Basal cell hyperplasia represents a reactive increase in the proliferative zone that normally is limited to the first 1 to 4 layers of cells just above the basement membrane (Figure 1, B). Basal cells have a high nuclear to cytoplasmic ratio compared with the maturing squamous cells above. Strictly defined, the basal layer extends to the point at which the nuclei are separated by a distance greater than the nuclear diameter9 or when 50% of the cells are separated by a distance less than the width of one nucleus.7 Generally, up to 15% of the total epithelial thickness is considered normal.9 Basal cell hyperplasia can be diagnosed when, either by measurement or by visual assessment, the thickness of the basal layer exceeds 15%. This should be assessed in well-oriented areas, as tangential sectioning may artifactually increase the basal layer thickness; areas close to papillae should also be avoided.
Papillary length should also be evaluated in a well-oriented area; if measuring this, the length is taken as the distance from the upper limit of the papillary vessel wall down to the basement membrane (or an approximation of the basal membrane with broad papillae) compared with the total epithelial thickness. Normally, papillae extend up no further than 50% of the epithelial thickness; extension above the midportion of the squamous mucosa indicates reactive changes.7
Normally, the squamous mucosa of the esophagus contains few or no inflammatory cells. Inflammatory infiltrates in GERD show considerable variability. Infiltrates in papillae should not be evaluated. In areas of erosions and mucosal breaks, clusters of neutrophils may be identified; large numbers of these in the superficial epithelium should suggest the possibility of fungal superinfection and trigger special stains to rule out Candida organisms. In GERD, lymphocytes are present scattered through the epithelium, often with an irregular contour as they are pressed between squamous cells (squiggle cells). Again, if numbers are high it is more suggestive of another disorder such as lichen planus or lymphocytic esophagitis (see later sections). The finding of occasional eosinophils is typical of GERD, with increased numbers raising the possibility of EoE. However, eosinophils are not found in all GERD biopsies and can be seen in asymptomatic patients,7,10,11 so this finding is neither specific nor sensitive. Granules from eosinophils, when the nucleus is not visible, should not be counted. Occasional mast cells may be identified.
The location of the biopsies must be considered: basal layer hyperplasia, elongation of the papillae, and occasionally eosinophils may be seen within 1 to 2 cm of the gastroesophageal junction, possibly as a result of physiologic reflux.12
The presence of erosions/ulcerations (necrosis, granulation tissue, fibrinopurulent debris) and areas of healing erosions with thinned regenerative epithelium overlying granulation tissue can also be included in the assessment.13 Changes to capillaries in papillae (dilation, congestion, extravasation of red blood cells) and damaged/ballooned squamous cells are described but are considered relatively soft findings for GERD.
Yerian et al,13 looking at interobserver variability in the assessment of GERD by experts in gastrointestinal pathology, found the strongest agreement for erosions, papillary elongation, and intraepithelial eosinophils. Basal cell hyperplasia and DIS showed lower agreement. They noted that further studies are needed to correlate histologic scoring with clinical symptoms and degree of acid reflux. Generally speaking, most pathologists do not evaluate these cases by strict counting of inflammatory cells or measurement of papillae and basal thickness, relying instead on a visual estimation of these lesions. A more strict interpretation of the diagnostic criteria and evaluation of these cases may become necessary if these future studies demonstrate the utility of a strict interpretation of GERD histologic scoring. Also, none of these features is specific for GERD; other causes such as EoE, infection, pill-induced/medication-induced esophagitis, inflammatory bowel disease, and inflammatory skin disorders involving the esophagus must be considered in the differential diagnosis.
The presence of increased intraepithelial eosinophils has been recognized for decades.16 Identified in both children and adults, it was generally considered to be a particularly marked form of GERD, though even in early publications, a link to allergies and atopy was noted in some patients. In the 1990s, EoE became recognized as a distinct disorder.17
The diagnosis of EoE is, essentially, a clinicopathologic diagnosis. Increased eosinophils in the esophagus are by no means specific to EoE. However, in the clinical setting of an otherwise nonspecific patient history and symptoms (allergies/atopy, vomiting, solid food dysphagia/impaction, lack of response to acid suppression) and endoscopic appearance (esophageal rings [Figure 1, C], edema, narrowing, longitudinal furrows and white dots/patches, mucosal fragility),18 typical histologic findings are of use. The squamous mucosa in EoE often has moderate to severe basal hyperplasia, more than that generally seen in GERD, so that on low power the epithelium appears quite hyperchromatic. Elongated papillae and DIS can be seen, similar to changes in GERD (Figure 1, B and D). The consensus on the number of intraepithelial eosinophils required to make the diagnosis of EoE is currently 15 eosinophils in at least one high-power field (Figure 1, D).19 Although this sounds quite specific, it must be noted that, although histologic studies on EoE have uniformly used ×400 as a high power field, there has been considerable variability in field size.20 This has led to suggestions that the count per square millimeter may be of more use.20 Only eosinophils where the nucleus is seen should be counted; isolated granules should not be included but may be a useful secondary clue to EoE.21,22 The findings may be patchy. It has been recommended that 2 to 4 biopsies from at least 2 locations in the esophagus be taken to maximize diagnostic yield; increased eosinophils may be seen in both proximal and distal biopsies or be more prominent in the proximal biopsies, in contrast to GERD where inflammation is usually more prominent in distal biopsies.19,23 Eosinophils are more common in the superficial layers of the squamous mucosa (surface layering) and may form microabscesses. Lamina propria fibrosis is common and may contribute to esophageal dysmotility.22 Other inflammatory cells such as lymphocytes and mast cells are often present; the number of mast cells can be significantly increased.21,22 Damage and sloughing of the surface squamous cells can also be seen. Various studies have evaluated the use of special stains to identify specific factors (ie, major basic protein, eotaxin-3); although these show promise, none are yet in clinical use.24
It is also now recognized that a proportion of patients who have clinical symptoms and signs as well as histologic patterns consistent with EoE will have a good response to acid suppression: proton-pump inhibitor–responsive esophageal eosinophilia.25 Whether or not this is a distinct disorder rather than severe GERD or a form of EoE with significant reflux is not yet known.
Aeroallergens are a significant cause of EoE, leading to treatment with swallowed corticosteroids. In some patients, food allergens play a role, as publications26,27 note both symptomatic and histologic improvement of both inflammation and fibrosis with dietary elimination therapy.
As noted above, the histologic appearance of EoE is not specific. At the time of endoscopy, biopsies of the stomach and duodenum should be taken, as eosinophilic gastroenteritis can cause significant increases in intraepithelial eosinophils in the mucosa more diffusely in the luminal tract. Other than GERD, the differential diagnosis should also include Crohn disease, connective tissue disorders, infections, and drug reactions.
Lymphocytic esophagitis is a diagnosis under recent discussion. It refers to the histologic pattern of significantly increased intraepithelial lymphocytes in the squamous mucosa, with few or no neutrophils and eosinophils.28 A significant proportion of the patients with lymphocytic esophagitis had Crohn disease, and some had celiac disease, which may predispose to increased intraepithelial lymphocytes throughout the gastrointestinal tract. Other patients presented with symptoms and endoscopic appearances highly suggestive of EoE.29 Haque et al29 note that asymptomatic patients can have mild increases in intraepithelial lymphocytes, up to 12 per high-power field; patients with Crohn disease had a mean of 5 intraepithelial lymphocytes per high-power field (up to 15 per high-power field). The lymphocytes tend to cluster around papillae, and are accompanied by DIS (Figure 2). Considering the lack of specificity of this description, it is not surprising that there is considerable overlap with GERD.30 This diagnosis may represent a general reactive change rather than a specific disorder.
SLOUGHING ESOPHAGITIS/ESOPHAGITIS DISSECANS SUPERFICIALIS
The histologic findings of sloughing esophagitis were reported in 2009,31 though the authors note that there were previous abstracts and cases where diagnosis was reported in clinical articles prior to this. These patients are noted by endoscopists to demonstrate peeling or sloughing off of the mucosa, with strips or sometimes entire casts of the epithelium coming loose. Patients tend to be elderly, ill, and on multiple medications. In this condition, the superficial portion of the squamous epithelium becomes necrotic, giving a two-tone appearance to the mucosa, with pyknosis resembling parakeratosis and necrosis of the superficial layers (Figure 3, A and B).32 The necrotic tissue sometimes separates from the viable squamous cells.32 This appearance is similar to that seen in bullous disorders involving the esophagus (see later section) and should be considered in the differential diagnosis. Neutrophilic infiltration is common and can be significant; therefore, superimposed infection must be ruled out.
CROHN DISEASE AFFECTING THE ESOPHAGUS
Although the paradigm of Crohn disease invokes inflammation from mouth to anus, involvement of the esophagus is relatively uncommon. It appears to be more common in pediatric patients.33,34 In most patients, this presents as subtle, nonspecific chronic inflammation (as in lymphocytic esophagitis, above) but it can also mimic GERD. Frank ulceration and granulomas are less common.
Particularly in elderly patients, pills can become impacted in the distal esophagus or at the level of the midesophagus by the aortic arch. This may be due to taking multiple medications with too little liquid, but may also be associated with age-related decreases in esophageal peristaltic motility. Mucosal damage can result from increased acidity or from direct toxic effects of the pill (ie, increased osmolality).35 Many drugs have been reported to cause mucosal damage (for a review, see Tutuian35 ); those most commonly implicated are antibiotics (especially of the tetracycline family), nonsteroidal anti-inflammatories, bisphosphonates, slow-release potassium medications, and iron supplements.36 Biopsies show acute inflammation and ulceration in a nonspecific pattern (Figure 4, A); if pill fragments are identified, this can aid in making a specific diagnosis (Figure 4, B). Sloughing esophagitis may be seen.
Candida is a common colonizer of the esophagus in healthy people. Overgrowth of Candida causing esophagitis occurs most commonly in immunosuppressed patients, particularly in the human immunodeficiency virus–infected population. In some patients, the Candida infection may be opportunistic, infecting areas of inflammation and ulceration from other causes.37,38 Cytologic brushings can be more useful than biopsies in the setting of Candida infection, where it has the same appearance as on Papanicolaou tests.37 On biopsies, a pattern of acute inflammation and reactive changes is seen. Candida spores and hyphae should be identified within fibrinopurulent debris and/or invading squamous epithelium to rule out the possibility of a component of the normal esophageal microbiota as a cause of damage (Figure 5, A). Special stains such as Gomori silver and periodic acid-Schiff–diastase may be of use in subtle cases.
Other infections most often seen in immune-compromised patients are herpes simplex and cytomegalovirus infections of the esophagus. Herpes simplex infection is also primarily seen in immune-compromised patients, often transplant patients, but is occasionally seen in otherwise healthy patients. Typical multinucleated cells with ground-glass nuclei and inclusions may be seen in the epithelium adjacent to areas of inflammation and ulceration (Figure 5, B). Cytomegalovirus rarely infects epithelial cells; the large cells with prominent intranuclear or cytoplasmic inclusions can be identified in the endothelial and stromal cells in the lamina propria. Biopsies of ulcer beds have the highest diagnostic yield (Figure 5, C). Immunohistochemistry for these viruses can be useful if the viral inclusions are not readily identified (Figure 5, D).38
SKIN DISORDERS AFFECTING THE ESOPHAGUS
Chronic inflammation, often involving the proximal to a greater extent than the distal esophagus, can be identified on biopsies from patients with lichen planus. In a significant proportion of cases, this is the presenting site of involvement, prior to development of skin lesions.39 The histologic pattern of ulceration, lymphohistiocytic inflammation along the interface, damage to the basal layer, and Civatte bodies is similar to the cutaneous version.
Bullous disorders can also affect the esophageal mucosa. Biopsies of squamous mucosa affected by pemphigus vulgaris show suprabasal clefts and bullae formation with acantholytic cells.40 Direct immunofluorescence for immunoglobulin G (IgG) and C3 is seen in intercellular spaces.41 Palleschi et al41 note that this was called oesophagitis dissecans superficialis because of the marked sloughing of the surface epithelium; there is significant overlap with the appearance of sloughing esophagitis. As in the skin, bullous pemphigoid will present in the esophagus with subepithelial bullae with IgG and C3 identified by immunofluorescence along the basement membrane.42
GUIDELINES FOR BIOPSIES
Some variation in biopsy patterns would be recommended if there is clinical/endoscopic suspicion of specific disorders. If clinical history or endoscopic appearance suggests EoE, separate sets of biopsies from the midesophagus and distal esophagus should be submitted, as changes can be patchy and more pronounced in the proximal esophagus. For reflux esophagitis, biopsies are generally targeted to the distal esophagus, with particular attention to possible areas of Barrett esophagus. White patches suggesting Candida infection should raise the possibility of brushing the area for more sensitive diagnosis, and consideration of biopsies sent to microbiology should arise in this and in patients where infection is a possibility. In bullous disorders, the ability to perform immunofluorescence can be essential for diagnosis; submission of biopsies of the edge of the lesion in appropriate medium rather than in formalin would be optimal.
The spectrum of inflammatory lesions in the esophagus is broad, and no histologic features are reliably sensitive and specific. Pathologists should be aware of these issues; clinical and endoscopic information can be very useful in distinguishing among the various lesions.
The authors have no relevant financial interest in the products or companies described in this article.