Non-Neoplastic Disorders of the Esophagus

Inflammatory Disorders

Pathologic Features

Gross Findings

Endoscopic examination in cases of reflux is variable, depending on the severity and the chronicity of the symptoms. Some patients may have erythema, erosions, or ulceration. Deep ulcerations, bleeding, and peptic strictures are seen in severe cases ( Fig. 1.1 ). Patients with NERD by definition have normal white-light endoscopy, although high-definition endoscopy or narrow-band imaging may reveal subtle changes, including prominent vascularity and irregularity of the gastroesophageal junction (GEJ), creating a group of patients with so-called minimal change esophagitis.

Microscopic Findings

Histologic findings are usually localized to the lower esophagus and taper off or are virtually absent in the proximal segment of esophagus. The typical histologic features include basal cell hyperplasia (thickening of the basal layer to >15% of the total epithelial thickness or more than four to six basal cell layers in well-oriented sections), elongation of the papillae (>60% of the total epithelial thickness), and spongiosis ( Fig. 1.2 ). Inflammatory changes include increased numbers of lymphocytes ( Fig. 1.3 ), neutrophils, and eosinophils ( Fig. 1.4 ). Erosions or ulcers are typically associated with severe GERD. Intraepithelial lymphocytes are predominantly T cells, which tend to acquire an elongated shape (“squiggly lymphocytes”) while traversing between the intercellular spaces. Additional findings including balloon cell change ( Fig. 1.5 ) and hyperkeratosis.

The presence of dilated intercellular spaces (spongiosis; see Fig. 1.3 ) was once considered to be a promising histologic marker of early GERD. It may be the predominant histologic finding in a patient with GERD; however, given the low interobserver agreement in assessing this feature, it remains less helpful compared with other typical features of GERD described already. It should be noted that many patients undergoing endoscopic biopsy have been on a trial of proton pump inhibitors (PPIs) and may have been asked to discontinue the medications 1 or 2 weeks or before endoscopy. In this setting, the most common histologic features are increased intraepithelial lymphocytes, basal layer hyperplasia, and elongation of the papillae. The finding of basal layer hyperplasia, elongation of the papillae, and a few eosinophils within 1 to 2 cm of the GEJ may also represent physiologic reflux. This finding is of no clinical significance. In a recent prospective evaluation of 336 patients with clinical symptoms of GERD, found that total epithelial thickness of 400 µm or greater at 0.5 cm and 430 µm or greater at 2.0 cm above the Z line was the best histologic feature to reliably identify patients with GERD.

Although endoscopically normal, patients with NERD may have dilated intercellular spaces (spongiosis), as well as basal layer hyperplasia and elongation of the papillae of the squamous epithelium, often grouped together as reactive epithelial change, without significant inflammation. Reporting these findings may be helpful to distinguish patients with NERD from those with functional heartburn.

Clinical Features

Eosinophilic esophagitis is a primary clinicopathologic disorder of the esophagus that has been associated with an increasing prevalence and has gained significant recognition over the past few years. It is defined as a chronic immune and antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Three specific criteria are required to diagnose EoE: symptoms related to esophageal dysfunction, a peak eosinophil count of at least 15 eosinophils/hpf on esophageal biopsy, and eosinophilia limited to the esophagus with other causes of esophageal eosinophilia excluded. Although one of the clinical features of EoE is the lack of response to PPIs, recent studies have shown that one-third or more patients with esophageal eosinophilia can show response to PPIs. This phenomenon has been termed PPI-responsive esophageal eosinophilia . A recent transcriptome analysis study by found significant molecular overlap between PPI-responsive esophageal eosinophilia and EoE, suggesting these two entities represent a diagnostic continuum or that PPI-responsiveness is a subphenotype of EoE. However, this relationship is yet to be fully characterized.

Eosinophilic esophagitis occurs in all age groups but is seen more frequently in young children with atopic symptoms such as eczema, asthma, and food allergies. Symptoms manifest differently in different age groups: whereas infants and children often present with feeding difficulties, regurgitation, dyspepsia, abdominal pain, and vomiting, adults usually describe dysphagia and food impaction with or without chest or abdominal pain. If not recognized early, EoE can progress to odynophagia and stenosis.

Pathologic Features

Gross Findings

Classic endoscopic findings include mucosal rings, furrows (also known as “trachealization” of the esophagus), granularity, exudates, and mucosal fragility ( Figs. 1.6 and 1.7 ). However, in some patients, the endoscopic findings can be completely normal. In long-standing cases, stricture formation may be seen.

Microscopic Findings

Biopsies show increased intraepithelial eosinophils (≥15 eosinophils/hpf) with concentration of eosinophils toward the luminal aspect of the epithelium (superficial layering). Eosinophilic microabscesses and degranulation of eosinophils ( Fig. 1.8 ) are frequently present. The density of eosinophils can vary with anatomic location of biopsy and within biopsy fragments. In general, biopsies from the proximal segment reveal more eosinophilia than the distal segment. It is therefore recommended that the total number of eosinophils per high-power field be generated by examining the fragments at low magnification and selecting the high-power field with maximum number of eosinophils ( Fig. 1.9 ). Care should be taken to avoid counting eosinophils within the papillae. Other findings include basal cell hyperplasia, elongation of the papillae to greater than 50% the thickness of the squamous epithelium, spongiosis, lamina propria, and submucosal fibrosis. In patients who have received diet elimination or steroid therapy, follow-up biopsies may be performed to evaluate response to therapy, in which case, giving the exact eosinophil count may be helpful.

Eosinophilic Esophagitis—Pathologic Features

Gross Findings

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  Endoscopic examination reveals mucosal rings, furrows (“trachealization” of esophagus), erythema, and granularity

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  In long-standing cases, strictures are seen

Microscopic Findings

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  Marked increase in intraepithelial eosinophils (≥15/hpf)

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  Eosinophil infiltrates may be more prominent in the proximal than in the distal esophagus

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  Superficial layering of eosinophils, eosinophilic microabscesses, and degranulation

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  Additional findings include basal cell hyperplasia, elongation of the papillae, spongiosis, and fibrosis of the lamina propria and submucosa

Differential Diagnosis

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  Reflux esophagitis changes are mostly seen in biopsy samples from the distal esophagus or gastroesophageal junction

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  In eosinophilic gastroenteritis, eosinophils are also present in other segments of the gastrointestinal tract

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  Drug-induced injury to the esophagus requires clinicopathologic correlation

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  Parasitic infections do not typically affect the entire esophagus. Biopsy specimens may show parasitic organisms

Differential Diagnosis

Eosinophilic esophagitis must be distinguished from reflux esophagitis, pill-induced esophagitis, eosinophilic gastroenteritis, and parasitic infections. It is important to note that any of the histologic features of EoE can also be seen in patients with reflux esophagitis. Distal esophagus-predominant mucosal changes with unremarkable proximal esophageal biopsy favors a diagnosis of reflux esophagitis. Pill-induced esophagitis is often accompanied by ulcer and granulation tissue. Some medications (alendronate, iron supplements) can be visualized on light microscopy. However, confirmation of drug-induced injury requires clinicopathologic correlation. Eosinophilic gastroenteritis is usually associated with peripheral blood eosinophilia and affects the rest of the gastrointestinal (GI) tract. Parasitic infections tend to be a localized phenomenon, and deeper levels may reveal the organism.

Prognosis and Therapy

The prognosis is excellent when treatment is given promptly. Dietary elimination of the six common offending foods (milk, egg, wheat, soy, peanuts and tree nuts, and seafood) and topical steroids leads to dramatic improvement in symptoms and histology. Rarely, patients refractory to steroid therapy may show disease progression in the form of esophageal strictures that require repeated dilation procedures.

Clinical Features

Symptoms include dysphagia, chest pain, heartburn, nausea, and odynophagia. Symptoms can lead to a clinical impression of EoE. Adults and children both can be affected, and most patients are diagnosed in the fifth or sixth decade of life. Men and women are equally affected. Many patients diagnosed with LE also have potentially confounding diagnoses, including GERD, inflammatory bowel disease (IBD), hypothyroidism, allergies or asthma, history of radiation or chemotherapy, and connective tissue disease.

Pathologic Features

Microscopic Findings

The esophageal biopsy shows increased intraepithelial lymphocytes, predominantly in a peripapillary distribution, with spongiosis of the associated peripapillary squamous epithelium ( Fig. 1.10 ). Similar to EoE, the distribution of intraepithelial lymphocytes is usually patchy and can vary between different biopsy fragments, with some papillae being unaffected. Neutrophils or eosinophils are rare or even absent. There may be accompanying basal cell hyperplasia and spongiosis. Unfortunately, there is no standard number of intraepithelial lymphocytes to diagnosis LE, and studies have included various minimum cut-offs of 20 lymphocytes, 30 lymphocytes, or 50 lymphocytes per high-power field. It is therefore appropriate to render a descriptive diagnosis of “LE pattern of injury” with a comment consisting of the various conditions that may result in this pattern of injury.

Differential Diagnosis

Increased intraepithelial lymphocytes can be seen in reflux esophagitis, which typically shows more neutrophils and eosinophils. Esophageal Crohn’s disease is characterized by increased intraepithelial lymphocytes, especially in the pediatric population. Granulomas may be seen in some cases. However, involvement of the rest of the GI tract is helpful in confirming a diagnosis of Crohn’s disease. Achalasia and other motility disorders can have increased intraepithelial lymphocytes on biopsy but usually show radiographic and endoscopic evidence of dysmotility. Inflammatory disorders of the skin, including lichen planus, can affect the esophagus resulting in increased intraepithelial lymphocytes. The presence of interface activity, hyperkeratosis, parakeratosis, dyskeratotic keratinocytes, or a history of inflammatory skin disease can be helpful.

Prognosis and Therapy

More than half of patients have symptomatic improvement with treatment, which most often includes a PPI. Patients with IBD may benefit from immunomodulatory therapy. Dilation is often helpful in patients with strictures. Follow-up endoscopic biopsies with the LE pattern of injury have shown persistence of LE, progression to reflux or Crohn’s disease, or complete resolution of histologic findings.

Clinical Features

Lichen planus of the esophagus, or lichen planus esophagitis, can occur with or without concurrent cutaneous lichen planus. For both lichen planus and lichenoid esophagitis pattern of injury, girls and women are affected about three times more often than boys and men. Adults and children can be affected, with a median age of about 64 years. Clinical symptoms include dysphagia and stricture and less commonly, esophagitis, heartburn, chest pain, and hiatal hernia. Whereas comorbidities including viral infections (HIV, hepatitis B, and hepatitis C) have been reported in patients with lichenoid esophagitis, hypothyroidism and rheumatologic diseases have been reported in patients with lichen planus esophagitis. Polypharmacy is associated with both conditions.

Pathologic Features

The squamous epithelium and lamina propria are involved by a dense band of predominantly T-cell lymphocytic infiltrates. Lymphocytic inflammation can be patchy or diffuse and affect the upper and lower esophagus. Apoptotic or otherwise degenerating squamous cells (Civatte bodies) in a lichenoid background are diagnostic of lichen planus esophagitis. The background squamous epithelium can be atrophic. Other inflammatory cell types are not prominent. Direct immunofluorescence demonstrates globular immunoglobulin M (IgM) deposits at the squamous–subsquamous interface in lichen planus and cases with negative direct immunofluorescence but with the other histologic features of lichen planus have been termed lichenoid esophagitis pattern of injury .

Differential Diagnosis

Graft-versus-host disease, achalasia and other motility disorders, Crohn’s disease, and reflux esophagitis with increased intraepithelial lymphocytes are prominent. LE has a peripapillary lymphocytosis, rather than bandlike, and lacks Civatte bodies.

Prognosis and Therapy

Lichen planus is a chronic progressive disease that can result in esophageal stricture or even squamous cell carcinoma (SCC). Immunomodulatory medications are the mainstay of treatment.

Clinical Features

Esophageal involvement in Crohn’s disease is uncommon, affecting about 6% of patients with Crohn’s disease.

Pathologic Features

Esophageal biopsies may show increased intraepithelial lymphocytes, especially in pediatric patients ( Fig. 1.11 ). Well-formed, non-necrotizing epithelioid granulomas may also be present. Active inflammation consisting of intraepithelial neutrophils, erosion, or ulceration can be seen.

Differential Diagnosis

Knowledge of a patient’s diagnosis of Crohn’s disease, by demonstrated involvement in other organs, is useful when considering the differential diagnosis. Granulomatous esophagitis and LE are the main considerations if there is no other evidence of Crohn’s disease in other organs. Granulomatous esophagitis can be caused by infections, such as mycobacteria and fungus, sarcoidosis, Wegener’s granulomatous, chronic granulomatous disease, or some medications.

Prognosis and Therapy

Patients with Crohn’s disease who have esophageal involvement are treated similar to those with disease elsewhere in the GI tract, including antiinflammatory agents and immunomodulators. There is no reported difference in prognosis for patients with Crohn’s disease who have esophageal involvement.

Clinical Features

Esophageal involvement is uncommon in patients with GVHD and usually accompanies involvement of other parts of the GI tract. Symptoms of esophageal involvement include dysphagia and chest pain. On endoscopy, the mucosa appears friable and may be ulcerated. Rarely, severe cases may show prominent sloughing of the esophageal mucosa.