Lymphocytic Esophagitis

Etiology

Lymphocytic esophagitis is a rare subtype of chronic esophagitis, and the etiology is unknown. It is unclear whether LE is a unique primary inflammatory esophageal disease or merely a marker of an underlying esophageal or systemic immune-mediated disease process.[2] However, with predominant clinical features such as persistent dysphagia, the suggestion of esophageal strictures documented during endoscopic evaluation, and histopathologic evidence consistent with lymphocytosis, LE is likely a chronic inflammatory disorder of the esophagus.[3] Extensive prospective studies are required to evaluate the natural history of LE.

Epidemiology

Knowledge of the natural history of LE is limited, given the relatively few studies of the condition. The incidence of LE has been reported to be 0.1% of total esophageal biopsies based on the results of a large pilot study in the United States of more than 40,000 patients.[4] Worldwide demographic data on the incidence of LE is limited. 

The signs and symptoms of LE mimic those of eosinophilic esophagitis; both are definitively diagnosed via endoscopic esophageal biopsy. Evaluations for eosinophilic esophagitis have been steadily increasing, and this increased number of endoscopic esophageal biopsies is presumed to be the reason behind the increasing incidence of LE diagnoses.

Initial studies of LE reported its association with immunologic conditions such as rheumatologic disorders, common variable immunodeficiency, and Crohn disease, especially in pediatric patients.[1][5][6][7] However, multiple subsequent studies evaluating the potential risk factors for developing LE have reported that the disorder is more likely in women in their sixth decade and is significantly associated with underlying GERD, primary motility disorders such as achalasia, a history of tobacco use, certain allergies, hypothyroidism and the use of aspirin or statin medications.[8][9][10][11][12]

Pathophysiology

The pathogenesis of LE is not well understood. The development of LE has been hypothesized to occur secondary to either a hypersensitivity reaction to an ingestant or an underlying autoimmune phenomenon.[13][14][15] Authors of a case series of 42 patients with LE refuted hypotheses suggesting an association of LE with any medication, concurrent disease, or allergies.[14]

The histological pattern reported by Rubio et al in their original study reported increased expression of CD3, CD4, and CD8 proteins by esophageal intraepithelial lymphocytes.[1]

A 36-month observational study by Xue et al of esophageal biopsies from 45 patients with LE reported that increased expression of CD4 by intraepithelial lymphocytes had a significantly higher prevalence of primary motility abnormalities compared to patients with CD8 predominant LE.[16]

Another study by Putra et al reported a strong association between LE and non-achalasia primary esophageal motility disorders with an odds ratio of 7.72 (95% CI, 2.26-27.9).[9]

Histopathology

Lymphocytic esophagitis is a histologic diagnosis. However, there is no consensus on the minimal number of intraepithelial lymphocytes required to diagnose LE. The 3 histologic findings widely recognized as characteristic of LE include peripapillary lymphocytosis, marked spongiosis or intercellular edema, and the absence or minimal presence of intraepithelial granulocytes such as neutrophils or eosinophils in the absence of any apparent infectious etiology.[17]

Spongiosis, found in many forms of esophagitis, has been noted as directly proportional to the degree of lymphocytosis.[3][18]

History and Physical

In contrast to eosinophilic esophagitis, usually diagnosed in young adult men, LE is predominantly seen in women in the sixth decade of life. The common presenting symptoms of LE include dysphagia, heartburn, or chest pain; nonspecific abdominal pain and nausea with or without vomiting have also been reported.[3][10] A meta-analysis from 2019 identified that most patients with LE were women presenting with dysphagia.[12]

A study of more than 100 patients with a histologic diagnosis of LE concluded that while most patients presented with clinical symptoms similar to eosinophilic esophagitis, they lacked the characteristic endoscopic features of that disease, including distinctive rings and furrows.[4]

A single-center retrospective study evaluating the prevalence of eosinophilic esophagitis and LE in adults presenting with esophageal food bolus impaction demonstrated that 17% of the total 228 participating patients had features of both eosinophilic esophagitis and LE and 9% of patients had evidence of only LE, implicating food bolus impaction as the presenting feature of LE.[19]

Evaluation

An endoscopic esophageal biopsy is required to obtain the necessary tissue sample to diagnose LE histologically. However, unlike eosinophilic esophagitis, there are no guidelines for a formal biopsy protocol when diagnosing LE.

Esophagogastroduodenoscopy 

The gross endoscopic features of LE vary widely. They may range from a normal-appearing esophagus to findings of esophageal strictures or rings, linear furrows, erosive esophagitis, esophageal edema, or white plaques.[3][10] With conventional endoscopy evaluation, as many as 23% to 55% of patients with histologic LE will have normal esophageal mucosa.[1][4]

Using narrow-band imaging magnifying endoscopy (NBI-ME), Tanaka et al aimed to distinguish the gross endoscopic features of LE, GERD, and eosinophilic esophagitis. Studied features included the presence of invisible submucosal vessels, beige-colored esophageal mucosa, and increased numbers of dot-shaped congested intrapapillary loops. Only 82% of patients in the LE cohort demonstrated all three features compared to 100% of patients in the eosinophilic esophagitis cohort.[20]

There is no consensus on the minimal number of lymphocytes per high-power field required to diagnose LE. However, esophageal biopsies demonstrating a histological pattern of more than 20 intraepithelial lymphocytes per high-power field, few or absent granulocytes, and mucosal injury such as spongiosis have been accepted widely as diagnostic criteria.[5]

Radiographic Studies

Radiographic studies such as barium esophagram can evaluate for structural causes of dysphagia, including moderate-to-severe esophagitis, esophageal strictures, hiatal hernia, and neoplasms. However, the role of radiographic studies in diagnosing LE is limited.

Other Studies

Patients with a confirmed histologic diagnosis of LE without gross endoscopic structural abnormalities should be evaluated for underlying achalasia and non-achalasia primary esophageal motility disorders using high-resolution esophageal manometry (HREM), given the significant association between motility disorders and LE. These patients also require laboratory evaluation for rheumatological and autoimmune diseases if the medical history and physical examination support such a diagnosis.

Treatment / Management

The management of LE remains ill-defined due to a lack of clinical guidelines. Current management strategies for LE mimic those of eosinophilic esophagitis due to the clinical and endoscopic similarities of the two disease processes. However, LE is more likely to respond to medical therapy than eosinophilic esophagitis.[8] Unlike eosinophilic esophagitis, the role of systemic steroids and biologic therapy has not been studied in patients with LE.(B2)

Lifestyle Modifications

Patients with LE who use tobacco should receive education and support regarding tobacco cessation.

Medical Management

Medical management of LE comprises high-dose proton pump inhibitor (PPI) therapy twice daily for 12 weeks. Changes in symptomatology or endoscopic findings should be assessed after this course of therapy. If no clinical or histologic improvement is achieved with high-dose PPI therapy, topical steroids such as budesonide 1 mg twice daily are recommended. Most patients report improved symptoms with the initiation of PPI therapy. However, it is unclear if the symptomatic improvement is secondary to the treatment of underlying GERD.[17] In a small study of 22 patients with a confirmed diagnosis of LE, histological remission was achieved in 40% of patients with a course of high-dose PPI therapy; given the small sample size, further studies are needed.[17][14](B2)

Endoscopic Therapeutic Interventions 

Serial endoscopic dilatation is advised for patients with LE with persistent symptomatic esophageal strictures or rings despite medical therapy.[21](B3)

Differential Diagnosis

The differential diagnosis of LE includes but is not limited to the following disease processes:

• Gastroesophageal reflux disease
• Erosive esophagitis
• Candida esophagitis
• Eosinophilic esophagitis 
• Esophageal lichen planus
• Achalasia 
• Non-achalasia esophageal motility disorder
• Peptic stricture
• Esophageal neoplasm
• IgG4-related esophagitis

Prognosis

Data delineating the natural history of LE are scarce. However, based on the described responses to conventional high-dose PPI medical therapy, the disease runs a chronic but benign course.[2] A retrospective study by Cohen et al of 81 patients with LE indicated that most patients report a good quality of life.[2] Early diagnosis of LE and monitoring for complications such as esophageal strictures are crucial to prevent long-term morbidity.

Complications

The complications of LE include esophageal strictures, webs, and perforation.