lymphocytic esophagitis

Lymphocytic esophagitis

Lymphocytic esophagitis is a rare disorder of the esophagus in which there are an increased number of lymphocytes in the lining of the esophagus, with most cases presenting with normal-appearing esophageal mucosa 1). Lymphocytic esophagitis is a form of chronic esophagitis characterized by edema and lymphocytic infiltration of the epithelial peripapillary fields, without eosinophils 2).

Lymphocytic esophagitis is defined by three histologic characteristics:

  1. Dense peripapillary lymphocytic infiltrates in the esophageal squamous mucosa (termed Peripapillary Lymphocytosis),
  2. Little to no intraepithelial granulocytes within these areas of focus and
  3. The presence of spongiosis, or intercellular edema, of the squamous epithelial cells specifically in the areas of focus.

Lymphocytic esophagitis significance is unclear, as it was previously thought to have little clinical impact. Lymphocytic esophagitis may be related to eosinophilic esophagitis or to gastroesophageal reflux disease (GERD).

In 2006, however, Rubio and colleagues 3) described 20 unique cases of chronic esophagitis postulating a new entity, lymphocytic esophagitis. Subsequent studies of lymphocytic esophagitis have noted endoscopic features similar to eosinophilic esophagitis, including esophageal rings, esophagitis, esophageal stricture, erythema, nodularity, plaques, furrows and webs 4).

Since its description, there have been numerous publications supporting lymphocytic esophagitis as a distinct clinical entity 5). Few have commented on the presence of esophageal rings.

Overall, lymphocytic esophagitis was detected in ~ 0.1 %, or 1 in 1000, of all patients who underwent esophageal biopsies for any cause 6). Lymphocytic esophagitis predominantly affects older women (60 %) with a median age of 63 7).  In contrast, eosinophilic esophagitis tends to affect younger men (66 %) with a median age of 43 8). The majority of lymphocytic esophagitis patients are white (86 %) 9). When compared to patients with normal esophageal biopsies, GERD (gastroesophageal reflux disease) and eosinophilic esophagitis, patients with lymphocytic esophagitis were more likely to use tobacco, had comparable rates of drug and food allergies, and were less likely to have allergic rhinitis 10).

Lymphocytic esophagitis patients typically present with symptoms of dysphagia, chest/ abdominal pain and heartburn 11). Common endoscopic features of lymphocytic esophagitis include esophagitis, strictures and stenosis, but there is a large portion of patients with a normal appearing esophagus. One technique that shows promise in increasing detection and decreasing sampling error is narrow-band imaging magnifying endoscopy (NBI-ME). Currently, there is no research guiding treatment for lymphocytic esophagitis, but proton pump inhibitors and swallowed corticosteroids have been used in the past 12).

Lymphocytic esophagitis cause

Unfortunately, there is not much known regarding the cause of lymphocytic esophagitis. One group of researchers hypothesized that since lymphocytic esophagitis is histologically similar to acute spongiotic dermatitis such as allergic contact dermatitis, irritant contact dermatitis and atopic dermatitis, the cause of lymphocytic esophagitis may have an allergic or irritant component 13). Unfortunately, their study found no statistically significant non-drug allergy or drug allergy association in patients diagnosed with lymphocytic esophagitis 14). Although the origin of lymphocytic esophagitis is currently unknown, further research into this condition will provide a greater insight as to how and why it develops. To date, there have been no specific testing pH monitoring evaluations for gastroesophageal reflux disease (GERD) in this population.

Associated conditions

Of the few studies done focusing on lymphocytic esophagitis, most have tried to find associated conditions but have failed. So far, there has been no associations between lymphocytic esophagitis and allergies (drug and non-drug), H. pylori gastritis or celiac disease 15); the association between lymphocytic esophagitis and Crohn’s disease is still controversial. One of the earlier studies done found that about 40% of patients with lymphocytic esophagitis also had Crohn’s disease 16). Subsequent studies have failed to show a statistically significant association, but interestingly, these studies were all done in adults 17). When looking back at the original study that demonstrated an association, about half of the patients with lymphocytic esophagitis were less than seventeen years old. Two newer studies done focusing on only pediatric patients, both found statistically significant associations between lymphocytic esophagitis and Crohn’s disease 18), 19). One even went as far to say that when lymphocytic esophagitis is found in a pediatric patient with Crohn’s disease, it is more likely to be an upper gastrointestinal manifestation of Crohn’s disease rather than another, separate entity 20).

Lymphocytic esophagitis symptoms

Clinical findings for lymphocytic esophagitis are non-specific. In a study of 119 cases of lymphocytic esophagitis, patients presented with similar symptoms as patients with eosinophilic esophagitis, most commonly dysphagia (lymphocytic esophagitis: 53 % vs. eosinophilic esophagitis: 63 %) 21). Across 4 studies of patients with lymphocytic esophagitis, complaints of dysphagia and heartburn were noted in 43 – 70 % and 18.5 – 47 % of patients respectively 22). Additional symptoms include odynophagia, abdominal pain, chest pain, nausea, vomiting, regurgitation, and heartburn (see Table 1). Notable complications of lymphocytic esophagitis include food impactions 23).

Although not a complete list, the most frequent symptoms of patients who are diagnosed with lymphocytic esophagitis are: dysphagia, chest/abdominal pain and heartburn/reflux 24). The rates of patients presenting with dysphagia and subsequently diagnosed with lymphocytic esophagitis are comparable to patients with dysphagia diagnosed with eosinophilic esophagitis. One difference noted was that lymphocytic esophagitis patients typically didn’t present with food impaction 25). There have been few reports of more serious symptoms in patients with lymphocytic esophagitis. One case report of a 35-year-old female who presented with chest pain, fever and hemodynamic shock was found to have diffuse thickening of the esophagus with bilateral pleural effusions, thought to be due to microperforation of the esophagus. Of note, she endorsed mild odynophagia following her most recent meal along with an acute non-productive cough. Upper endoscopy performed one week after the acute event was unremarkable, but biopsies from the mid and distal esophagus showed large numbers of intramucosal peripapillary lymphocytes along with spongiosis, with a lack of eosinophils, viral inclusions or dysplastic/neoplastic lesions. Workup for autoimmune and chronic inflammatory disease was negative. This case study is one of the first to describe a potentially lethal diagnosis of spontaneous esophageal perforation in which lymphocytic esophagitis might have played a role 26).

Lymphocytic esophagitis diagnosis

There are no serum biomarkers currently known to correlate with lymphocytic esophagitis. A smaller study had found that patients with peripapillary lymphocytosis, one of criteria of lymphocytic esophagitis, were associated with higher inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein 27). More research in this area is needed to determine if these tests would be useful clinically in this setting.

Histopathologic characterization is what defines lymphocytic esophagitis. Histology of lymphocytic esophagitis is characterized by a chronic inflammation of the mid and distal esophagus with epithelial lymphocytic infiltration, particularly involving the peripapillary fields, distinct from other forms of chronic esophagitis where lymphocytes predominate in the interpapillary fields 28). The relative absence of granulocytes is a notable feature of lymphocytic esophagitis.

The overall pattern of inflammation, distribution of lymphocytes within the squamous epithelium, and clinical presentation are important in making a diagnosis 29). Lymphocytic esophagitis is a pathologic diagnosis characterized as having the following:

  1. Large number of lymphocytes in the peripapillary region of the esophageal squamous epithelium;
  2. Frequent absence of granulocytes (i. e. eosinophils, neutrophils) 30); and
  3. Marked intracellular edema/spongiosis 31).

In contrast, biopsies in patients with gastroesophageal reflux disease (GERD) demonstrate minimal, if any, reactive histologic changes. There has been no association identified between lymphocytic esophagitis and lymphocytic infiltration at other sites in the gastrointestinal tract 32).

The lymphocytes identified on biopsy of patients with lymphocytic esophagitis expressed CD3, CD4, CD8 and rarely granzyme B, without T-cell intracytoplasmic antigen 33). No granulocytes were present in 60 % of biopsies meeting diagnostic criteria for lymphocytic esophagitis, and only occasional granulocytes were seen in the remaining 40 %. In contrast, many granulocytes were present in the other forms of esophagitis, including grade 2 and 3 gastroesophageal reflux and Candida albicans esophagitis 34).

Endoscopic features

Patients with lymphocytic esophagitis can have a variety of endoscopic findings (Table 1). Studies have shown that esophagitis was present only 18-24% of the time 35), with strictures appearing 10.1% 36) and narrow-caliber/stenosis seen in 36% of patients with lymphocytic esophagitis 37). Interestingly, about 18 % to 31 % of patients with a normal looking esophagus were ultimately diagnosed with lymphocytic esophagitis 38); this highlights the importance of biopsy in making this diagnosis, and not only relying on gross appearance. Esophageal rings were present in 19.8 % of patients (vs. 18.8 % of patients with eosinophilic esophagitis) 5 . In contrast to eosinophilic esophagitis, patients with lymphocytic esophagitis had fewer esophageal strictures (8.6 % vs. 16.3 %) 39), however the incidence of strictures in lymphocytic esophagitis ranged from 8.6 % to 37 % 40). Overall, based on the endoscopic appearance of the esophagus, eosinophilic esophagitis was suspected by physicians in one third of lymphocytic esophagitis cases 41), demonstrating that these clinically distinct entities have overlapping features.

Trying to differentiate between eosinophilic esophagitis and lymphocytic esophagitis based on a gross view of the esophagus can be challenging. Researchers have reported that about 70% of patients diagnosed with lymphocytic esophagitis had at least 1 feature suggestive of eosinophilic esophagitis on esophagogastroduodenoscopy (felinization with furrows, white plaques and strictures) 42). As mentioned above, gross endoscopic features may not always provide a clear picture as to what is truly occurring within the esophagus. One study recommends using narrow-band imaging magnifying endoscopy (NBI-ME) in order to improve detection rates of lymphocytic esophagitis and eosinophilic esophagitis 43). Narrow-band imaging magnifying endoscopy is commonly used to assess invasiveness of superficial esophageal cancers by visualization of intrapapillary capillary loops. These researchers demonstrated that patients with lymphocytic esophagitis and eosinophilic esophagitis were found to have at least 1 of the following characteristics on narrow-band imaging magnifying endoscopy:

  • Beige color (normal color of the esophagus is light green)
  • Increased and congested intrapapillary capillary loops (IPCLs), viewed as a dot-like appearance – seen with both white light and narrow band imaging.
  • Lack of visible submucosal vessels.

Additionally, these lymphocytic esophagitis patients exhibit the same “crepe paper fragility” of the mucosa, similar to what has been described with eosinophilic esophagitis. Patients with gastroesophageal reflux disease (GERD) did not exhibit any of these features 44). Therefore, this technique could be helpful in differentiating between lymphocytic esophagitis or eosinophilic esophagitis from GERD, and assist with biopsy locations within the esophagus in order to reduce sampling error.

Table 1. Symptoms and endoscopic findings in patients with lymphocytic esophagitis across 4 studies

Purdy et al. 45) (%)Haque et al. 46) (%)Cohen et al. 47) (%)Pasricha et al. 48) (%)
Clinical manifestations
Dysphagia4352.966.770
Heartburn/reflux2618.546.926
Abdominal/chest pain44.4
Abdominal pain15
Chest pain19
Nausea/vomiting29.619
Odynophagia12.34
All esophageal symptoms57
Endoscopic impressions
Normal3122.629.618
Esophagitis2418.516.033
Eosinophilic esophagitis33.6
Esophageal rings1219.826
Stricture10.18.637
Motility disorder5.0
Schatzki’s ring2.5
Candida1.615
Achalasia0.8
Hiatal hernia1026
Narrow caliber44

Lymphocytic esophagitis pathology

A diagnosis of lymphocytic esophagitis must meet 3 histological characteristics 49):

  1. Dense peripapillary lymphocytic infiltrates in the esophageal squamous mucosa (termed Peripapillary Lymphocytosis),
  2. Little to no intraepithelial granulocytes (neutrophils, eosinophils) within these areas of focus and
  3. The presence of spongiosis, or intercellular edema, of the squamous epithelial cells specifically in the areas of focus.

The exact number of lymphocytes present to satisfy the first requirement has varied across different studies, with minimum cutoffs set as low as 30 per high power field 2 up to 50 per high power field 50). The study that originally used 30 intraepithelial lymphocytes per high power field concluded that having a minimum cutoff could be misleading and would not increase the specificity of making the diagnosis; the researchers felt that that the focus should rather lie in the distribution of the lymphocytes rather than the sheer number 51).

Lymphocytic esophagitis treatment

Treatment options for lymphocytic esophagitis have not been well studied or defined. Given one of the main symptoms of lymphocytic esophagitis being heartburn, proton pump inhibitors (PPI) have been prescribed to patients. One study found that about half of patients diagnosed with lymphocytic esophagitis felt improvement of their initial symptoms after starting a PPI, although it was unsure if there was concomitant GERD that was being treated. It is not clear if there will be a PPI lymphocyte responsive subset of patients as was seen in the PPI responsive eosinophilic esophagitis patients 52). Similarly there has not been a dietary exclusion trial assessment for clinical success as has been shown with eosinophilic esophagitis 53). Others have tried esophageal dilation and topical swallowed steroids (e.g., swallowed fluticasone), which are similar treatments for other forms of esophagitis 54).

Lymphocytic esophagitis prognosis

Although extremely limited data is available, the course of lymphocytic esophagitis appears to be favorable. Almost 90% of patients with lymphocytic esophagitis were still living three years after being diagnosed 55). Most patients report a good quality of life and satisfaction with their health at follow-up visits within three years post diagnosis 56). Only about 33% of patients with lymphocytic esophagitis had visited the emergency room with a gastrointestinal complaint 57). Repeat upper endoscopy on patients with previously diagnosed lymphocytic esophagitis demonstrated persistent lymphocytic esophagitis in 41 % of cases, with the remaining cases showing normal or alternative diagnoses 58). Nearly 60 % of this cohort of lymphocytic esophagitis patients reported improvement in initial symptoms, largely attributed to escalation of medical management (70.6 % of cases), usually with a proton pump inhibitor 59).

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