Abstract
Lymphocytic esophagitis is a new and rare entity, first described in 2006. Histologically, the esophageal mucosa is characterized by a dense peripapillary lymphocytic infiltrate and an intercellular edema without granulocytosis. To this day, it is not yet considered as a disease. Its etiology and clinical significance are still unclear. The predominant symptom is dysphagia and the main endoscopic feature is a normal esophagus. The absence of relationship between lymphocytic esophagitis and specific clinical conditions justifies further studies. Currently, it remains a histologic entity.
Keywords
- lymphocyte
- esophagitis
- dysphagia
- Crohn
- CD4
- CD8
- motility
1. Introduction
Lymphocytic esophagitis is a histopathological entity described for the first time in 2006 by Rubio
2. Prevalence
Lymphocytic esophagitis is a very rare condition. In 2012, Haque
Moreover, since it is a novel entity and most of the studies are from North America, worldwide prevalence has not been evaluated.
3. Histology
A small amount of intraepithelial lymphocytes is normally present in the esophagus [4, 5]. A majority of these lymphocytes are CD8 T cells, whereas CD4 are a minority and usually present in the lamina propria. An increase in CD8 T cells is seen in peptic and eosinophilic esophagitis. In addition, this lymphocytosis is generally accompanied by eosinophils and/or neutrophils [5–8].
Compared to other esophageal pathologies, lymphocytic esophagitis is characterized by an isolated lymphocytosis. The main histologic findings are a dense peripapillary intraepithelial lymphocytic infiltrate, an intercellular edema known as spongiosis, as well as the absence or rarity of granulocytes ( Figure 1 ) [1]. The intraepithelial lymphocytes express CD3, CD4, and CD8, as shown by immunohistochemistry [1, 9, 11].
Unfortunately, because the histologic criteria are not yet standardized, it can sometimes lead to misdiagnosis. For instance, the presence of rare intraepithelial granulocytes is accepted in lymphocytic esophagitis [1, 2, 10, 11]. However, granulocytes can be found in various esophageal diseases, making diagnosis more difficult [11]. The acceptable number of granulocytes still needs to be better defined.
Because the lymphocytosis is patchy and uneven, we suggest not to establish a minimum number of intraepithelial lymphocytes [2]. In fact, the various studies about this entity have all used different cutoff, ranging between 10 and 50 lymphocytes per high-power field (HPF) [2, 3, 12, 13].
Furthermore, lymphocytic esophagitis affects the whole esophagus, but predominantly the distal esophagus. Thus, multiple biopsies are necessary to avoid a false negative because the lymphocyte infiltrates are not distributed evenly throughout the entire esophagus [12].
The mucosal involvement is considered mild if the intraepithelial lymphocytosis is only peripapillary and is severe if there is also an interperipapillary lymphocyte infiltration [12].
4. Clinical manifestations
Lymphocytic esophagitis seems to affect mostly women around 60 years old and smokers [2, 3, 10, 11]. The most common symptom is dysphagia [2, 8, 11, 13]. Nausea, vomiting, chest pain, heartburn, and episodes of impactions have also been reported; however, dysphagia remains the principal and most frequent complaint in 53% of cases [2, 3, 12]. Patients with lymphocytic esophagitis do not appear to show weight loss or fever.
The most serious complication is esophageal perforation. In 10 years, two cases of perforation have been reported. One of the two perforations occurred after the removal of a piece of impacted meat, while the second case was a spontaneous microperforation [14, 15].
5. Endoscopic features
Endoscopically, the most frequent findings are a normal esophagus or esophagitis [2, 3, 11]. Up to 33% of cases from the cohort by Haque
The endoscopic features are variable and not specific, which makes it impossible to identify and diagnose lymphocytic esophagitis by only relying on symptoms and gastroscopy. It is still a histologic condition, which is why biopsy is essential for the diagnosis.
6. Clinical associations
Some retrospective studies and case reports have tried to identify an association between lymphocytic esophagitis and other clinical conditions. Whether it was inflammatory bowel disease, gastroesophageal reflux disease, celiac disease, asthma, allergies, irritants, or connective tissue diseases (lupus, Behçet’s disease), no relationship could be identified [2, 11–13, 16].
Lymphocytic esophagitis is isolated to the esophagus. It does not coexist with other digestive lymphocytosis such as lymphocytic colitis or lymphocytic gastritis. There is no correlation between these distinct entities. In a case series from Purdy
6.1. Gastroesophageal reflux disease
One of the main research efforts was to identify a relationship between lymphocytic esophagitis and reflux. Unfortunately, no association has been established between these two conditions [2, 12]. Indeed, only 22 out of 119 patients in the cohort from Haque
6.2. Crohn’s disease
In the cohort from Rubio
6.3. Eosinophilic esophagitis
Eosinophilic esophagitis has also been a subject of study and comparison with lymphocytic esophagitis. The clinical and endoscopic manifestations of lymphocytic esophagitis can be confused with those of eosinophilic esophagitis. It is only histology that allows us to differentiate these two entities. Felinization is not pathognomonic of eosinophilic esophagitis, hence the importance of biopsy [2].
In a recent cohort from Rubio
6.4. Motility disorders
Since 2014, an interest for esophageal motility disorders in lymphocytic esophagitis has arisen. Recent studies have demonstrated an association with achalasia and primary esophageal motility disorder (nutcracker esophagus, ineffective esophageal motility, and diffuse spasm) [18].
In 2015, Xue
7. Treatment
Treatment of lymphocytic esophagitis remains controversial. Very few studies addressed this subject. Because it is still a recent and rare entity, a majority of therapeutic trials have been reported in the form of case reports or retrospective studies.
Proton pump inhibitor, topical or oral steroids as well as esophageal dilation or injections of Botox have been tried. All these treatments have been partially effective [3, 13–16, 19–21]. Nevertheless, it is too early to establish which treatment is better and should be recommended.
The use of proton pump inhibitor is based on the belief that lymphocytic esophagitis may be associated with esophageal reflux. However, as mentioned earlier, this association remains unclear and unlikely. Nevertheless, given the low toxicity of proton pump inhibitors, we suggest using them as first line of treatment.
Concerning the efficacy of corticosteroids, it may suggest that lymphocytic and eosinophilic esophagitis belong to the same family.
8. Natural history
Unfortunately, we have very little data on the clinical course of this condition. Cohen
Current available literature points out that lymphocytic esophagitis is a chronic condition [12]. The risk of esophageal neoplasia is still unknown.
9. Conclusion
Lymphocytic esophagitis is a newly described clinical and histologic condition that will probably be increasingly recognized upon the next years. Recent publications have allowed us to establish clear criteria, thus facilitating the diagnosis. Clinicians need to be aware of this entity because lymphocytic esophagitis may eventually be in the diagnostic algorithm of dysphagia.
Pathologists are increasingly recognizing this condition, which is an asset for research. With larger cohorts, we will be able to further characterize its worldwide epidemiology, clinical associations, as well as treatment and natural history. Single-cell analysis of the intraepithelial lymphocyte subtypes may help in understanding the pathophysiology of the condition and compare subgroups with compound eosinophilic esophagitis and those without. As Haque once said, “it is a condition in search of a disease.”
Acknowledgments
We are grateful to Dre Amélie Therrien (Hôpital Saint-Luc, CHUM, Montréal) and Dre Elizabeth Arslanian (Hôpital Saint-Luc, CHUM, Montréal) for the critical review of the manuscript.
References
- 1.
Rubio CA, Sjödahl K, Lagergren J. Lymphocytic esophagitis: A histologic subset of chronic esophagitis. American Journal of Clinical Pathology. 2006; 125 :432–437 - 2.
Haque S, Genta RM. Lymphocytic oesophagitis: Clinicopathological aspects of an emerging condition. Gut. 2012; 61 :1108–1114 - 3.
Cohen S, Saxena A, Waljee AK, Piraka C, Purdy J, Appelman H, McKenna B, Elmunzer BJ, Singal AG. Lymphocytic esophagitis: A diagnosis of increasing frequency. Journal of Clinical Gastroenterology. 2012; 46 :828–832 - 4.
Carmack SW, Lash RH, Gulizia JM, Genta RM. Lymphocytic disorders of the gastrointestinal tract: A review for the practicing pathologist. Advances in Anatomic Pathology. 2009; 16 :290–306 - 5.
Resnick MB, Finkelstein Y, Weissler A, et al. Assessment and diagnostic utility of the cytotoxic T-lymphocyte phenotype using the specific markers granzyme-B and TIA-1 in esophageal mucosal biopsies. Human Pathology. 1999; 30 :397–402 - 6.
Podolsky DK, Camilleri M, Fitz JG, Kalloo AN, Shanahan F, Wang TC. Yamada’s Textbook of Gastroenterology. United States: John Wiley & Sons Inc. Vol. 2, Set. 6th Edition; 2015. P.49 - 7.
Lucendo AJ, Navarro M, Comas C, et al. Immunophenotypic characterization and quantification of the epithelial inflammatory infiltrate in eosinophilic esophagitis through stereology: An analysis of the cellular mechanisms of the disease and the immunologic capacity of the esophagus. American Journal of Surgical Pathology. 2007; 31 :598–606 - 8.
De Jonge PJ, Siersema PD, Van Breda SG, et al. Proton pump inhibitor therapy in gastro-oesophageal reflux disease decreases the oesophageal immune response but does not reduce the formation of DNA adducts. Alimentary Pharmacology & Therapeutics. 2008; 28 :127–136 - 9.
Rubio CA, Ichiya T, Schmidt PT. Lymphocytic oesophagitis, eosinophilic oesophagitis and compound lymphocytic-eosinophilic oesophagitis. I: Histological and immunohistochemical findings. Journal of Clinical Pathology. 2017; 70 :208–216 - 10.
Ebach DR, Vanderheyden AD, Ellison JM, et al. Lymphocytic esophagitis: A possible manifestation of pediatric upper gastro-intestinal Crohn’s disease. Inflammatory Bowel Diseases. 2011; 17 :45–49 - 11.
Xue Y, Suriawinata A, Liu X, Li Z, Gabbard S, Rothstein R, Lacy B, Lisovsky M. Lymphocytic esophagitis with CD4 T-cell- predominant intraepithelial lymphocytes and primary esophageal motility abnormalities: A potential novel clinicopathologic entity. American Journal of Surgical Pathology. 2015; 39 :1558–1567 - 12.
Purdy JK, Appelman HD, Golembeski CP, et al. Lymphocytic esophagitis: A chronic or recurring pattern of esophagitis resembling allergic contact dermatitis. American Journal of Clinical Pathology. 2008; 130 :508–513 - 13.
Pasricha S, Gupta A, Reed CC, Speck O, Woosley JT, Dellon ES. Lymphocytic esophagitis: An emerging clinicopathologic disease associated with dysphagia. Digestive Disease Science. 2016; 61 :2935–2941 - 14.
Hendy PJ, Wong DS, Florin TH. Spontaneous oesophageal perforation: An unreported complication of lymphocytic oesophagitis. Gut. 2013; 62 :1668–1669 - 15.
Mandaliya R, Dimarino AJ, Cohen S. Lymphocytic esophagitis mimicking eosinophilic esophagitis. Annals of Gastroenterology. 2012; 25 :355–357 - 16.
Figueiredo PC, Pinto-Marques P, Borralho P, Freitas J. Unusual cause for smoldering dysphagia. Lymphocytic esophagitis. Dysphagia. 2014; 29 :283–285 - 17.
Basseri B, Vasiliauskas EA, Chan O, Wang HL, Basseri RJ, Pimentel M, Soffer E, Conklin JL. Evaluation of peripapillary lymphocytosis and lymphocytic esophagitis in adult inflammatory bowel disease. Gastroenterology & Hepatology (N Y). 2013; 9 :505–511 - 18.
Putra J, Muller KE, Hussain ZH, Parker S, Gabbard S, Brickley EB, Lacy BE, Rothstein R, Lisovsky M. Lymphocytic esophagitis in nonachalasia primary esophageal motility disorders: Improved criteria, prevalence, strength of association, and natural history. American Journal of Surgical Pathology. 2016; 40 :1679–1685 - 19.
Zhang Z, Jain D, Brand M. Ringed esophagus secondary to lymphocytic esophagitis. Gastroenterology & Hepatology (N Y). 2016; 12 :237–239 - 20.
Vangimalla S, Gordon I, Thota PN. Image of the month: Lymphocytic esophagitis in common variable immune deficiency. American Journal of Gastroenterology. 2016; 111 :170 - 21.
Kasirye Y, John A, Rall C, Resnick J. Lymphocytic esophagitis presenting as chronic dysphagia. Clinical Medicine & Research. 2012; 10 :83–84