Gastroenterology 2018;154:263–266

INTRODUCTION
Esophageal Diseases

Rebecca C. Fitzgerald1 Michael F. Vaezi2

1
MRC Cancer Unit, University of Cambridge, Cambridge, United Kingdom and 2Division of Gastroenterology, Hepatology, and
Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee

T his special issue of Gastroenterology provides

in depth discussions of esophageal diseases with
significant public health interest for which there have been
observed that there is a complex but conserved bacterial
population resident in the normal esophagus, with an
estimated 140 bacterial species, of which 95 are identified.
substantial advances in recent years, including gastro- The diversity and composition of these florae may alter in
esophageal reflux disease, eosinophilic esophagitis, and the context of esophageal disease —although a causal
esophageal cancer. These disorders could be considered relationship is more difficult to establish.13–15 Another
“bread and butter” areas for GI clinicians and yet, like so common theme is improved sub-classification of esophageal
many areas of medical practice, these subjects have become disease. This progress is in part due to sequencing tech-
increasingly specialized as we gain a better understanding nologies which can now be applied to a single cell resolu-
of their underlying pathogenesis and as new technologies tion. This enables us to classify esophageal diseases more
emerge for their diagnosis and therapy. precisely as to etiology, thereby potentially allowing preci-
The importance of esophageal disease is highlighted sion diagnosis and therapy – this is most prominent in the
when one considers the striking epidemiological trends of area of cancer but it is also becoming relevant across
these diseases. In the Western world it is estimated that one inflammatory disorders. There is also progress towards less
in ten adults complains of reflux symptoms; this is becoming invasive and more sensitive diagnostic tools. For example,
a global problem with the obesity epidemic and the global reflux disease can be assessed using ambulatory tools and
adoption of western dietary patterns1,2 (see article by Drs devices, in some cases linked to laboratory tests. These have
Joel E. Richter and Joel H. Rubenstein on pages 267–276).3 the potential for application in primary care, for assessment
There has also been a stark increase in incidence of of mucosal inflammation and diagnosis of Barrett’s esoph-
esophageal adenocarcinoma over the past forty years which agus.16 Whichever methods gain widespread adoption in the
has led to a hitherto uncommon cancer type pre-occupying future, it is clear that in order to identify patients at risk for
GI oncologists in the western world4,5 (see article by Drs esophageal cancer we need to overcome the barriers to
Helen G. Coleman, Shao-Hua Xie, and Jesper Lagergren on investigation which includes improving public awareness
pages 390–405).6 Many reviews focus on esophageal about symptoms and bringing diagnostic technologies
adenocarcinoma, given its surge in incidence; however, nearer to the patient.17
esophageal squamous cell carcinoma still accounts for The first section evaluates GERD; a key theme for its
90% of esophageal cancers globally, including a significant articles is the overlap between acid reflux, gastroparesis,
part of clinical practice in the West (see article by Drs functional dyspepsia and EoE, leading to frequent mis-
Christian C. Abnet, Melina Arnold, and Wen-Qiang Wei on diagnosis. This is important from an epidemiological
pages 360–373).7 Eosinophilic esophagitis (EoE) is also an perspective (see article by Drs Joel E. Richter and Joel H.
emergent disease, which was probably overlooked as a Rubenstein3 on pages 267–276), as well as in terms of
cause of bolus obstruction in the past.8,9 The prevalence pathophysiology (see article by Drs Jan Tack and John E.
rates of EoE are now estimated to be as high as 1 in 1000 Pandolfino18 on pages 277–288), diagnosis (see article by
and it accounts for a substantial part of the endoscopic Drs Michael F. Vaezi and Daniel Sifrim19 on pages 289–301)
workload in the US10,11 (see article by Drs Evan S. Dellon and therapy (see article by Drs C. Prakash Gyawali and
and Ikuo Hirano on pages 319–332).12
Some common themes emerge from this collection of
articles. There is a growing appreciation of the microbiome Most current article
and the immune micro-environment in the pathophysiology
© 2018 by the AGA Institute
of these disorders. The importance of the microbiome in 0016-5085/$36.00
colonic disease is well established; however, it is now https://doi.org/10.1053/j.gastro.2017.12.017
264 Fitzgerald and Vaezi Gastroenterology Vol. 154, No. 2

Ronnie Fass20 on pages 302–318). New diagnostic strategies The third section focuses on esophageal cancer. Each
for GERD and EoE in the developmental phase will likely article discusses the two histological subtypes (squamous
lead to more accurate diagnostic strategies. In the past, and adenocarcinoma) separately or together as seemed
therapy for GERD has focused on either acid suppression or most logical, to avoid repetition whilst highlighting distinc-
mechanical anti-reflux therapy (endoscopic or surgical) tions when required.
across the whole spectrum of conditions. Proton pump The etiology of esophageal squamous cell carcinoma
inhibitors are now one of the most widely prescribed is linked to smoking, alcohol, polycyclic aromatic hydro-
medications available without a medical consultation. In the carbons exposure from a variety of sources and high
long-term, their over-use can lead to complications and to temperature ingestion. Despite initial reports of a potential
overlooking underlying conditions such as EoE or Barrett’s etiologic link between human papilloma virus and esopha-
esophagus. However, with improved understanding of geal squamous cell carcinoma (ESCC), the number of cases
pathophysiology more tailored treatment approaches are caused by these viruses appears to be very low (see article
evolving with the possibility of adding neuromodulators, by Drs De-Chen Lin, Ming-Rong Wang, and H. Phillip Koeffler
psychological interventions and electrical sphincter stimu- on pages 374–389).25 In contrast, reflux disease, obesity and
lation into the armamentarium.21,22 Therefore, diagnostic tobacco smoking (to some extent) have been established as
modalities are required which can differentiate between the the primary risk factors for esophageal adenocarcinoma,
different phenotypes of reflux disease, including non- although it is not yet clear whether interventions to reduce
erosive reflux disease, which can lead to atypical manifes- these risk factors can reduce the risk of progression to
tations including ENT and respiratory manifestations. cancer.26 More speculative is the suggestion that the
Advances in impedance testing and biomarkers such microbiome may also be relevant to the pathogenesis of
as salivary pepsin are interesting approaches that have this disease and it is provocative to consider how the
been evaluated recently and are discussed by Vaezi et al.19 widespread introduction of antibiotics may have altered
It should be remembered that whether or not the reflux- the gastrointestinal flora with untold effects on disease
ate will cause epithelial damage depends on the balance susceptibility.
between aggressive (degree of refluxate) and defensive The cellular and molecular pathogenesis of Barrett’s
forces (eg, epithelial resistance). The sensory mechanisms esophagus has been an active topic of research over many
will then determine the relationship between reflux expo- years and the precise mechanisms are still under debate.
sure and symptom generation and here other factors such Drs Michael Quante, Trevor A. Graham and Marnix Jansen27
as stress and psycho-social co-morbidities will also play a (pages 406–420) suggest that Barrett’s can be seen as a
role, as discussed by Drs Jan Tack and John E. Pandolfino18 successful adaptation to esophageal damage.26 In carcino-
(pages 277–288). genesis, this evolutionary process continues as an interac-
The second section focuses on eosinophilic esophagitis. tion between the inflammatory microenvironment on the
The cause for this newly defined disease seems closely one hand and the acquisition of somatic genomic alterations
related to an allergic-type reaction, which promotes eosino- in evolving stem cell populations on the other. In this article
phil mediated inflammation. In some cases, there is expres- the various model frameworks for understanding the origin
sion of a unique set of genes, which probably relates to of Barrett’s esophagus are discussed in favor of the devel-
underlying genetic susceptibility and interactions with envi- opment from a stem cell, such as a gastric cardia stem cell,
ronmental exposures in early life. The microbiome may also or a submucosal stem cell (squamous gland duct cells).28
play a role, although details of this are not yet fully under- Although there are a number of unanswered questions
stood (see article by Drs Kelly M. O’Shea, Seema S. Aceves, about the development of Barrett’s, what is clear is that the
Evan S. Dellon, Sandeep K. Gupta, Jonathan M. Spergel, Glenn resulting metaplasia and its risk for cancer result in a
T. Furuta, and Marc E. Rothenberg on pages 333–345).23 complex and heterogeneous landscape which makes the
Currently, treatment hinges on dampening down the in- development of predictive biomarkers challenging.
flammatory response including through the use of topical The revolution in sequencing technology has enabled
steroids and dietary manipulation. Long-term topical steroid us to study the esophageal genome at an unprecedented
use is a concern in patients diagnosed as children who may level of detail and the The Cancer Genome Atlas (TCGA)28
have long duration of disease. However, as our understanding and International Cancer Genome Consortium (ICGC)
of the pathogenesis increases this may inform specific ther- efforts29–31 have rendered a vehicle for standardized data-
apeutic strategies, including disruption of allergic inflam- sets available to the wider research community.10,29 The
matory and T- helper type 2 cytokine-mediated responses. initial hopes that this new understanding would result in a
The duration of untreated disease is the best predictor of paradigm shift for therapeutic approaches have not mate-
stricture risk; this highlights the importance of early diag- rialized. However, a new era of trials are starting to emerge
nosis and therapy. Prospective long-term outcome studies, in which; a) histological subtypes are considered as distinct
focused on multiple aspects of disease activity, are needed to entities; b) the imaging assessments and surgical manage-
fully understand the disease pathogenesis and to develop ment are standardized; and c) molecular targeted therapies
new therapeutic strategies. Such studies would be aided by are introduced to the relevant patient groups following
less invasive, bedside diagnostic tools that avoid reliance on stratification. It is vital that we continue to refine the
repeated endoscopy and biopsy (see article by Drs Alex trial designs to be more adaptive as new information is
Straumann and David A. Katzka on pages 346–359).24 gleaned and as new agents become available. To make the
January 2018 Introduction 265

step change in outcome that we are all waiting for, the with these common, debilitating and in some cases life-
challenge now is to understand the functional relevance of threatening conditions.
the genomic changes that we are describing and to integrate We are grateful to our dedicated and expert authors
the host and micro-environmental factors into these studies. for this issue’s content, to our thoughtful reviewers for
This requires better model systems and, thanks to progress honing the articles, and to the staff at AGA and Elsevier for
in mouse models and human 3D models, this should be their tireless efforts. In particular, we would thank Laura
possible in the near future.32,33 Flecha and Brook Simpson, special issue managing editors;
Early detection is a key to progress. In some ways, Tiffany Slaybaugh DaVanzo, medical illustrator; Sarah
esophageal cancer has led the way for early detection and Williamson, senior medical illustrator; and Kristine Novak,
monitoring strategies, due to the recognition of Barrett’s science editor.
esophagus as a pre-cancerous lesion. In the past decade,
treatment options for these patients have been one of the
real success stories in cancer prevention, with endoscopic References
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