Review
Submucosal surgery: novel interventions in the third space
Lancet Gastroenterol Hepatol
2018; 3: 134–40
Department of Surgery,
Northwestern University
Feinberg School of Medicine,
Chicago, IL, USA
(E N Teitelbaum MD); Institute
of Image-guided Surgery,
Strasbourg, France
(Prof L L Swanstrom MD);
Interventional Endoscopy and
Foregut Surgery, The Oregon
Clinic, Portland, OR, USA
(Prof L L Swanstrom); and
Oregon Health Science
University, Portland, OR, USA
(Prof L L Swanstrom)
Correspondence to:
Dr Ezra N Teitelbaum,
Department of Surgery, Division
of GI/Oncologic Surgery,
Northwestern University
Feinberg School of Medicine,
Chicago, IL 60611, USA
ezra.teitelbaum@nm.org
134 www.thelancet.com/gastrohep Vol 3 February 2018
Ezra N Teitelbaum, Lee L Swanstrom
Traditional surgeries involve accessing body cavities, such as the abdomen and thorax, via incisions that divide skin and
muscle. These operations result in postoperative pain and convalescence, and a risk of complications such as wound
infection and hernia. The development of flexible endoscopy allowed diseases as varied as gastrointestinal bleeding and
colon adenomas to be treated without incisions, but this technique is restricted by its endoluminal nature. A novel
category of surgical endoscopic procedures has recently been developed that uses flexible endoscopic techniques to
enter and access the submucosa of the gastrointestinal tract. Through this approach, the advantages of incisionless
endoscopy can be applied to areas of the body that previously could only be reached with surgery. This Review introduces
this new class of interventions by describing two examples of such submucosal surgeries for the treatment of benign
gastrointestinal disease: per-oral endoscopic myotomy and per-oral pyloromyotomy. The approach to pre-procedure
patient evaluation, operative technique, and the published outcomes are discussed, as well as potential future
applications of similar techniques and procedures in this so-called third space.
Introduction pre-malignant and early-stage malignant lesions could be
Over the past 150 years, surgery has evolved along two effectively treated without the morbidity of an open
parallel trajectories: the introduction of innovations that surgical approach. Following these endoscopic and
have allowed surgeons to safely and effectively operate in endovascular advances, laparoscopic and thoracoscopic
an increasing number of cavities, or spaces, within the surgeries were introduced in the late 1980s and early
human body; and the development of techniques and 1990s, respectively. These novel and minimally invasive
technologies that have allowed such operations to techniques greatly reduced the postoperative conval­
become less invasive. From the mid-19th to mid-20th escence period and morbidity associated with a wide
centuries, progress was largely due to medical advances range of operations. As technology, ex­ perience, and
in anaesthesia, sterile technique, transfusion medicine, education have continued to progress, medicine has
and postoperative care, that allowed surgeons to safely reached a point at which almost any disease process
operate in the abdominal and, subsequently, thoracic requiring a procedural intervention can be treated with a
cavities. By the 1970s and 1980s, advances in fibre optics, minimally invasive surgical or endoscopic approach.
video technology, and fluoroscopy led to the introduction This Review will focus on a novel set of techniques and
of flexible endoscopy and endovascular procedures. procedures that now allow physicians to intervene in a
These advances allowed proceduralists to assess and so-called third space: within the submucosal layer of the
treat pathologies in a second space, the intra­ luminal gastrointestinal tract. Flexible endoscopists have long
cavities of the gastrointestinal, pulmonary, vascular, used a saline lift technique, or injection of fluid into the
and genitourinary systems. Conditions as varied as submucosa, to separate the mucosa and muscularis
gastrointestinal bleeding, abdominal aortic aneurysm, propria layers of the oesophagus, stomach, and colon
benign prostatic hypertrophy, and a range of during mucosal focused treatments such as polypectomy.
As endoscopists became comfortable with more
advanced procedures, such as mucosectomy or endo­
Panel 1: Gastrointestinal diseases treated with submucosal scopic submucosal dissection, they realised that, by
dissection techniques incising the mucosa overlying an area of saline lift, the
Oesophagus tip of the endoscope could be inserted through this
• Achalasia mucosotomy and into the submucosal space. Once
• Barrett’s oesophagus with low-grade or high-grade inside, the use of CO2 insufflation and clear dissecting
dysplasia caps (also called hoods) create space for the endoscopist
• T1a oesophageal adenocarcinoma to navigate between the various layers of the submucosa.
• Leiomyoma This procedure allows for interventions to be done within
• Zenker’s diverticulum or cricopharyngeal bar the lining of the bowel wall, an approach that cannot be
achieved by laparoscopy or simple flexible endoscopy.
Stomach This new technique has led to the introduction of novel,
• Gastroparesis less invasive, and sometimes unique, surgical approaches
• Gastrointestinal stromal tumour to various gastrointestinal diseases (panel 1). This Review
• T1a gastric adenocarcinoma describes the technical aspects of two such operations for
Colon the treatment of benign diseases: per-oral endoscopic
• Polyps that are not resectable with standard polypectomy myotomy (POEM) for achalasia, and per-oral endoscopic
techniques pyloromyotomy (POP) for gastroparesis. The discussion
will focus on the preoperative evaluation of patients, the

technical aspects of the operations, their reported
outcomes to date, and the ways in which the third space
might be used to treat disease processes in the future.
Per-oral endoscopic myotomy
Achalasia is a rare disease of oesophageal motility that
results from an immune-mediated loss of neurons in the
myenteric plexus of the oesophagus. This loss causes a
failure of both lower oesophageal sphincter relaxation
and oesophageal body peristalsis in response to
swallowing, leading to symptoms of dysphagia,
regurgitation, and chest pain.1 There is no known means
to reverse the neuronal loss that causes achalasia, so
treatments aim to mechanically disrupt the muscles of
the lower oesophageal sphincter to facilitate the passive
transit of food boluses into the stomach. The first such
treatment strategy, oesophageal dilation, was done by
Thomas Willis in the 17th century by inserting a
whale­ bone through the patient’s mouth.2 Although
treatment modalities have advanced considerably since
that time, the basic tenant of lower oesophageal sphincter
disruption remains the same. Two standard of care
options exist that achieve this disruption via markedly
different means. Endoscopic pneumatic dilation uses an
inflatable balloon to stretch the lower oesophageal
sphincter muscle fibres radially, whereas laparoscopic
Heller’s myotomy is a surgical procedure involving a
controlled longitudinal division of the lower oesophageal
sphincter muscular complex. Endoscopic dilation offers
the advantage of a less invasive, incisionless approach
with a quicker recovery, whereas Heller’s myotomy
provides more durable symptomatic relief without the
need for multiple reinterventions.3,4
POEM is a novel operation that combines the
advantages of pneumatic dilation and Heller’s myotomy
in a single procedure. In POEM, the submucosal space
is used to create a controlled endoscopic myotomy
across the lower oesophageal sphincter. Expanding on
techniques of endoscopic submucosal dissection, such
as saline lift, mucosal incision, and submucosal
tunnelling, this procedure was first accomplished in an
animal model by Pasricha and colleagues.5 In 2008,
POEM was translated into clinical use by Inoue and
colleagues,6 who perfected the technique and aided its
dissemination by teaching the procedure to visiting
physicians from around the world. Although long-term
outcome data are certainly needed, patients have
grasped the potential advantages of POEM, and it is
quickly supplanting pneumatic dilation and Heller
myotomy as the procedure of choice for the treatment of
achalasia and other oesophageal motility disorders.
Indications and preoperative evaluation
Achalasia and other oesophageal motility disorders are
the primary indications for POEM. Panel 2 outlines
the indications and contraindications for the procedure.
A diagnostic flexible upper endoscopy is an essential
www.thelancet.com/gastrohep Vol 3 February 2018 135
Review
Panel 2: Indications and contraindications for per-oral
endoscopic myotomy (POEM)
Indications
• Achalasia (types I, II, and III)
• Oesophagogastric junction outflow obstruction with
preserved peristalsis*
• Distal oesophageal spasm†
• Jackhammer oesophagus†
Contraindications
• Inability to tolerate general anaesthesia
• Oesophageal varices or uncorrectable coagulopathy
• Para-oesophageal hernia
• Type I hiatal hernia‡
*Patients with oesophagogastric junction outflow obstruction require careful clinical
evaluation to establish whether their oesophageal dysmotility is the result of another
disease process, such as gastro-oesophageal reflux. †Patients with distal oesophageal
spasm and jackhammer oesophagus should undergo a medical therapy trial (nitrates,
calcium channel blockers, etc) before POEM. ‡Type I hiatal hernia is a contraindication
to POEM, as it predisposes patients to higher rates of postoperative iatrogenic
gastro-oesophageal reflux than in those without hiatal hernias.
Panel 3: Operative steps and key principles of per-oral
endoscopic myotomy
Submucosal injection and mucosotomy
• Accurately identify the oesophagogastric junction and
measure it in relation to the planned mucosotomy site
• Use CO2 rather than air insufflation (for the entire
procedure)
• Use an oesophageal overtube (for the entire procedure)
• Use a transparent dissecting cap (for the entire procedure)
• Keep the mucosotomy straight, longitudinal, and just
large enough to accommodate the endoscope tip
(around 1 cm diameter)
Submucosal tunnel creation
• Keep the tunnel directly on the circular muscle side to
avoid inadvertent mucosal injury
• Accurately assess the endpoint of the tunnel to ensure a
gastric myotomy that extends 2–3 cm beyond the
oesophagogastric junction
Myotomy
• Hook and cauterise individual muscle fibres
• Perform a selective myotomy of the inner, circular muscle
fibres
Mucosotomy closure
• Close the mucosotomy with either clips or an endoscopic
suturing device
• Begin the closure at its most distal aspect and work
proximally
first step in the evaluation of patients with dysphagia to
rule out an obstructing tumour, peptic stricture, or other
forms of mechanical obstruction (ie, pseudo-achalasia).
 Review
A B C D
Oesophagus
Diaphragm
Lower
oesophageal
Stomach sphincter
Figure 1: Steps of per-oral endoscopic myotomy
(A) Mucosotomy. (B) Entry into submucosal space. (C) Submucosal tunnel. (D) Beginning of myotomy. (E) Myotomy completed. (F) Clip closure. Reproduced from
Hungness and colleagues,8 by permission of Wolters Kluwer Health.
Patients with dysphagia and a negative endoscopy should
then undergo a high-resolution manometry to confirm
the diagnosis of achalasia or other oesophageal motility
disorders, according to the Chicago classification.7 Finally,
a timed contrast oesophagram should be done, as it pro­
vides the best anatomical evaluation of the oesophagus
and can serve as a valuable tool for longitudinal follow-up.
Important anatomical consider­ations related to POEM
are oesophageal dilatation and tortuosity, and the degree
of angulation at the oesophagogastric junction. Severe
dis­tortions of these parameters can make POEM
technically challenging. The detection of a hiatal hernia
on either oesophagram or endoscopy can also be
considered a contraindication to POEM, as the presence
of a hiatal hernia will predispose the patient to iatrogenic
gastro-oesophageal reflux postoperatively.8
Operative technique
See Online for video Panel 3, figure 1, and the video outline the operative steps
of POEM. Here, we describe our specific technique for the
procedure. POEM is done under general anaesthesia with
endotracheal intubation and muscle paralysis. A standard
high-definition flexible gastroscope is used, but it must be
equipped with the capacity for insufflation with CO2,
rather than room air, to avoid the formation of tension
pneumothorax or pneumoperitoneum. An oesophageal
overtube is placed and the gastroscope is fitted with a
transparent dissecting cap to enable tissue retraction and
the creation of tension and counter-tension while the
surgeon is working in the submucosal space.
After a diagnostic upper endoscopy, the oesophagus
and stomach are irrigated and suctioned clear. Measure­
ments from the incisors to the squamocolumnar junction
are made using the scope shaft markings to calibrate
the scope’s location during subsequent dissection.
136 www.thelancet.com/gastrohep Vol 3 February 2018
E F
Understanding of the location of the scope tip in relation
to the oesophagogastric junction is crucial in order for
the final myotomy to transect the entire lower
oesophageal sphincter. To aid visualisation, we begin the
procedure by injecting blue dye into the submucosa
of the stomach, approximately 2–3 cm distal to the
oesophagogastric junction on the anterior lesser
curvature. This injection marks where the submucosal
dissection will end and helps to ensure that the
subsequent myotomy will extend across the lower
oesophageal sphincter and onto the gastric wall.
An endoscopic injection needle is then used to create a
submucosal bleb in the right anterior wall of the distal
oesophagus, at a 2 o’clock to 3 o’clock position. A mixture
of normal saline and methylene blue dye is used, because
the blue dye helps to differentiate the layers of the
oesophageal wall and marks the tunnel’s progression.
The length of the myotomy depends on the Chicago
classification7 and the degree of oesophageal dilation,
with Chicago type III achalasia usually requiring a
longer myotomy that ablates the entire segment of
spastic oesophageal contraction, and end-stage achalasia
(sigmoid oesophagus) having a relatively short myotomy
addressing just the lower oesophageal sphincter. The
injection is done approximately 3 cm proximal to the
start point of the planned myotomy, to allow a gap
between the mucosotomy and the beginning of the
myotomy. This gap helps to prevent a full-thickness leak
into the mediastinum, in case of a failure in the closure
of the mucosotomy. An endoscopic cautery knife is used
to create a longitudinal incision in the mucosa overlying
the submucosal bleb, allowing access into the submucosa.
With the aid of the dissecting cap, the gastroscope is then
manoeuvered through the mucosotomy to a plane between
the submucosa and muscularus propria. Electrocautery

dissection is used to clear areolar tissue and create a
longitudinal tunnel between muscle and submucosa down
the oesophagus, past the oeso­phagogastric junction, and
into the stomach. It is essential to stay directly on the
circular muscle layer of the tunnel during this dissection,
both because it is the surgical target and to avoid inadvertent
mucosal injuries. The tunnel should extend at least 3 cm
onto the gastric wall so that the subsequent myotomy has
an adequate length. The length and endpoint of the tunnel
can be verified in several ways, including the presence of
the full-strength blue dye that was injected 3 cm distal to
the squamocolumnar junction. Additionally, several anato­
mical changes are noted as the oesophago­gastric junction
is crossed, including the presence of disorganised oblique
muscle fibres in the stomach (as opposed to the neatly
arranged circular and longitudinal layers of the
oesophagus), the palisading mucosal blood vessels in the
stomach mucosa, and the tightening of the submucosal
tunnel as the lower oesophageal sphincter is crossed before
it opens up widely in the stomach. Some endoscopists have
even used a second paediatric gastroscope to check the
position of the tunnelling scope light from a retroflexed
position in the lumen of the stomach.9
Once the submucosal tunnel is completed, the myotomy
is performed. The myotomy should begin at least 2 cm
cephalad to the proximal extent of the lower oesophageal
sphincter high-pressure zone and should extend 2–3 cm
into the stomach. POEM was first described with use of a
selective myotomy technique, in which only the circular
fibres of the oesophageal muscularis propria are divided,
with the longitudinal fibres left intact. We still use this
technique, primarily to keep the longitudinal fibre layer as
a safety margin, to prevent injury to the surrounding
mediastinal structures, but also because there is evidence
that post-myotomy reflux rates might be lower than with a
full-thickness myotomy.10 The circular layer is much
thicker than the longitudinal layer, and preserving the thin
longitudinal fibres does not seem to result in functionally
inferior outcomes. However, some endoscopists have
advocated doing a full-thickness myotomy primarily to
save time.11 To do a selective myotomy, individual circular
muscle fibres are hooked and divided with an endoscopic
cautery knife with either a triangular, circular, or straight
tip. Care is taken to avoid injuring the mediastinal
structures outside the longitudinal layer and the mucosal
layer on the opposite side of the submucosal tunnel. Once
the myotomy is complete, the gastroscope is withdrawn
into the true oesophageal lumen and the mucosotomy is
closed. This closure can be done with either clips or an
endoscopic suturing device, but the use of clips is quicker
than sutures and provides a secure closure in almost
all cases.12
Outcomes
The published worldwide experience with POEM now
numbers many thousands of cases, and the perioperative
safety and short-term outcomes of the procedure have
www.thelancet.com/gastrohep Vol 3 February 2018 137
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been fairly well established.13 POEM is a safe operation,
with a complication profile similar to that of laparoscopic
Heller’s myotomy. Serious complications such as tension
capnothorax, bleeding, and oesophageal or gastric
perforation have occurred in 0–3% of patients in larger
series.8,14–16 Because of the absence of incisions, recovery
after POEM seems to be faster than after laparoscopic
Heller’s myotomy, with a shorter hospital stay and a
faster return to activities of daily living.16,17
POEM seems to have a procedural learning curve that
is associated with perioperative outcomes. The novel
nature of operations within the submucosal space makes
it challenging even for experienced endoscopists to
become proficient at POEM. Studies have shown an
increased operative time and rate of mucosal perforations
early in the learning curve.18,19 Therefore, POEM should
be done only by physicians with substantial interventional
endoscopy experience and an adequate number of
achalasia patients in their practice. Even for seasoned
endoscopists, we recommend a gradated introduction to
POEM consisting of live obser­vations of an experienced
POEM practitioner, followed by extensive laboratory
practice with explant, live animal, and cadaver models,
and finally doing the initial clinical POEM procedure
with the assistance of an experienced proctor.20
Short-term symptomatic and physiological outcomes
after POEM for the treatment of achalasia are excellent
and similar to those of laparoscopic Heller’s myotomy and
endoscopic pneumatic dilation, the standard of care
treatments. Patients who underwent POEM experience
immediate improvement of dysphagia and regurgitation
symptoms in 90–95% of cases.16,21,22 As with other
interventions for achalasia, improvements in chest pain
were not as uniform. Few data for long-term outcomes are
available, but initial results are promising. As with Heller’s
myotomy and pneumatic dilation, symptom recurrence
can occur years after POEM, even in patients with an
excellent initial response to the procedure. Studies looking
at symptomatic relief 2–3 years after POEM have shown a
durability of success in 79–92% of patients.8,14,15 In our own
institutional series, the rate of symptomatic success at
5 years is 83% in patients with achalasia,23 similar to the
5-year outcomes of the European achalasia trial published
in 2016,24 comparing laparoscopic Heller’s myotomy
(84% success) with pneumatic dilation (82% success).
An early concern when POEM was introduced was
that the rate of iatrogenic gastro-oesophageal reflux after
the procedure would be prohibitive, because POEM is
done without the addition of an anti-reflux procedure
(which is typically done during Heller’s myotomy, by use
of a partial fundoplication). Thus far, POEM series have
shown rates of abnormal distal oesophageal acid
exposure ranging from 37% to 40%8,16 on 24 h pH
monitoring.8,15,16 These rates were only slightly higher
than the incidences of reflux after Heller’s myotomy
with partial fundoplication, which have ranged from
21% to 42% in well-controlled trials.25,26 This might be
 Review
because the phreno-oesophageal ligament and angle of
His, which form the body’s natural anti-reflux valve, are
left intact during POEM, whereas they must be disrupted
during laparoscopic Heller’s myotomy in order to access
the oesophagus.
In the future, long-term outcomes of POEM and direct
comparisons with both laparoscopic Heller’s myotomy
and endoscopic pneumatic dilation will be of key interest.
However, patients have already begun to seek treatment
with POEM, because of its theoretical advantages over
Heller’s myotomy, in terms of faster recovery, and over
pneumatic dilation, with respect to effectiveness and
durability. As further data emerge and more practitioners
become trained, POEM is likely to become the preferred
initial treatment for achalasia and other primary
oesophageal motility disorders.
Per-oral pyloromyotomy
Gastroparesis is a disease defined by delayed gastric
emptying in the absence of mechanical obstruction.
Patients have postprandial bloating, nausea, and vomiting
that can progress to near-complete food intolerance and
malnutrition. Gastroparesis can be caused by diabetes or
iatrogenic vagus nerve injury during foregut surgery.
However, in most cases the disease is idiopathic. Dietary
modifications, tight glycaemic control, and promotility
medications, such as metoclopramide and erythromycin,
form the mainstay of treatment, but many patients are
refractory or develop tolerance to these therapies.27 In
A B
C D
Figure 2: Steps of per-oral pyloromyotomy
(A) Mucosotomy site selection. (B) Mucosotomy. (C) Submucosal tunnel. (D) Myotomy.
138 www.thelancet.com/gastrohep Vol 3 February 2018
patients who have not responded to medical therapy,
surgical interventions have been attempted. The most
rigorously studied of these interventions is gastric electrical
stimulation with an implanted subcutaneous generator,
which connects to leads that are laparoscopically inserted
into the stomach wall. Gastric stimulation has been shown
to improve gastroparesis symptoms in several studies,
including one randomised and blinded cross-over study in
which patients were not aware whether their device was
turned on or off after implantation.28 However, this effect
appeared to be restricted to patients with diabetic
gastroparesis, whereas those with idiopathic disease did
not have a symptomatic improvement with stimulation.
Laparoscopic pyloroplasty has also been used as a treat­
ment for medically refractory gastroparesis. Although not
as well studied as gastric electrical stimulation, lapa­roscopic
pyloroplasty has been shown in small studies to improve
gas­troparesis symptoms and gastric emptying times.29
Just as POEM is an endoscopic alternative to
laparoscopic Heller’s myotomy, a novel procedure, POP,
has been introduced as an endoscopic alternative to
laparoscopic pyloroplasty. The worldwide experience with
POP (sometimes called G-POEM) is just starting and only
a handful of single-centre case series have been reported.
However, the possibility of an effective incisionless
procedure for patients with gastroparesis, who are often
in chronic pain and prone to complications due to
malnutrition, makes POP an attractive therapy.
Indications and preoperative evaluation
POP is being used to treat patients with gastroparesis
whose symptoms are refractory to diet modification and
medical therapy. Because POP is a novel procedure with
few data on outcomes, its use should be restricted to
centres and practitioners with substantial therapeutic
endoscopy experience, including POEM, and patients
should be enrolled with appropriate consent in studies
with a protocol approved by an institutional review board.
Patients should undergo an upper endoscopy to rule out
malignancies, strictures, or other forms of mechanical
obstruction, and the diagnosis of gastroparesis should be
confirmed with a gastric emptying study based on 4 h
emptying time.30 A 24 h pH monitoring study should also
be considered in patients with symptoms of gastro-
oesophageal reflux in addition to gastroparesis. If
objective reflux is present, the combination of an
antireflux procedure (such as laparoscopic or transoral
incisionless fundoplication) with any proposed gastric
emptying procedure should be considered, because
fundoplication itself can improve gastric emptying while
also eliminating reflux.31
Operative technique
POP is done in a similar manner to POEM and includes
the same basic operative steps: submucosal injection and
mucosotomy, submucosal tunnel creation, myotomy,
and mucosotomy closure (figure 2). The injection and

mucosotomy are done in the anterior wall of the antrum,
and along the greater curvature, beginning approximately
5 cm proximal to the pylorus. A key difference between
POP and POEM is that the stomach can be very dilated
and J shaped in patients with gastroparesis. This feature
makes the endoscope more difficult to manoeuvre than
in the oesophagus, and one-to-one motion of the scope
tip can be difficult to achieve. The use of a long overtube
to reduce scope looping can be helpful.
The submucosal tunnel is created to the end of the
pyloric ring but not onto the duodenum, staying on the
muscle side to avoid inadvertent mucosal injuries.
A full-thickness myotomy is then done to ablate the
pyloric ring, taking care to avoid extending the myotomy
onto the duodenum, which can risk a full-thickness
perforation that might require an immediate conversion
to laparoscopic repair. Once the myotomy is complete, the
mucosotomy is closed. The gastric mucosa is considerably
thicker than that of the oesophagus, which makes
mucosotomy closure during POP more challenging.
During POEM, the mucosotomy can almost always be
closed with endoscopic clips, but during POP, an
endoscopic suturing device is often required.
Outcomes
Data on outcomes after POP are restricted to small, single-
centre series. We reported a series of seven patients
treated with POP for idiopathic and post-surgical gastro­
paresis.32 One perioperative complication occurred, a
bleeding ulcer in the pyloric channel in a patient who
did not take the recommended proton-pump inhibitor
post­operatively. Six of the seven patients had improve­
ments in their gastr­oparesis symptoms as a result of POP
at an average follow-up of 6·5 months, and a substantial
improvement in gastric emptying times was observed.32
Other groups have reported successful completion of
small series of POP procedures, with resulting
improvements in symptoms, gastric emptying times,
and quality of life at short-term follow-up.33,34 One multi-
centre study of 30 patients showed that POP was
completed in all patients with a low morbidity rate of
6·7% and normalisation or improvement of gastric
emptying times in almost all patients (47% normalised
and 35% improved).35 Obviously, more experience with
the procedure and data on long-term outcomes are
required before the safety and efficacy of POP can be fully
evaluated, but the procedure is an exciting potential option
for patients and a disease with few effective therapies.
Future directions
As surgical endoscopists gain experience in accessing
and operating in the submucosal space, several potential
novel procedures could make use of these techniques.
Submucosal tunnelling has already been used to create a
safe entry into the peritoneal cavity during natural orifice
transluminal endoscopic surgery procedures (NOTES).36
As flexible endoscope technology advances to allow for
www.thelancet.com/gastrohep Vol 3 February 2018 139
Review
Search strategy and selection criteria
References for this Review were identified through searches
of PubMed with the search terms “submucosal surgery”,
“interventional endoscopy”, “peroral endoscopic myotomy”,
“achalasia”, “peroral pyloromyotomy”, and “gastroparesis”
from Jan 1, 2007, to July 1, 2017. Articles were also identified
through searches of the authors’ own files. Only papers
published in English were reviewed. The final reference list
was generated on the basis of scientific importance and
relevance to the scope of this Review.
more sophis­ticated retraction and tissue manipulation,
operating in the abdomen via transgastric, incisionless
access might become a more feasible reality. Access to the
third space also offers the potential for delivery of devices
and drugs that interact with the enteric musculature and
nervous system. Studies in animal models and small
human case series have shown the feasibility of implanting
electrical stimulators into the submucosal space.37,38 These
stim­ulators could be used to augment lower oesophageal
sphincter tone to treat gastro-oesophageal reflux disease
or increase gastric peristalsis in patients with gastroparesis.
Another pilot study in patients with gastro-oesophageal
reflux disorder used submucosal access to inject Plexiglas
(Evonik, Essen, Germany) microspheres into the lower
oesophageal sphincter, resulting in the improvement of
symptoms and decreased oesophageal acid exposure on a
follow-up 24 h pH testing.39 Although these techniques
and technologies are all in the early stages of development
and clinical evaluation, they offer a novel approach to
treating diseases of the gastrointestinal tract that could
benefit patients with a broad range of conditions.
Conclusions
Procedural interventions will undoubtedly continue to
evolve along a trajectory towards reduced invasiveness.
Central to these advances is the increased use of flexible
endoscopy to treat diseases that were once the domain
of open surgical procedures. As endoscope technology
advances to include robotics and instruments that can
more effectively retract, suture, and divide tissues via
transoral access, the capabilities of flexible endoscopy
will continue to expand. In addition to technological
innovation, the use of existing devices in novel ways is of
equal importance. The techniques for submucosal surgery
were developed using pre-existing endoscopic instruments,
such as injection needles, cautery knifes, and clips, all of
which were originally developed for other purposes. This
overlap allowed for the rapid adoption of POEM in centres
around the world, placing the procedure on a trajectory to
potentially supplant both endoscopic pneumatic dilation
and laparoscopic Heller’s myotomy as the intervention of
choice for patients with achalasia. Although physicians
must continue to carefully evaluate the outcomes of
submucosal surgical procedures, and to counsel their
 Review
patients regarding more established therapeutic alter­
natives, they likewise need to be assertive in learning and
perfecting these novel techniques so that more patients
can benefit from an incisionless approach to the treatment
of their disease.
Contributors
ENT participated in concept development, literature search, manuscript
composition, and manuscript revision. LLS participated in concept
development, manuscript composition, and manuscript revision.
Declaration of interests
We declare no competing interests.
References
1 Boeckxstaens GE, Zaninotto G, Richter JE. Achalasia. Lancet 2014;
383: 83–93.
2 Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to
laparoscope. JAMA 1998; 280: 638–42.
3 Yaghoobi M, Mayrand S, Martel M, Roshan-Afshar I, Bijarchi R,
Barkun A. Laparoscopic Heller’s myotomy versus pneumatic
dilation in the treatment of idiopathic achalasia: a meta-analysis of
randomized, controlled trials. Gastrointest Endosc 2013; 78: 468–75.
4 Schoenberg MB, Marx S, Kersten JF, et al. Laparoscopic Heller
myotomy versus endoscopic balloon dilatation for the treatment of
achalasia: a network meta-analysis. Ann Surg 2013; 258: 943–52.
5 Pasricha PJ, Hawari R, Ahmed I, et al. Submucosal endoscopic
oesophageal myotomy: a novel experimental approach for the
treatment of achalasia. Endoscopy 2007; 39: 761–64.
6 Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy
(POEM) for esophageal achalasia. Endoscopy 2010; 42: 265–71.
7 Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago Classification
of oesophageal motility disorders, v3.0. Neurogastroenterol Motil
2015; 27: 160–74.
8 Hungness ES, Sternbach JM, Teitelbaum EN, Kahrilas PJ,
Pandolfino JE, Soper NJ. Per-oral endoscopic myotomy (POEM)
after the learning curve: durable long-term results with a low
complication rate. Ann Surg 2016; 264: 508–17.
9 Worrell SG, Alicuben ET, Boys J, DeMeester SR. Peroral endoscopic
myotomy for achalasia in a thoracic surgical practice.
Ann Thorac Surg 2016; 101: 218–24.
10 Wang XH, Tan YY, Zhu HY, Li CJ, Liu DL. Full-thickness myotomy
is associated with higher rate of postoperative gastroesophageal
reflux disease. World J Gastroenterol 2016; 22: 9419–26.
11 Li C, Gong A, Zhang J, et al. Clinical outcomes and safety of partial
full-thickness myotomy versus circular muscle myotomy in peroral
endoscopic myotomy for achalasia patients. Gastroenterol Res Pract
2017; published online Feb 21. DOI:10.1155/2017/2676513.
12 Pescarus R, Shlomovitz E, Sharata AM, et al. Endoscopic suturing
versus endoscopic clip closure of the mucosotomy during a per-oral
endoscopic myotomy (POEM): a case-control study. Surg Endosc
2016; 30: 2132–35.
13 Crespin OM, Liu LWC, Parmar A, et al. Safety and efficacy of POEM
for treatment of achalasia: a systematic review of the literature.
Surg Endosc 2017; 31: 2187–201.
14 Inoue H, Sato H, Ikeda H, et al. Per-oral endoscopic myotomy:
a series of 500 patients. J Am Coll Surg 2015; 221: 256–64.
15 Werner YB, Costamagna G, Swanstrom LL, et al. Clinical response
to peroral endoscopic myotomy in patients with idiopathic achalasia
at a minimum follow-up of 2 years. Gut 2016; 65: 899–906.
16 Bhayani NH, Kurian AA, Dunst CM, Sharata AM, Rieder E,
Swanstrom LL. A comparative study on comprehensive, objective
outcomes of laparoscopic Heller myotomy with per-oral endoscopic
myotomy (POEM) for achalasia. Ann Surg 2014; 259: 1098–103.
17 Ujiki MB, Yetasook AK, Zapf M, Linn JG, Carbray JM, Denham W.
Peroral endoscopic myotomy: A short-term comparison with the
standard laparoscopic approach. Surgery 2013; 154: 893–97.
18 Teitelbaum EN, Soper NJ, Arafat FO, et al. Analysis of a learning
curve and predictors of intraoperative difficulty for peroral
oesophageal myotomy (POEM). J Gastrointest Surg 2014; 18: 92–98.
19 Kurian AA, Dunst CM, Sharata A, Bhayani NH, Reavis KM,
Swanstrom LL. Peroral endoscopic oesophageal myotomy:
defining the learning curve. Gastrointest Endosc 2013; 77: 719–25.
140 www.thelancet.com/gastrohep Vol 3 February 2018
20 Swanstrom LL, Rieder E, Dunst CM. A stepwise approach and early
clinical experience in peroral endoscopic myotomy for the
treatment of achalasia and oesophageal motility disorders.
J Am Coll Surg 2011; 213: 751–56.
21 Teitelbaum EN, Soper NJ, Santos BF, et al. Symptomatic and
physiologic outcomes one year after peroral oesophageal myotomy
(POEM) for treatment of achalasia. Surg Endosc 2014; 28: 3359–65.
22 von Renteln D, Inoue H, Minami H, et al. Peroral endoscopic
myotomy for the treatment of achalasia: a prospective single center
study. Am J Gastroenterol 2012; 107: 411–17.
23 Teitelbaum EN, Dunst CM, Reavis KM, et al. Clinical outcomes
five years after POEM for treatment of primary oesophageal motility
disorders. Surg Endosc 2017; published online June 29.
DOI:10.1007/s00464-017-5699-2.
24 Moonen A, Annese V, Belmans A, et al. Long-term results of the
European achalasia trial: a multicentre randomised controlled trial
comparing pneumatic dilation versus laparoscopic Heller myotomy.
Gut 2016; 65: 732–39.
25 Boeckxstaens GE, Annese V, des Varannes SB, et al.
Pneumatic dilation versus laparoscopic Heller’s myotomy for
idiopathic achalasia. N Engl J Med 2011; 364: 1807–16.
26 Rawlings A, Soper NJ, Oelschlager B, et al. Laparoscopic Dor versus
Toupet fundoplication following Heller myotomy for achalasia:
results of a multicenter, prospective, randomized-controlled trial.
Surg Endosc 2012; 26: 18–26.
27 Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L.
Clinical guideline: management of gastroparesis. Am J Gastroenterol
2013; 108: 18–37.
28 Abell TL, Van Cutsem E, Abrahamsson H, et al. Gastric electrical
stimulation in intractable symptomatic gastroparesis. Digestion
2002; 66: 204–12.
29 Shada AL, Dunst CM, Pescarus R, et al. Laparoscopic pyloroplasty is
a safe and effective first-line surgical therapy for refractory
gastroparesis. Surg Endosc 2016; 30: 1326–32.
30 Abell TL, Camilleri M, Donohoe K, et al. Consensus
recommendations for gastric emptying scintigraphy: a joint report
of the American Neurogastroenterology and Motility Society and
the Society of Nuclear Medicine. Am J Gastroenterol 2008;
103: 753–63.
31 Farrell TM, Richardson WS, Halkar R, et al. Nissen fundoplication
improves gastric motility in patients with delayed gastric emptying.
Surg Endosc 2001; 15: 271–74.
32 Shlomovitz E, Pescarus R, Cassera MA, et al. Early human
experience with per-oral endoscopic pyloromyotomy (POP).
Surg Endosc 2015; 29: 543–51.
33 Dacha S, Mekaroonkamol P, Li L, et al. Outcomes and quality-of-life
assessment after gastric per-oral endoscopic pyloromyotomy
(with video). Gastrointest Endosc 2017; 86: 282–89.
34 Gonzalez JM, Lestelle V, Benezech A, et al. Gastric per-oral
endoscopic myotomy with antropyloromyotomy in the treatment of
refractory gastroparesis: clinical experience with follow-up and
scintigraphic evaluation (with video). Gastrointest Endosc 2017;
85: 132–39.
35 Khashab MA, Ngamruengphong S, Carr-Locke D, et al.
Gastric per-oral endoscopic myotomy for refractory gastroparesis:
results from the first multicenter study on endoscopic
pyloromyotomy (with video). Gastrointest Endosc 2017; 85: 123–28.
36 Pauli EM, Haluck RS, Ionescu AM, et al. Directed submucosal
tunneling permits in-line endoscope positioning for transgastric
natural orifice translumenal endoscopic surgery (NOTES).
Surg Endosc 2010; 24: 1474–81.
37 Deb S, Tang SJ, Abell TL, et al. Development of innovative techniques
for the endoscopic implantation and securing of a novel, wireless,
miniature gastrostimulator (with videos). Gastrointest Endosc 2012;
76: 179–84.
38 Banerjee R, Pratap N, Kalpala R, Reddy DN. Effect of electrical
stimulation of the lower oesophageal sphincter using
endoscopically implanted temporary stimulation leads in patients
with reflux disease. Surg Endosc 2014; 28: 1003–09.
39 Feretis C, Benakis P, Dimopoulos C, et al. Endoscopic implantation
of Plexiglas (PMMA) microspheres for the treatment of GERD.
Gastrointest Endosc 2001; 53: 423–26.