Surgical Treatment of High-Grade Dysplasia and Early ...
Transcript of Surgical Treatment of High-Grade Dysplasia and Early ...
SURGICAL SYMPOSIUM CONTRIBUTION
Surgical Treatment of High-Grade Dysplasia and EarlyEsophageal Cancer
Patrick J. McLaren1 • James P. Dolan1
Published online: 3 March 2017
� Societe Internationale de Chirurgie 2017
Abstract
Background The treatment of early-stage esophageal cancer and high-grade dysplasia of the esophagus has changed
significantly in recent years. Many early tumors that were traditionally treated with esophagectomy can now be
resected with endoscopic therapy alone. These new endoscopic modalities can offer similar survival outcomes
without the associated morbidity of a major operation. However, a number of these cases may still require surgical
intervention as the best treatment option.
Methods The current scientific literature, national and international guidelines were reviewed for recommendations
regarding optimal treatment of early esophageal malignancy.
Results The primary advantage of surgery over endoscopic treatment lies in the reduced risk of recurrence as well as
the ability to assess harvested lymph nodes for regional disease. We recommend that esophageal tumors that have
invaded into the submucosa (T1b) or beyond should be treated with an esophagectomy. In addition, dysplastic lesions
and cancers that demonstrate poorly differentiated pathology or lymphovascular or perineural invasion should be
surgically resected. Finally, large tumors, multifocal lesions, tumors within a long segment of Barrett’s esophagus,
tumors adjacent to a hiatal hernia, tumors that cannot be resected enbloc with endoscopic techniques should also be
treated with an esophagectomy.
Conclusions When performed at high-volume centers in experienced hands, esophagectomy can have consistently good
outcomes for high-grade dysplasia and early esophageal cancers, and should be considered as a treatment option.
Introduction
Esophageal cancer is a deadly malignancy, and long-term
survival is greatly dependent on the cancer stage at diag-
nosis. Overall 5-year survival for all stages of esophageal
cancer is reported to be no better than 19% [1]. Fortunately,
one-third of US esophageal cancers are now diagnosed in
the early stages of progression [2]. Consequently, if proper
treatment is rendered, high-grade dysplasia (HGD) and
early-stage cancer can have excellent outcomes, with five-
year survival rates as high as 90% [3–10]. Historically,
HGD and early esophageal cancer were treated with sur-
gical resection. The emergence of endoscopic treatments
over the last decade has led to many innovative treatments
for early cancers. Despite advances in these endoscopic
treatments, surgical resection still plays a major role in the
treatment of early esophageal cancers and HGD. In an
increasingly specialized medical continuum, it is important
that clinicians have updated information on treatment
options that maximize the chances of remission and mini-
mize unnecessary risk to their patients. Endoscopic
& James P. Dolan
1 Division of Gastrointestinal and General Surgery,
Department of Surgery, Oregon Health and Science
University, 3181 Sam Jackson Park Rd., Portland, OR 97239,
USA
123
World J Surg (2017) 41:1712–1718
DOI 10.1007/s00268-017-3958-y
treatments can often provide similar oncologic outcomes
without the morbidity and mortality associated with an
esophagectomy. However, in some circumstances these
endoscopic modalities have limitations that make
esophagectomy a better treatment option. When deter-
mining the best treatment, clinicians must weigh the
increased risk of cancer recurrence associated with endo-
scopic therapies against the morbidity and mortality
attributable to esophagectomy. In this article, we will dis-
cuss the contemporary guidelines for treatment of early
esophageal cancer and HGD and also examine the clinical
scenarios where surgical resection remains the best option.
Pathogenesis and staging of early esophagealcancer
Before discussing the surgical treatment of HGD and early
esophageal cancer, it is important to understand the histo-
logic features and terminology used to describe the stages
of disease. Furthermore, it may be informative to outline
the refined histopathologic staging system that has been
developed to guide treatment recommendations. There are
two main histologic types of esophageal cancer; squamous
cell carcinoma and adenocarcinoma. Squamous cell carci-
noma is the most common histology worldwide. In western
nations, the incidence of adenocarcinoma is rising at
alarming rates, overtaking squamous cell as the most
common subtype [1, 11]. The pathogenesis and risk factors
differ for the two subtypes, although the treatments are
generally the same and based on tumor stage, location, and
patient characteristics. Squamous cell carcinoma arises
from the squamous mucosal lining of the esophagus and is
more closely related to tobacco and alcohol consumption
[11]. On the other hand, the primary risk factor for the
development of adenocarcinoma is gastroesophageal reflux
disease (GERD) [11]. Repetitive exposure of the normal
esophageal mucosa to acidic gastric secretions or bile leads
to the development of intestinal metaplasia—an abnormal
histology commonly termed Barrett’s esophagus [12]. The
hallmark of Barrett’s esophagus is the finding of mucous
producing goblet cells within the epithelial lining of the
esophagus [12]. Cellular metaplasia may progress to dys-
plasia and predispose to the subsequent development of
HGD and esophageal adenocarcinomas. This being said, it
should also be noted that the presence of Barrett’s esoph-
agus is not absolutely required for HGD or invasive ade-
nocarcinoma to develop [13]. HGD represents a pre-
malignant carcinoma in situ which has not yet invaded
beyond the esophageal epithelium while subsequent deeper
penetration signifies invasive cancer. Spread to lymph
nodes is described as regional disease and metastasis rep-
resent the advanced stages of esophageal cancer.
At present, the T (tumor), N (node), M (metastatic dis-
ease) staging classification system, as described by the
American Joint Committee on Cancer (7th Edition, 2010),
is used to stage esophageal cancers [14]. By definition,
early cancers show no evidence of lymph node invasion or
distant metastasis on clinical staging; thus, the T-stage is
the most important determinant in deciding the best treat-
ment of early esophageal cancer. Stage is determined by
the depth of invasion through the layers of the esophageal
wall. These layers are shown in Fig. 1. High-grade dys-
plasia (Tis) is confined to the epithelium and does not
invade the lamina propria. T1 tumors are invasive cancers,
but do not extend beyond the submucosal layer of the
esophageal wall. T2 cancers extend into the muscularis
propria, but not through this layer, and T3 tumors extend
entirely through the muscularis propria to the adventitia.
Lastly, T4 tumors invade nearby organs such as the aorta,
pleura, trachea, and diaphragm. Early T1 tumors can be
further broken down into intramucosal cancer (T1a) and
submucosal cancer (T1b) [14]. The Japanese society for
esophageal disease classification further sub-classifies
tumors based on the depth of invasion into the lamina
propria (T1a-lp), muscularis mucosa (T1a-mm), and sub-
mucosa (T1b-sm1-3) [15]. This extent of T staging is
outlined in Table 1.
Initial evaluation and guidelines for treatment
The current National Comprehensive Cancer Network
(NCCN) guidelines (Version 3, 2015) [16] can be used to
guide workup and treatment once the diagnosis of HGD or
esophageal cancer is established by tissue biopsy. In a
Fig. 1 Tumor (T)-stage for esophageal cancer is determined by the
depth of invasion into the esophageal wall. The image shows the
layers of the esophagus from innermost (epithelium) to outermost
(adventitia)
World J Surg (2017) 41:1712–1718 1713
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patient who is found to have HGD or esophageal cancer a
staging workup should include a CT with oral and IV
contrast of the chest, abdomen, and pelvis [16]. In addition,
a whole body positron emission tomography scan should be
performed to rule out metastatic disease [16]. Endoscopic
ultrasound (EUS) is then used to evaluate the depth of
invasion of the local tumor as well as regional nodal
metastasis. If the EUS evaluation demonstrates T1 disease
with no evidence of nodal involvement, endoscopic
resection should be performed for the most accurate stag-
ing [16]. Endoscopic resection may also be used as a
treatment modality.
When deciding on treatment, it is important to note that
the NCCN guidelines acknowledge that esophagectomy
remains an acceptable treatment for all HGD and intra-
mucosal lesions. However, endoscopic resection is cur-
rently preferred, when possible, due to the less invasive
nature of this modality [16]. Current NCCN guidelines
recommend endoscopic resection for HGD (Tis) and
intramucosal (T1a) cancer without nodal disease. The
treatment recommendations for superficial submucosal
tumors (T1b-sm1) are less clear. Although submucosal
lesions may be completely resected to negative margins
with endoscopic treatments, most authors support
esophagectomy for these lesions due to the increase in
incidence of lymph node metastasis (Table 2). The NCCN
guidelines also identify a number of additional tumor
characteristics that warrant surgical treatment rather than
endoscopic resection. These characteristics include tumor
size greater than 2 cm, presence of lymphovascular inva-
sion, and poorly differentiated histology [16]. Even with
this guidance, determining the optimal treatment for early
esophageal cancer is often more problematic and demands
a consideration of individual patient factors and familiarity
with current literature.
Endoscopic and surgical treatment options
Endoscopic therapy approaches fall into two categories:
ablation or resection. Ablative procedures are frequently
used for the eradication of both HGD as well as Barrett’s
esophagus, but not for invasive cancers. Radiofrequency
ablation has become the most popular ablative procedure in
the USA because tissue destruction is generally restricted
to the mucosal layer and stricture formation appears to be
less common than with other therapies [13]. For superficial
invasive cancers, ablative procedures are often used as an
adjunct to endoscopic resection. Patients with HGD and
early cancers can be first treated with endoscopic resection
followed with serial ablations for residual Barrett’s
esophagus to reduce the risk of metachronous
malignancies.
Resection procedures include endoscopic mucosal
resection (EMR) and endoscopic submucosal dissection
(ESD) [13, 17]. EMR is a well-established endoscopic
procedure where the superficial esophageal layers under
the region of interest are elevated, usually with injection of
fluid into the submucosal layer, and suction is applied to
create a pseudopolyp. Electrocautery is then used to incise
the borders around and under the pseudopolyp thus freeing
it up for removal. During an EMR, both the mucosa and
portions of the submucosa are removed. ESD differs in the
sense that a deeper tunnel between the submucosa and the
muscularis propria is created using blunt dissection and
electrocautery prior to resection of the tumor. This elevates
the submucosal connective tissue with the lesion and
allows for complete resection of this portion of the sub-
mucosa and removal of larger tumors enbloc [17]. The
Table 1 A combined American Joint Committee on Cancer (AJCC)
and Japanese society for esophageal disease sub-classification system
for reporting T-stage in esophageal cancer
Primary tumor
(T) stage
Depth of invasion
Tis High-grade dysplasia, carcinoma in situ, does not
invade the lamina propria
T1
Intramucosal
(T1a)
T1a-lp Invasion into the lamina propria
T1a-mm Invasion to the muscularis mucosa
Submucosal
(T1b)
T1b-sm1 Invasion into the superficial 1/3 of the submucosa
T1b-sm2 Invasion in the middle 1/3 of the submucosa
T1c-sm3 Invasion into the deep 1/3 of the submucosa
T2 Invades into the muscularis propria
T3 Invades through the muscularis propria into
adventitia
T4 Invades surrounding structures
Table 2 Probability of lymph node positivity based on T-stage
T-stage % of patients with positive lymph
node, pooled mean (% range)
Tis (n = 50) [38, 41, 45, 46] 0
T1a-lp (n = 187)
[38, 41, 42, 45, 46]
1.6 (1.3–4.3)
T1a-mm (n = 352) [14, 37–46] 2.3 (2.0–6.7)
T1b-sm1 (n = 161)
[38, 39, 41, 42, 44–46]
14.9 (0–32)
T1b-sm2 (n = 295) [14, 37–46] 22.4 (11–36)
T1b-sm3 (n = 204)
[38, 39, 41, 42, 45, 46]
45.0 (20–67)
Pooled data from eleven studies
1714 World J Surg (2017) 41:1712–1718
123
primary disadvantage of ESD is the reported high post-
procedural stricture rates, although preventative therapies
like steroid injections and stenting have shown promise in
reducing these complications [18].
Surgical resection of the esophagus with reconstruction
has long been the treatment of choice for early esophageal
cancers and HGD. The operation has historically been
associated with the some of the highest perioperative
mortality rates among gastrointestinal surgeries. Concur-
rent with this, up to half of all patients who underwent
esophagectomy suffered from a perioperative complication
[19]. Fortunately, advances in surgical techniques and
improved treatment algorithms have shown consistent
improvements in morbidity and mortality. Esophagectomy
for HGD and early cancers, in particular, have now shown
excellent perioperative and survival outcomes.
Esophagectomy performed for T1 cancer or HGD, for
instance, now has 5-year survival ranging from 82 to 90%
[4–6] and procedure-related mortality that ranges from 0 to
2% [3–8, 10]. A recent meta-analysis from seven retro-
spective studies demonstrated that although major com-
plication rates were higher for esophagectomy, the
recurrence risk was significantly reduced with surgical
treatment compared to endoscopic therapy [9]. Recurrences
rates for endoscopic treatment were as high as 20%, but
only 0–2% for esophagectomy [9]. This improved onco-
logic outcome is the primary advantage of surgical therapy.
An additional benefit of surgical resection is that regional
lymph nodes are resected to allow for a complete patho-
logic assessment and accurate staging. Lymph node
metastasis is probably the most important independent
predictor of survival in esophageal cancer, and thus,
accurate nodal staging is critical to provide clinicians and
patients with the most precise prognosis [20, 21]. An
analysis of the surveillance, epidemiology, and end results
database from 1988 through 2005 found that lym-
phadenectomy of greater than 18 nodes was an independent
predictor of survival in patients undergoing esophagectomy
for esophageal adenocarcinoma [22].
Two major advancements in surgical care of esophageal
cancer have been paramount in improving both short-term
and long-term outcomes following esophagectomy. First,
the introduction of minimally invasive surgical techniques
have decreased hospital length of stay, improved postop-
erative quality of life, and decreased pulmonary compli-
cations when compared to open surgery [23–26]. Second,
treatment of esophageal malignancy at high-volume cen-
ters has shown improved perioperative outcomes and
increased overall survival [27, 28]. These improved out-
comes are related to the implementation of standard peri-
operative care pathways along with dedicated clinical
teams that are familiar with the complex management of
esophagectomy patients. At this point in time, esophageal
resections that are performed at specialized centers using
advanced surgical techniques have low perioperative
mortality and complication rates and excellent survival
outcomes. This allows us to again consider esophagectomy
an alternate first-line treatment option for early cancers and
HGD [27, 28].
Treatment recommendations
In agreement with the current NCCN guidelines, we rec-
ommend surgical resection for any submucosal (T1b) or
deeper tumor. Tumors that invade the submucosa have a
considerably increased probability of lymph node metas-
tasis and should therefore be treated with esophagectomy.
Surgical resection allows a pathologic assessment of the
regional lymph nodes for accurate staging and may impart
a survival advantage by removing micrometastatic disease.
Table 2 shows pooled data from eleven studies that
examined the prevalence of lymph node involvement based
on tumor depth. In concordance with these data, a recent a
systematic review of over 7000 esophageal cancer patients
demonstrated lymph node positivity to be only 0–8% for
intramucosal (T1a) tumors, but submucosal (T1b) lesions
had lymph node positivity rates ranging from 27 to 54%
[29]. Consequently, this dramatic increase in nodal
metastasis for submucosal tumors forms the basis for the
current recommendation that all submucosal (T1b) lesions
be treated with esophagectomy. Other tumor characteristics
that increase the probability of lymph node involvement
include lymphovascular or perineural invasion, poorly
differentiated histology, and multifocal HGD [30]. If any
one of these characteristics is present, the patient should be
considered for esophagectomy instead of endoscopic
treatment. Beyond this, technical issues such as long seg-
ment Barrett’s esophagus, large tumors, visible ulceration,
and the presence of a hiatal hernia or prior fundoplication
should warrant consideration of surgical over endoscopic
treatment.
Current NCCN guidelines recommend esophagectomy
for any tumor larger than 2 cm [16]. Perhaps, a more
important consideration, aside from size, is whether the
tumor can be resected enbloc. A recent large systematic
review examined outcomes of over 4000 patients from 80
studies undergoing endoscopic treatment for early eso-
phageal cancer. The authors found that a piecemeal endo-
scopic resection was an independent predictor of local
recurrence with the recommendation that all efforts should
be made to avoid piecemeal resection [31]. Likewise, a
tumor that lies within a long segment of Barrett’s esoph-
agus or a multinodular lesion also poses a significant
challenge for endoscopic eradication. A long segment of
metaplastic mucosa is a potential source for future
World J Surg (2017) 41:1712–1718 1715
123
malignant transformation and mandates periodic post-pro-
cedural surveillance. In addition, large resections of mul-
tiple nodules or large segments of metaplasia carry
significant post-procedure stricture risks and are better
treated surgically.
As always, specific patient considerations should be
taken into account. High-risk surgical patients with car-
diopulmonary or other functional comorbidities may be
best treated with the less invasive endoscopic options
despite an increased risk of local recurrence. Even sub-
mucosal (T1b) disease may be treated endoscopically in
high-risk surgical patients. Endoscopic therapy requires
close long-term follow-up, and patients must be able to
comply with a routine surveillance regimen. Some clini-
cians recommend as many as six endoscopies within the
first year of endoscopic resection [32, 33]. Moreover,
symptomatic strictures requiring treatment can occur in as
many as half of all patients who undergo endoscopic
resection, and additional ablative procedures are typically
needed to eradicate residual metaplasia [33, 34]. For these
reasons, patients who undergo endoscopic treatments for
esophageal malignancies need to be able and willing to
participate in close follow-up; otherwise, esophagectomy
may be a better treatment option. Our treatment decision
pathway for determining surgical versus endoscopic treat-
ment for esophageal cancer is outlined in Fig. 2.
Discussion
GERD is a highly prevalent disease, with up to 25% of the
US population suffering from symptoms of acid reflux on a
weekly basis [35]. As a result, the incidence of Barrett’s
esophagus is on the rise in western nations, leading to an
increase in the incidence of esophageal adenocarcinoma
[13]. The development of esophageal cancer from benign
mucosa is highly unpredictable. The best method to screen
patients for GERD and survey patients newly diagnosed
with Barrett’s esophagus is still being defined against a
backdrop where routine endoscopy for GERD patients is
falling out of favor [13]. The efficacy of routine endoscopy
for Barrett’s esophagus has even been called into question
primarily due to the fact that only a small fraction of
patients go on to develop esophageal cancer [13]. Recent
large population-based studies estimate that the annual rate
of progression from Barrett’s esophagus to esophageal
adenocarcinoma is only 0.18% per year [36]. Management
is further complicated by the fact that as many 40% of
patients with Barrett’s esophagus do not demonstrate
classic symptoms of GERD resulting a significant number
of cases going undiagnosed [13]. In addition, HGD and
early esophageal cancer are usually asymptomatic.
Dysphagia and obstructive symptoms do not typically
present until esophageal tumors have invaded beyond what
Fig. 2 Treatment pathway to define surgical versus endoscopic management of patients diagnosed with esophageal malignancy
1716 World J Surg (2017) 41:1712–1718
123
is treatable with endoscopic therapies. Consequently, two-
thirds of current esophageal cancers are diagnosed in the
later stages of disease [2]. There is significant room for
improvement in screening protocols and new techniques
that could further improve early detection and outcomes for
esophageal cancer patients. Unfortunately, at this time, a
large proportion of patients diagnosed with esophageal
cancer are not amenable to endoscopic therapies and sur-
gical resection remains the mainstay of treatment for most
esophageal tumors. This will likely continue to play a
major role in the management of most esophageal tumors
into the future. Few studies have directly compared long-
term outcomes of endoscopic therapy versus esophagec-
tomy for early-stage tumors. Endoscopic therapies show
promise as less invasive options and are preferred when
clinically feasible, but do have some limitations in terms of
recurrence risk and in their ability to evaluate nodal status.
Quality of life after treatment is another important
consideration for all patients. No studies to date have
compared quality of life indices between surgical treatment
and endoscopic treatment for early esophageal lesions. It
seems reasonable to assume that a large operation would
have a more negative impact on the quality of life when
compared to endoscopic treatments. It is notable that
endoscopic therapies do require periodic follow-up and can
require repeat interventions for residual metaplasia and
stricture formation which may adversely affect quality of
life. Further prospective studies to help define long-term
outcomes and quality of life after endoscopic versus sur-
gical treatment are needed in order to better define the best
treatment regimens. A complete understanding of all
available options, as well as collaborative care between
primary care physicians, gastroenterologists, and surgeons,
is the best way to manage early esophageal malignancies
moving forward.
Conclusion
In many circumstances, endoscopic treatments for early
esophageal cancer and HGD can offer similar survival
outcomes without the associated morbidity of an
esophagectomy to a significant number of patients. In other
circumferences, surgical treatment is the best option. Our
recommendation is to consider esophagectomy for any
submucosal (T1b) tumor or greater. If initial pathology
examination demonstrates lymphovascular or perineural
invasion, or poorly differentiated pathology, then these
patients should be treated surgically as opposed to EMR or
ESD due to the increased risk of lymph node involvement.
Tumors within a long segment of Barrett’s esophagus,
mutifocal lesions, large tumors, tumors adjacent to a hiatal
hernia, and patients with a history of fundoplication, should
also be considered for esophagectomy. It is also worth
recognizing that, in order to achieve optimal outcomes,
treatment of esophageal cancer should be managed by a
multidisciplinary team at a high-volume center with spe-
cialists trained in the management of this complex disease.
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