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

dolanj@ohsu.edu

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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