Review Article

Esophageal cancer: staging system and guidelines for staging and

treatment
Mark F. Berry

Department of Surgery, Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina, USA
Correspondence to: Mark F. Berry, MD. Associate Professor, DUMC Box 3652, Department of Surgery, Duke University Medical Center, Durham,
NC 27710, USA. Email: [email protected].

Abstract: Survival of esophageal cancer is improving but remains poor. Esophageal cancer stage is
based on depth of tumor invasion, involvement of regional lymph nodes, and the presence or absence
of metastatic disease. Appropriate work-up is critical to identify accurate pre-treatment staging so that
both under-treatment and unnecessary treatment is avoided. Treatment strategy should follow guideline
recommendations, and generally should be developed after multidisciplinary evaluation.

Keywords: Esophageal neoplasms; neoplasm staging; esophagectomy

Submitted Feb 08, 2014. Accepted for publication Mar 05, 2014.
doi: 10.3978/j.issn.2072-1439.2014.03.11
View this article at: http://dx.doi.org/10.3978/j.issn.2072-1439.2014.03.11

Introduction distributed throughout the distal two thirds (2).

Obtaining accurate pre-treatment staging and then
The incidence of esophageal cancer is increasing, with an
subsequently providing stage-appropriate treatment is
estimated 17,460 new cases in the United States in 2012 (1-5).
crucial in optimizing esophageal cancer outcomes. Overall
More than 90% of esophageal cancers in the United
5-year survival for patients with esophageal cancer remains
States are either adenocarcinomas (57%) or squamous
poor, although some improvement has been achieved
cell carcinomas (37%) (1-3,6). The distribution of tumor
with an increase from 5% to 17-19% over the past four
types varies according to race: 64% of cases in whites are
decades (4-6). These survival improvements have likely
adenocarcinomas, while 82% are of squamous cell origin
resulted from earlier detection in the setting of Barrett’s
among the black population (6). Interestingly, the incidence
esophagus, improvements in perioperative care, and the
among white males has almost doubled while the incidence
use of adjuvant and induction chemotherapy and radiation.
among blacks has decreased by almost 50% (6). Tobacco
However esophageal cancer treatment and particularly
use and a history of mediastinal radiation are risk factors for
esophagectomy is also associated with significant morbidity.
both tumor types (2). Other risk factors for adenocarcinoma
Accurate staging and appropriate treatment can avoid
include gastroesophageal reflux disease (GERD), obesity,
both inadequate and unnecessary treatment to balance
and Barrett’s esophagus (2). Barrett’s esophagus with high-
the potential benefits of improving prognosis with risks of
grade dysplasia is considered a premalignant condition as
treatment-related morbidity.
50% are found to harbor occult malignant disease at time
of biopsy (7). Additional risk factors for squamous cell
carcinoma are conditions that cause chronic esophageal Staging system and guidelines
irritation and inflammation such as alcohol abuse, achalasia,
Staging definitions
esophageal diverticuli, and frequent consumption of
extremely hot beverages (2). Approximately three quarters Esophageal cancer staging is defined by the American
of all adenocarcinomas are found in the distal esophagus Joint Committee on Cancer (AJCC) Staging System
whereas squamous-cell carcinomas are more evenly t h a t e s t a b l i s h e s t u m o r- n o d e - m e t a s t a s i s ( T N M )

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S290 Berry. Esophageal cancer staging and treatment

Table 1 T, N, and M status and histologic grade definitions for were subdivided into tumors that involved resectable
th
esophagus and esophagogastric junction cancer in the 7 edition local structures such as pleura and diaphragm (T4a) and
of the American Joint Committee on Cancer (AJCC) Cancer unresectable local structures such as aorta and vertebral
Staging Manual bodies (T4b).
T status Regional lymph nodes were also redefined as any
Tis High-grade dysplasia paraesophageal lymph node, including cervical or celiac
nodes. The N status had been categorized simply as
T1 Invasion into the lamina propria, muscularis
node-negative or node-positive in the 6th edition and was
mucosae, or submucosa
redefined in the 7th edition to N0-N3 based on the number
T2 Invasion into muscularis propria
of lymph nodes. The M1a and M1b subclassifications from
T3 Invasion into adventitia
the 6th edition were redefined to M1. The 7th edition stage
T4a Invades resectable adjacent structures (pleura,
groupings were also defined to consider the importance of
pericardium, diaphragm)
histopathologic cell type, tumor grade, and tumor location.
T4b Invades unresectable adjacent structures (aorta, Table 2 shows stage grouping for adenocarcinoma and
vertebral body, trachea) squamous cell carcinoma, which are no longer equivalent in
N status the 7th edition.
N0 No regional lymph node metastases
N1 1 to 2 positive regional lymph nodes
Diagnostic and staging work-up
N2 3 to 6 positive regional lymph nodes
N3 7 or more positive regional lymph nodes The Society of Thoracic Surgeons has published guidelines
M status on the diagnosis and staging of patients with esophageal
M0 No distant metastases cancer (12). The work-up for esophageal cancer often
starts when patients present with symptoms such as
M1 Distant metastases
dysphagia and weight loss in the setting of an unremarkable
Histologic
physical exam (2,13). Therefore, the most common tests
grade
used to initially identify and diagnosis esophageal cancer
G1 Well differentiated
are upper gastrointestinal (GI) tract contrast studies and
G2 Moderately differentiated
upper endoscopy with biopsy. An upper GI contrast study
G3 Poorly differentiated typically shows a stricture or ulceration when malignancy is
G4 Undifferentiated present. Upper GI endoscopy identifies tumor location and
length and allows biopsy for pathologic examination. After
a histologic cancer diagnosis has been obtained, subsequent
sub-classifications based on the depth of invasion of the studies are performed to determine clinical stage as
primary tumor (T), lymph node involvement (N), and accurately as possible before treatment is initiated.
extent of metastatic disease (M). The most recent, 7 th Obtaining a computed tomographic (CT) scan of the
edition of the AJCC Cancer Staging Manual for esophagus chest and abdomen with both oral and intravenous contrast
should be the first staging study when esophageal cancer
and esophagogastric junction cancers was developed
is diagnosed histologically. The CT scan is somewhat
based on a database of 4,627 esophagectomy patients who
limited in defining the local extent and nodal involvement
were not treated with induction or adjuvant therapy (8).
of esophageal cancer but is most useful in identifying the
This data from 13 institutions in five countries and three
presence of distant disease such as liver or lung metastases.
continents was collected by the Worldwide Esophageal Further studies that evaluate T and N status would not
Cancer Collaboration (WECC) (9). Table 1 shows the typically impact treatment and therefore are generally
specific 7 th edition TNM definitions. The 7 th edition unnecessary if distant disease is identified and subsequently
differed from the 6th edition in several respects (10,11). The confirmed by biopsy. Positron-emission tomography (PET)
T status classification was changed to define Tis as high- scans improve staging by detecting previously unsuspected
grade dysplasia and all non-invasive neoplastic epithelium. metastatic disease in up to 15-20% of patients and should
Tumors with T4 status due to invasion of local structures be considered in place of CT scans or as an additional study

© Pioneer Bioscience Publishing Company. All rights reserved. www.jthoracdis.com J Thorac Dis 2014;6(S3):S289-S297
Journal of Thoracic Disease, Vol 6, Suppl 3 May 2014 S291

Table 2 AJCC 7th edition stage groupings

Adenocarcinoma Squamous cell carcinoma
Stage
T N M Grade T N M G Location
0 is 0 0 1 is 0 0 1 Any
IA 1 0 0 1-2 1 0 0 1 Any
IB 1 0 0 3 1 0 0 2-3 Any
2 0 0 1-2 2-3 0 0 1 Lower
IIA 2 0 0 3 2-3 0 0 1 Upper, middle
2-3 0 0 2-3 Lower
IIB 3 0 0 Any 2-3 0 0 2-3 Upper, middle
1-2 1 0 Any 1-2 1 0 Any Any
IIIA 1-2 2 0 Any 1-2 2 0 Any Any
3 1 0 Any 3 1 0 Any Any
4a 0 0 Any 4a 0 0 Any Any
IIIB 3 2 0 Any 3 2 0 Any Any
IIIC 4a 1-2 0 Any 4a 1-2 0 Any Any
4b Any 0 Any 4b Any 0 Any Any
Any 3 0 Any Any 3 0 Any Any
IV Any Any 1 Any Any Any 1 Any Any
Cancer location definitions: upper thoracic, 20-25 cm from incisors; middle thoracic, 25-30 cm from incisors; lower thoracic, 30-40 cm
from incisors.

when the CT scan does not show metastatic disease (14,15). Small liver or lung metastases can be missed by both PET
If CT and PET do not demonstrate distant disease, and CT scans, and patients can also have undetected pleural
endoscopic ultrasound (EUS) should be performed to or peritoneal disease (23). Staging via minimally invasive
establish the extent of locoregional disease (2). EUS surgical techniques of thoracoscopy and laparoscopy
provides more accurate evaluation of the depth of improves the accuracy of the above non-invasive testing
tumor invasion (T status) and the extent of lymph-node (23-25). Use of these invasive techniques is relatively
involvement (N status) than both PET and CT (16,17). uncommon but should be considered in select patients,
However, EUS is less accurate for early-stage lesions such such as those who may be considered to have a high risk
as T1 or T2 compared to more advanced tumors (18-21). of treatment-related complications. Staging laparoscopy in
Most incidences of understaging are due to missing nodal particular may have a role for patients with adenocarcinoma
disease. The specificity and the sensitivity for identifying of the esophagus or esophagogastric junction (26).
lymph node disease are better when EUS is combined with
fine-needle aspiration (FNA) compared to EUS alone (22).
Treatment guidelines
Performance of the above staging modalities establishes
the pre-treatment clinical stage which can be used to The National Comprehensive Cancer Network (NCCN)
guide subsequent treatment, as will be discussed in the provides guidelines for the treatment of esophageal cancer (27).
following sections. However, occasionally additional studies Treatment options include local mucosal resection or
may be worthwhile before initiation of treatment. First, ablation therapies, esophagectomy, chemotherapy, and
bronchoscopy should be considered for tumors in the upper radiation therapy. Recommended treatment is primarily
and middle esophagus to rule out airway invasion. CT dictated by stage, tumor location, and patients’ medical
scan and EUS can be suggestive of airway involvement but fitness for receiving a particular therapeutic modality.
are not as accurate as direct visualization of the airway. In However, definitive data from randomized trials to guide the
addition, distant metastases are unfortunately missed even treatment of esophageal cancer is lacking for many clinical
with completion of the staging evaluation described above. situations. Outcomes also generally are relatively poor with

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S292 Berry. Esophageal cancer staging and treatment

many treatment strategies, so establishing optimal treatment treatment. However, local mucosal therapies at the present
for different clinical situations remains an area of active time are generally not considered appropriate for superficial
research (28). The NCCN guidelines reflect the lack of tumors that involve the submucosa (T1b), as these lesions
definitive evidence and often allow a spectrum of potential have occulted lymph node involvement in as many as 50%
treatments for many clinical situations. Given both the of patients (51,52). Therefore esophagectomy without
generally poor overall prognosis and the potential morbidity induction therapy is recommended for superficial tumors
associated with therapy, multidisciplinary evaluation by that involve the submucosa (T1b),
surgery, medical oncology, and radiation oncology should The optimal management of esophageal cancer clinically
be considered for all patients before a treatment strategy is staged as T2N0M0 is somewhat more controversial (53).
initiated. Treatment that does not follow guidelines should Clinical staging modalities for this subset are somewhat
probably only be used in the context of clinical trials. unreliable, with significant percentages of patients being
The stage groupings described above are very useful for both under and over staged (18,54-57). Perhaps because
both providing prognosis and guiding treatment. However, clinical staging inaccuracies lead to a relatively high
patients can be categorized even more simply when incidence of patients actually having nodal disease present
considering treatment. When considering treatment for at the time of surgical resection, induction therapy use in
esophageal cancer patients, the approach is initially dictated this setting has been increasing and was shown recently
by whether the patients have been determined to have early to exceed 50% for cases that were reported to the Society
stage superficial cancers, cancers that are locally advanced of Thoracic Surgeons General Thoracic Database in
with locoregional disease but no distant metastases, 2011 (54). However, data that proves a survival benefit to
and cancers with distant disease. The general treatment induction therapy over surgery alone is still lacking (58).
guidelines for each of these categories will be discussed in Consistent with the uncertainty of optimal treatment, the
the following sections. NCCN guidelines for medically fit patients allow a wide
spectrum of treatment possibilities that include definitive
chemoradiation and esophagectomy with or without
Superficial cancers
induction or adjuvant therapy (27).
Patients with T1-2N0 esophageal cancer typically are
recommended to undergo surgery without induction
Locoregional or locally advanced disease
treatment (27). The prognosis for patients treated for intra-
and submucosal (T1) esophageal cancers is significantly Approximately 32% of esophageal cancer patients have
better than the prognosis for all other patients found to regional disease at the time of diagnosis, with a 5-year survival
have esophageal cancer, even those also found in other of only 10-30% (1,2,8). The treatment for locally advanced
relatively early-stage disease (8). Esophagectomy is effective esophageal cancer that does not have distant metastases and
oncologically for these cancers, but is associated with is potentially resectable (T3-4aN0, T1-4aN1M0) is highly
considerable morbidity and mortality despite improvements variable in practice (59). The NCCN guidelines reflect a
over time and the development of minimally invasive lack of available definitive data on the optimal treatment
techniques (29-35). Although recent data from high-volume and essentially consider any combination of esophagectomy
centers have shown low mortality rates of 1% to 3.5%, and chemoradiation or even definitive chemoradiation as
studies involving population-based databases or multi- acceptable therapy (27).
center trials show that esophageal resection continues to Many studies involving various combinations of surgery,
have relatively high perioperative mortality rates of 8.8% chemotherapy, and radiation to treat locally advanced
to 14% (30,32,35-37). Local treatments with modalities esophageal cancer have been conducted and showed
such as endoscopic mucosal resection, radiofrequency conflicting results (28,37,60-66). However, recent evidence
ablation, cryotherapy, and photodynamic therapy can suggests that induction chemoradiation followed by surgical
provide effective cancer treatment for superficial cancers resection is the optimal treatment for patients with T3-4a
with much less treatment-related morbidity (38-50). These tumors or nodal disease. Several recent trials, retrospective
local treatments are good treatment options for patients studies, and meta-analyses all showed a survival benefit
with superficial tumors that involve only the mucosa (T1a), to both combined and induction therapy (67-72). Most
but close endoscopic surveillance should be planned post- importantly, a recently published randomized trial

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Journal of Thoracic Disease, Vol 6, Suppl 3 May 2014 S293

demonstrated a survival benefit to induction chemoradiation techniques, with the most appropriate technique for any
followed by surgery compared to surgery alone for specific individual patient being dependent on both patient
esophageal or esophagogastric junction cancer (73). and surgeon factors. Several studies have suggested that
Radiation alone followed by surgery does not improve complete surgical resection provides the best chance for
survival compared with surgery alone and therefore cure in patients who do not have distant disease (64,78,79).
induction radiation alone is not recommended (27,65). For patients with stage I-III disease who receive surgical
Induction chemotherapy without radiation has variably treatment, 5-year survival is 28%, compared to 10%
shown to be beneficial but is used by some high-volume for those treated medically (78). However, surgery for
centers, and is recommended as a potential treatment by locoregional esophageal cancer is utilized in only 30-40%
the NCCN for patients with adenocarcinoma (27,37,64). of resectable cases, perhaps because esophagectomy is
Definitive chemoradiation is the preferred treatment for historically associated with significant morbidity and
patients with T4b (unresectable) tumors and occasionally mortality and disappointing long-term results (78,80).
can facilitate surgical resection in selected cases. Minimizing perioperative morbidity in any manner possible
is critical to increase the use of surgical resection so that
primary nonsurgical treatment is reserved for those who
Metastatic or unresectable disease refuse surgery, have unresectable cancers, or are not thought
Approximately 50% of patients have evidence of distant to be surgical candidates for other reasons.
metastatic disease at the time of diagnosis (2,6). Palliative
therapy is recommended for these patients, and can include Squamous cell carcinoma versus adenocarcinoma
chemotherapy, clinical trial enrollment if available, or
best supportive care. Best supportive care is often the Squamous cell carcinoma was previously the most common
most appropriate treatment option. Patients’ performance histology but now accounts for 37% of esophageal cancers (1,3).
status should determine whether chemotherapy is added Adenocarcinoma is now the most common esophageal
to best supportive care. Specific symptoms that often need cancer. Patients with adenocarcinoma and squamous cell
palliation include dysphagia, pain, and nausea. Oncologists carcinoma have been observed to have similar long-term
often are hesitant to pursue feeding tubes in patients with survival across major treatment modalities, suggesting that
stage IV cancer, but feeding tubes may be reasonable both histologies respond similarly to treatment and may share
options in some select patients. Radiation or endoscopic significant physiologic and cellular features (81). Accordingly,
management techniques such as dilation and stenting can staging and treatment guidelines for adenocarcinoma
be used to palliate dysphagia or cases of bleeding from and squamous cell carcinoma were previously essentially
esophageal tumors. Palliative esophagectomy for patients equivalent. However, recognition of prognosis and response
with metastatic disease may have a role in very few cases, to treatment between the two subtypes led to separate stage
but should be considered only in very select cases given groupings and treatment algorithms in the latest, revised
the morbidity of surgery and the poor prognosis with or staging system and in the NCCN guidelines (8,27).
Esophageal cancer treatment guidelines are still generally
without surgery.
similar to both adenocarcinoma and squamous cell carcinoma (27).
However, the benefit of surgical resection in improving
Other considerations survival compared to definitive chemoradiation for esophageal
squamous cell carcinoma has been questioned (82).
Role of esophagectomy for esophageal cancer
In particular, several randomized trials have suggested that
Concurrent chemoradiation is an effective treatment definitive chemoradiation could offer equivalent survival to
option for patients with squamous cell carcinoma of the treatment that involves surgery for locally advanced, non-
cervical esophageal cancer (74-77). The NCCN guidelines metastatic esophageal SCC (83-85). Currently for medically
recommend definitive chemoradiation for these patients (27). fit patients with resectable disease, the NCCN treatment
Surgery is recommended as possible treatment for most guidelines only recommend definitive chemoradiation for
other cases of esophageal cancer that do not have invasion patients who decline surgery (27). However, some centers
of unresectable structures or distant metastatic disease. advocate treatment with chemoradiation for esophageal
Esophageal resection can be performed via several different squamous cell carcinoma, with surgery subsequently used

© Pioneer Bioscience Publishing Company. All rights reserved. www.jthoracdis.com J Thorac Dis 2014;6(S3):S289-S297
S294 Berry. Esophageal cancer staging and treatment

only when there is persistent or recurrent local disease (86). Health (NIH) funded Cardiothoracic Surgical Trials Network.
There are no disclosures or potential conflicts to report.
Disclosure: The author declares no conflict of interest.
Adjuvant therapy

Adjuvant therapy after resection may have a role for some

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Cite this article as: Berry MF. Esophageal cancer: staging

system and guidelines for staging and treatment. J Thorac Dis
2014;6(S3):S289-S297. doi: 10.3978/j.issn.2072-1439.2014.03.11

© Pioneer Bioscience Publishing Company. All rights reserved. www.jthoracdis.com J Thorac Dis 2014;6(S3):S289-S297