Journal of Surgical Oncology 2009;99:189–193

REVIEW

The Role of Lymphadenectomy in Esophageal Cancer

GAIL DARLING, MD, FACS, FRCSC*University of Toronto, Toronto, Ontario, Canada

Lymph node metastases are common in esophageal cancer and are associated with a poor prognosis. Resection and examination of 15–18 lymph

nodes is required for adequate staging of esophageal cancer. Improved survival is associated with involvement of five or fewer nodes or lymph

node ratio (LNR) of < 0.10–0.20. More extensive lymph node dissection during esophagectomy offers improved staging but may also provide

therapeutic benefit in terms of control of locoregional disease and possibly improved overall survival.

J. Surg. Oncol. 2009;99:189–193. � 2008 Wiley-Liss, Inc.

KEY WORDS: esophageal cancer; lymph nodes; staging; survival

INTRODUCTION

The incidence of esophageal cancer is increasing making

esophageal cancer the 8th leading cause of cancer deaths in North

America. Historically, the survival of patients with resected esophageal

cancer was dismal, especially if there were associated lymph node

metastases. Because of this, many surgeons believed that more radical

surgery with extensive lymph node dissection added little to survival

but increased morbidity and mortality. However, operative mortality

for esophagectomy has decreased considerably from 29% in the

1960s–1980s [1] to less than 5% in high volume centers in the current

era [2]. With reduced operative mortality, improving long-term

survival has become more important. In an effort to achieve improved

long-term survival some surgeons have applied the principles of cancer

surgery to esophagectomy including en-bloc resection and formal

lymphadenectomy. However, the role of en-bloc resection and the

extent of lymph node dissection required during esophagectomy

remain controversial.

The fact that lymph node metastases are an important factor in

staging of esophageal cancer is well accepted but there is increasing

evidence that the number of metastatic nodes, the ratio of involved

nodes to total nodes sampled (lymph node ratio (LNR)) and even the

total number of nodes resected are of prognostic significance. There is

also accumulating evidence in terms of the number of nodes required

for optimal staging and this has implications in terms of the operative

approach to esophagectomy.

Lymphadenectomy offers the opportunity for improved staging

accuracy, and likely improves locoregional control but whether it

yields improved survival is more controversial. If nodal disease is

limited, a more extensive lymphadenectomy potentially increases the

chance of an R0 resection and thereby may improve survival; however

survival advantage seems less likely if there is extensive nodal

involvement.

Reports from recent surgical series of more extensive lymph

node dissection report higher survival than older series of limited

lymphadenectomy [2–4]. However whether these reports of

improved survival are due to better control of disease, improved

perioperative care, reflects better outcomes from high volume

centers with high volume surgeons or simply stage migration, is

not clear.

PREVALENCE OF LYMPH NODEMETASTASES IN ESOPHAGEAL CANCER

Lymph node involvement is common in esophageal cancer and

occurs even with early cancers, likely related to the anatomy of the

esophagus wherein the lymphatics run in the submucosa. Lymph

node metastases have been found in up to 35% of T1b tumors and in

78–85% of T3 tumors [3,4] (see Table I).

Lymph node involvement may occur in the abdominal, thoracic, or

cervical nodes regardless of whether the primary tumor is located at the

gastroesophageal junction, distal, mid, or upper esophagus. Metastatic

nodes in the cervical lymph nodes have been found in 17% of

gastroesophageal junction tumors and 23% of distal third tumors [3].

Distant lymph node metastases (abdominal nodes for upper third

cancers and cervical nodes for lower third cancers) may occur in up to

37–40% of patients [4,5].

As tumor depth increases the extent of lymph node involvement

increases both in terms of number of nodes involved as well as the

involvement of distant nodes (see Table II). Patients who are

symptomatic with dysphagia most commonly have T2 or T3 tumors.

Lymph node metastases are found in 85% of T3 tumors and 45% had

more than four nodes involved including 40% with distant lymph node

involvement of which 27% were celiac nodes. Celiac node involve-

ment was found in 23% of T2 tumors [4].

LYMPHADENECTOMY INESOPHAGEAL CANCER

It is controversial whether lymphadenectomy is of therapeutic value

or whether increased lymph node harvest simply allows better staging.

*Correspondence to: Dr. Gail Darling, MD, FACS, FRCSC, AssociateProfessor and Program Director Thoracic Surgery, University of Toronto,Toronto General Hospital 9N-955, 200 Elizabeth St, Toronto, ON, CanadaM5G 2C4. Fax: 416-340-3660. E-mail: gail.darling@uhn.on.ca

Received 9 October 2008; Accepted 17 October 2008

DOI 10.1002/jso.21209

Published online 19 December 2008 in Wiley InterScience(www.interscience.wiley.com).

� 2008 Wiley-Liss, Inc.

Controversy also exists as to the extent of lymph node dissection

required.

EXTENT OF LYMPHADENECTOMY ANDACCURACY OF STAGING

As might be expected, more lymph nodes are harvested with more

extensive surgery. Junginger [6] reported a median of 16 (0–67) nodes

resected via a transhiatal resection versus 28 (0–84) for a transthoracic

procedure (P¼ 0.000). With increase in the number of lymph nodes

harvested the number of nodes found to have metastases also increased.

In a study of 2,597 patients from the SEER database, patients classified

as N0 had fewer lymph nodes identified than those classified as N1 [7].

Other investigators have reported a strong correlation between the

number of lymph nodes examined and number involved [8]. For

example, patients who were N0 had a mean lymph node count of

14.2� 7.1 whereas the lymph node count was 18.0� 9.3 in patients

found to have lymph node metastases [9]. Barbour [10] reported on

366 patients of whom 68% had examination of at least 15 nodes. These

patients were more likely to have positive lymph node metastases

compared to patients who had less than 15 nodes examined (P< 0.01).

Comparing transthoracic with transhiatal esophagectomy, the ratio

of N0: N1 in transthoracic resections was 39.2%: 60.8%, whereas for

transhiatal resections the ratio was 56.1%: 43.9% [11]. Similarly, Kang

[12] also found increased lymph node involvement with increased

number of nodes dissected. Nodal metastases were found in 53% of

patients having a three-field dissection with a median of 33 nodes

resected, whereas nodal metastases were found in 33% of patients

having a one-field dissection with a median of 17 nodes resected.

NUMBER OF LYMPH NODES REQUIREDFOR ACCURATE STAGING

A consensus conference of experts meeting in 1995 suggested that

accurate pathological staging of esophageal cancer required resection

of at least 15 nodes [13].

Although a minimum number of more than 12 nodes examined

provided >90% staging sensitivity, data from others suggest that

the minimum number required is at least 15 [14]. Bollschweiler [8]

reported that survival for N0 patients was significantly less if 15 or

fewer lymph nodes were examined. This suggests that, examination

of less than 15 nodes understages the patient and supports the

recommendation that a minimum of 15 nodes must be examined for

accurate staging. In Junginger’s study, the median survival for the

patients having a transthoracic versus transhiatal resection was

24 months versus 13 months (P¼ 0.004) and 5-year survival was

33% versus 12%. However this survival benefit was limited to only

those who were N0. Further, patients who had a transthoracic resection

but <16 nodes resected had a similar prognosis to those having a

transhiatal resection suggesting that these patients were understaged

[6] (see Fig. 1).

Barbour’s finding that patients with less than 15 nodes examined are

less likely to have nodal metastases identified also supports the concept

that a minimum of 15 nodes must be examined for accurate staging

[10] van Sandick [15] also recommended 15 nodes as the minimum

number required for accurate staging in that with less than 15 nodes

examined, N0 versus N1 was the deciding factor in prognosis but with

greater than 15 nodes examined, LNR became the most important

prognostic factor.

Rizk [16], however, identified 18 lymph nodes as the minimum

number of nodes required for optimal staging. When 18 or more lymph

nodes are removed, depth of invasion (T-status) was no longer

prognostic for survival.

INFLUENCE OF NUMBER OF LYMPH NODESEXAMINED AND SURVIVAL

Utilizing the Surveillance, Epidemiology and End-Results (SEER)

database, Schwartz and Smith [7] examined a cohort of 2,597 patients

who had resection for whom complete data was available and found

that total lymph node count or negative lymph node count are

independent predictors of survival in multivariate analysis. Lymph

node counts >30 were associated with the best overall survival, but this

finding was most significant for N0 patients although still a factor

for N1 patients. In multivariate analysis, negative lymph node count

>15 and total lymph node count >30, were interchangeable.

Patients with 30þ lymph nodes examined had a 5-year overall

survival of 41% versus 25% for 2–4 nodes examined (P< 0.05). Even

in patients with N1 disease this benefit persisted with 5 year

overall survival of 19% for those with 30þ resected nodes versus

9% for 2–4 nodes. The effect of lymph node count on survival applied

equally to both squamous and adenocarcinoma. The authors projected

an increase in overall survival at 5 years of 4–5% for every 10 lymph

nodes identified [7].

Bollschweiler also reported a correlation between number of nodes

examined and prognosis. For patients without lymph node metastases,

prognosis was better if they had more than 15 nodes examined

compared to those with <15 nodes examined, (HR¼ 0.3 95% CI: 0.1–

0.6, P< 0.01). Once lymph node metastases were identified this

finding was no longer applicable [8].

Various investigators have reported the optimum number of

resected nodes and have attempted to identify a ‘‘cut point’’ above

which there is no further improvement in survival. However in the

population-based study reported by Schwarz and Smith, no cut point

could be identified. They reported continually improving survival in all

categories from 2–4 nodes up to 30þ nodes. This finding applied

equally to patients with negative nodes as well as those with positive

nodes [7].

Journal of Surgical Oncology

TABLE I. Prevalence of Nodal Disease in Relation to T Stage[3]

T-status Positive nodes (%)

pT1s 0/1 (0.0)

pT1a 0/1 (0.0)

pT1b 8/23 (34.8)

pT2 17/24 (70.8)

pT3 96/123 (78.0)

pT4 1/2 (50.0)

All 122/174 (70.1)

TABLE II. Relationship Between Tumor Depth and Lymph Node Status[4]

T-stage

Prevalence of

positive nodes (%)

Median number of

positive nodes 1–4 nodes positive (%) >4 nodes positive (%)

Prevalence of positive

distant nodes (%)

T1a 1/16 (6) 2 1/16 (6) 0/16 (0) 0/16 (0)

T1b 5/16 (31) 1 4/16 (25) 1/16 (6) 1/16 (6)

T2 10/13 (77) 2 9/13 (69) 1/13 (8) 4/13 (31)

T3 47/55 (85) 5 22/55 (40) 25/55 (45) 22/55 (40)

190 Darling

NUMBER OF METASTATIC LYMPH NODES

The number of lymph nodes involved by metastatic disease also

influences survival and reflects burden of disease. With fewer

metastatic nodes, survival is better than if many nodes are involved.

Various investigators have identified <3 nodes [17,18], <4 nodes

[19,20], <5 nodes [8,21,22], or <7 involved nodes as predictive of

survival [23]. However in a series where 40þ lymph nodes were

resected in all patients, there was no adverse effect on prognosis with

increased lymph nodes involvement suggesting a therapeutic benefit to

lymphadenectomy [5].

Rizk [16] used recursive repartitioning and identified that the

presence of involved nodes as the most important predictor of survival

using the current AJCC staging system but adding the number of

involved nodes as a separate variable demonstrated that >4 metastatic

lymph nodes was single most important predictor of survival

irrespective of T-stage.

LYMPH NODE RATIO (LNR)

The ratio of metastatic to total lymph nodes (the LNR) has been

shown to be a prognostic factor in esophageal cancer but the value of

LNR that is most predictive of survival is debated (see Table III).

It appears from the data that the more lymph nodes examined, the

lower the value of LNR, which is prognostic. However if insufficient

nodes are examined the LNR ceases to be useful as a prognostic tool.

LNR was identified as the strongest predictor of survival (P< 0.0001)

if 15 or more nodes were resected, with LNR >0.3 having the

poorest survival (HR 5.6 95% CI: 3.0–11.4) whereas for patients with

<15 nodes resected the presence or absence of lymph node metastases

was predictive of survival but not the LNR [16].

RELATIONSHIP BETWEEN LYMPH NODECOUNT AND PROGNOSIS

In patients with N1 disease who have a transthoracic R0 resection,

dissection of 16 or more lymph nodes offers a survival advantage over

those who have <16 nodes (Fig. 1). Also, in a multivariate analysis

total number of lymph nodes resected was a significant independent

predictor of survival (P¼ 0.019) [6]. Rizk identified that survival was

improved in patients with T2–3 tumors with 0–4 involved

lymph nodes if more than 18 lymph nodes were removed and

suggested that the improved survival was related to improved staging

and stage migration with more extensive lymph node dissection. The

likelihood of finding positive nodes was higher and the number of

positive nodes was higher with an adequate (>18 nodes) lymph node

resection [16].

RELATIONSHIP BETWEEN EXTENT OFSURGICAL RESECTION AND PROGNOSIS

A number of studies report improved survival with more extensive

surgery [2–4].

In Japan, three-field lymphadenectomy has been standard practice

since the 1980s. Nishimaki [24] reported 5 year survival of 68% after

three-field lymphadenectomy and Akiyama reported 5 year survival of

54% compared to 34% for three versus two-field lymphadenectomy in

node negative patients [25]. Similarly a randomized trial of cervical

and upper mediastinal lymph node dissection for squamous cell

carcinoma of the thoracic esophagus reported overall survival of 66%

at 5 years for the extended dissection with harvest of a mean of

82 nodes versus 48% for standard dissection with a harvest of 43 nodes

[26].

In a study examining the effect of one-, two-, or three-field

lymphadenectomy increased survival was reported with increasing

extent of lymph nodes resection. Overall survival at 5 years was 21.2%

versus 36.3% versus 53.7% for patients resected with a one-, two-, or

three-field lymphadenectomy (P¼ 0.019). However the benefit of

more extensive lymphadenectomy was predominantly in the N0 group

[12]. This suggests that the benefit is predominantly related to stage

migration.

These series all document high lymph node counts with more

extensive surgery.

In the only randomized trial of transthoracic esophagectomy versus

transhiatal esophagectomy in which the lymph node count for the

former was 31 and 16 for the latter, improved survival was reported

with 5 year overall survival of 39% versus 29% but this did not reach

statistical significance [27]. However, in a larger population based

study of 402 patients from Finland, there was a survival benefit with

two-field lymphadenectomy with a 5 year survival of 50.0% for

patients who had a two-field lymphadenectomy versus 23.2% for those

who had less extensive operations (P¼ 0.005) [28] (see Fig. 2).

Although Junginger [6] reported improved survival after transthor-

acic resection compared to transhiatal esophagectomy, the survival

benefit was statistically significant only for patients who had an

R0 resection, or were N0 or if N1 with 16 or more nodes resected

Journal of Surgical Oncology

Fig. 1. Kaplan–Meier curves for patients with pN1 squamous cellcarcinoma of the esophagus undergoing R0 resection by transhiatal(TH) versus transthoracic (TT) (�16 vs. <16 dissected thoracic lymphnodes) [6]. Reproduced with permission.

TABLE III. Lymph Node Ratio as a Predictor of Survival

LNR Author

Nodes

examined

>0.10 Hagen [4] 48 P< 0.001

>0.10 Eloubeidi [20] HR 1.63 (95%CI: 1.25–2.11

P¼ 0.0013)

>0.105 Tachibana [5] 40þ HR¼ 3.366 (95% CI: 1.092–10.37)

P¼ 0.0345

0.01–01.9 Schwarz [7] 8 P< 0.0001

>0.20 Roder [22] 34 P< 0.001

>0.20 Bollschweiler [8] 28 P< 0.01

>0.20 Wijnhoven [17] 11 HR 2.39 (95% CI: 1.51–3.76)

P< 0.001

>0.20 Greenstein [23] 11 P< 0.001

>0.30 van Sandick [15] 12 HR 5.6 (95% CI: 3.0–11.4)

(P< 0.0001)

Role of Lymphadenectomy in Esophageal Cancer 191

(see Table IV). Others have reported a survival benefit with more

extensive lymph node dissection for N0 patients (P¼ 0.0379) but not

for the overall group of patients (median disease specific survival for

transthoracic vs. transhiatal resections; 31.4months vs. 16.7 months)

[11].

In a case control study of patients with locally advanced esophageal

cancer (T3 N1), overall survival was 32% with en-bloc esophagectomy

(52 nodes) versus 9% with transhiatal esophagectomy. Inclusion

criteria for this study mandated that 20 or more lymph nodes must be

resected. Although the number of nodes resected with the en-bloc

procedure (median 52 nodes, range 21–85) was significantly higher

than for the transhiatal procedure (median 29 nodes, range 20–60)

(P¼ 0.03), the number of involved nodes was similar (median 5 vs. 7),

suggesting that more extensive surgery confers a survival advantage

not just related to stage migration. However, this benefit disappeared if

>9 nodes were involved. This suggests that with increasing numbers of

lymph node metastases the likelihood of distant metastatic disease is

increased and hence more radical surgery is unlikely to provide any

survival advantage [29].

SITE OF LYMPH NODE METASTASES

Although the current staging system classifies certain lymph node

groups as M1 disease, several investigators have found that involve-

ment of these nodal groups does not have a different prognosis from

other sites of lymph node involvement and furthermore does not have

the same prognostic implications as distant organ involvement. In the

report by Rizk et al., [16] there is no survival difference between M1a

or b lymph node groups and survival for these patients was similar to

patients with >4 positive lymph nodes irrespective of their AJCC

stage. This suggests that the M1a/b designation adds little to the

staging system and specifically should not be used to exclude patients

from therapeutic options. Others also report no difference between

M1a and b lymph node metastases in terms of survival and these

patients have similar survival to stage III patients and specifically have

better survival than patients with M1 disease in non-lymph node sites

[5,17,19,20,21,27]. Hagen [4] reported no difference in 5-year survival

between M1a or b nodes (33%) and regional node metastases (37%)

(P¼ 0.214). Survival at 5 years was 37% for celiac node negative

patients versus 29% for celiac node positive patients (P¼ 0.63).

CORRELATION OF LYMPH NODEINVOLVEMENT WITH RISK OF DISTANT

METASTATIC DISEASE

Increasing lymph node involvement is predictive of distant

metastatic disease. Distant metastatic disease was found 92% of

patients with more than 10 involved lymph nodes, as compared to 45%

of patients with only 1–4 nodes involved and 0% with no nodal

involvement [20]. LNR also predicts distant metastatic disease. In

patients with a LNR of >0.10 metastatic disease was found in 84%

versus 43% with a LNR 0.01–0.10 and 0% if LNR was zero

(P< 0.001) [4].

From several studies it is clear that with increasing number of

metastatic lymph nodes, there is an increasing risk of systemic disease

such that more extensive lymph node dissection offers no further

survival advantage over more limited dissection.

EXTENT OF LYMPHADENECTOMY ANDLOCOREGIONAL RECURRENCE

Locoregional recurrence is high after transhiatal esophagectomy

occurring most often in the mediastinum (40–52%) whereas

locoregional recurrence is reduced to 5–8% after en-bloc resection.

This is clearly related to the ability to perform a complete

lymphadenectomy. Control of locoregional disease is important from

a quality of life perspective but may also impact on overall survival

[3,30].

SUMMARY

More extensive lymph node dissection clearly provides more

accurate staging of nodal disease. All studies reported increased

proportion of N1 patients with more extensive nodal dissection. It is

also clear that more extensive node dissection reduces locoregional

recurrence. Whether more extensive dissection improves survival is

unclear, however from the available data, it appears that if lymph

node involvement is limited to <3–5 perhaps even up to 7 nodes,

long term survival may be improved by more radical lymph

node dissection. However, with greater number of nodes involved,

there is a higher probability of systemic disease and more extensive

lymph node dissection appears to add little in terms of survival benefit

although it still confers advantage in terms of local control and

prognostication.

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Journal of Surgical Oncology

TABLE IV. Prognosis in Patients With Squamous Cell Carcinoma After

Transthoracic (TTE) Versus Transhiatal Esophagectomy (THE)[6]

Surgical

procedure

Median survival

(months)

5-year

survival (%) P-value

R0N0

TTE 38 41 0.023

THE 14 17

R0N1

TTE 12 26

TTE< 16

nodes

10 18

TTE� 16 25 32 0.034 (vs. THE)

THE 12 0

Fig. 2. Five-year survival of patients with resection of adenocarci-noma of the esophagus with either two-field lymphadenectomy (-) orless extensive lymphadenectomy (- - -). Reproduced with permission.

192 Darling

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Journal of Surgical Oncology

Role of Lymphadenectomy in Esophageal Cancer 193