ORIGINAL ARTICLE – THORACIC ONCOLOGY

Nodal Metastasis From Locally Advanced Esophageal Cancer:How Neoadjuvant Therapy Modifies Their Frequencyand Distribution

Carlo Castoro, MD1, Marco Scarpa, MD1, Matteo Cagol, MD1, Alberto Ruol, MD2, Francesco Cavallin, MSc1,

Rita Alfieri, MD1, Gianpietro Zanchettin, MD2, Massimo Rugge, MD3, and Ermanno Ancona, MD1,2

1Oncological Surgery Unit, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy; 2Department of Surgical and

Gastroenterological Sciences, University of Padova, Padova, Italy; 3Department of Pathology, University of Padova,

Padova, Italy

ABSTRACT

Background. Neoadjuvant chemoradiotherapy (CT-RT)

before esophagectomy seems to affect the number of nodal

metastasis and to alter the distribution of those that remain.

The aim of this study was to define how neoadjuvant

chemoradiotherapy changes nodal metastasis patterns in

locally advanced esophageal cancer.

Methods. A total of 402 consecutive patients with cancer

of the esophagus or esophagogastric junction (181 adeno-

carcinoma [AC] and 221 squamous cell carcinoma [SCC])

(evaluated at clinical stage T1N1, T2N1, T3N0, or T3N1

and pathological stage M0) presenting in our Department

between 1992 and 2007 and who underwent complete

resection (R0) were included in this retrospective study on

a prospectively collected database. All dissected lymph

nodes were retrieved and microscopically analyzed. Nodal

metastasis patterns in patients who underwent chemother-

apy (CT) or chemoradiotherapy (CT-RT) neoadjuvant

therapy were compared with those in patients who under-

went surgery alone.

Results. Almost 30% of the adenocarcinoma patients and

approximately 40% of the SCC patients showed effective

tumor downstaging after neoadjuvant therapy. There were

fewer paracardial node metastases (P = .002) in the AC

patients who underwent CT-RT neoadjuvant therapy.

There were, likewise, significantly fewer paraesophageal,

paracardial, and subcarinal node metastases in the SCC

patients in whom the perigastric nodes became the second-

most frequent site of metastasis.

Conclusion. Not only was frequency of lymph node

metastases decreased after neoadjuvant therapy, but nodal

localization and pattern were also significantly modified.

Esophagectomy with lymphadenectomy remains the

mainstay of curative therapy in patients with esophageal

cancer without systemic metastases.1–3 Nodal stage clas-

sification is considered the most useful predictor of

survival and an indicator of risk for disease recurrence.4 In

a recent multicenter study, the number of lymph nodes

removed as well as tumor depth and the pattern of lymph

node distribution were found to be independent predictors

of survival.1

Recent studies suggest that neoadjuvant therapy can

effectively downstage locally advanced esophageal cancer

and consequently enhance survival rate following radical

esophagectomy resection (R0 resection).5–8 Achieving a

node-negative status (N0) is the major determinant of

outcome following neoadjuvant chemoradiotherapy and

surgery.9 Therefore, after neoadjuvant therapy, lymphade-

nectomy is still necessary at least for staging purposes, and

a recent authoritative study concluded that lymphadenec-

tomy is optimized when the surgeon can identify individual

lymph node stations and can submit lymph node packets

separately.10 However, we hypothesize that neoadjuvant

chemoradiotherapy (CT-RT) not only reduces the number

of affected lymph nodes, but it also modifies the frequency

of nodes sites involvement and a postneoadjuvant therapy

map of nodal metastasis is not currently available.

Carlo Castoro and Marco Scarpa contributed equally to this study.

� Society of Surgical Oncology 2011

First Received: 29 September 2010;

Published Online: 10 May 2011

C. Castoro, MD

e-mail: carlo.castoro@unipd.it

Ann Surg Oncol (2011) 18:3743–3754

DOI 10.1245/s10434-011-1753-9

In fact, several important studies have investigated and

described nodal metastasis distribution in esophageal can-

cer to provide surgeons with definite indications for

lymphadenectomy, but none has attempted to assess lymph

nodal metastatic distribution after neoadjuvant ther-

apy.11–15 Moreover, in the last years minimally invasive

surgery gained consensus in esophageal surgery, and the

distribution of nodal metastasis after neoadjuvant therapy

could be useful information in planning the operative

techniques. Although the clinical relevance of the sentinel

node concept in the current treatment of esophageal cancer

seems now limited because of the high false-negative rate

and the high frequency of sentinel nodes in more than 1

nodal station, further studies could combine the findings of

the sentinel nodes with the postneoadjuvant nodal distri-

bution patterns.16–18 Moreover, some authors performing

minimally invasive esophageal surgery suggest reducing

the extent of nodal dissection according to tumor site.19

Finally, Orringer et al. in 2007 admitted that when per-

forming a transhiatal esophagectomy for cancer after

preoperative chemoradiotherapy they counted on preoper-

ative staging of esophageal cancer to know with fair

accuracy that they were ‘‘not leaving a lot of involved

lymph nodes behind in the mediastinum.’’20 The findings of

positive nodes on restaging would suggest performing a

transthoracic resection and mediastinal lymph dissection

instead of a transhiatal approach.20 Clearly, a map of nodal

metastasis after neoadjuvant therapy could be helpful in the

decision-making process.

Therefore, the aim of the present study is to define how

neoadjuvant chemoradiotherapy can affect lymph node

distribution and frequency in order to provide surgeons

with a more precise map in preparation for adequate

lymphadenectomy.

PATIENTS AND METHODS

Patients

A total of 1328 patients with esophageal cancer were

treated at the Regional Center for Esophageal Diseases

located in Padova, Italy, between January 1, 1992 and

December 31, 2007. Their data were recorded in a pro-

spectively collected database. Of these, 402 consecutive

patients presenting with cancer of the thoracic esophagus or

esophagogastric junction, evaluated at clinical stages T1N1,

T2N1, T3N0, or T3N1 and pathological stage M0, and who

underwent a complete R0 resection, were included in the

current study. Patients operated on with minimally invasive

or transhiatal approaches were excluded from this analysis.

Clinical staging was based on results from barium

swallow examination, endoscopic ultrasound, and computed

tomography of chest and abdomen. Endoscopy and endo-

scopic ultrasound were performed by an experienced team

for all patients. Since 2005 most patients were also evaluated

with fluorodeoxyglucose positron emission tomography-

computed tomography (FDG PET-CT) scan both as an initial

workup and as restaging tool before surgery (after neoadju-

vant therapy). In recent years, patients with locally advanced

tumors (T2N1/T3) were frequently offered the option of

neoadjuvant CT-RT, while in the early years covered by this

retrospective study, surgery alone was the standard treat-

ment. Tumor node metastasis (TNM) staging was performed

according to the criteria of the International Union Against

Cancer (UICC).21 Of these patients, 221 had squamous cell

carcinoma (SCC), and 181 had AC (Table 1). Informed

consent was obtained from all the patients who participated

in this study, which was performed in accordance with the

principles of the Declaration of Helsinki.

Surgical Resection Details on surgical techniques have

already been published elsewhere.22 Briefly,

esophagectomy was performed using an Ivor-Lewis

procedure, via a laparotomy and right thoracotomy, for

tumors of the mid-lower esophagus and esophagogastric

junction. A 3-stage McKeown’s procedure, with an

additional left cervical incision, was reserved for tumors

in the upper third of the esophagus. At least 6–8 cm of

healthy esophagus was resected above the proximal edge of

the tumor to avoid neoplastic involvement of the resection

margins. In this group of patients en bloc lymph node

dissection was performed, including the paraesophageal,

subcarinal, posterior mediastinal, and paracardial lymph

nodes, as well as those located along the lesser gastric

curvature, the origin of the left gastric artery, the celiac

trunk, the common hepatic artery, and the splenic artery. In

2001, prophylactic ligation of thoracic duct was introduced

to reduce the incidence of chylothorax.23 Since 2000,

epidural analgesia has been routinely used intraoperatively

and postoperatively. Intraoperative fluid restriction and

early postoperative extubation was introduced in 1995 to

reduce intensive care unit (ICU) stay. The alimentary tract

was reconstructed using the gastric pull-up technique; if the

stomach was unavailable, either a jejunal loop or the left

colon was used.24 The site of the nodes was identified by

the operating surgeons during the operation, and, at the end

of it, the different groups of lymph nodes were separately

sent for histology. Patients were examined at regularly

scheduled intervals by members of the surgical team after

1, 3, 6, and 12 months and every 6–12 months thereafter.

Neoadjuvant Therapy During the study period the

number of patients who had neoadjuvant therapy

progressively increased from the 30% in the first 3 years

to more than the 50% in the last 3 years. The most

3744 C. Castoro et al.

common preoperative chemotherapy regimen consisted of

5-fluorouracil and a platinum agent (standard regimen was

100 mg/m2 DDP on day 1, and 5-FU 1000 mg/m2 per day

in continuous infusion from day 1–5 for 3–4 cycles), but

taxanes were also prescribed as part of the treatment

regimen in some of the patients. Chemotherapy was usually

administered concurrently with radiation therapy, but the

exact sequence depended on the clinical protocol or on the

physician’s preference.

Standard radiotherapy was usually performed in 1.8 Gy

daily fractions for a total dose of 45–50 Gy. The planned

target volume for carcinomas of the upper or middle third

of the esophagus included the primary tumor with 5-cm

longitudinal margins, metastatic nodes with 2-cm margins,

supraclavear fovea and mediastinum. For carcinomas of the

lower third of the esophagus, the field was extended to

include both the perigastric and celiac nodes. This involved

an initial phase using anteroposterior-posteroanterior fields

to a total dose of 30.6 Gy in 1.8 fractions. The radiation

portals were then modified to encompass the primary tumor

and metastatic nodes with 2-cm margins up to a dose of

45 Gy.

In all patients, surgery was performed 4–8 weeks after

the last cycle of chemotherapy.25 Only 16% patients

received postoperative adjuvant chemotherapy and/or

radiotherapy.

Pathology Histopathological examination of all resected

specimens consisted in evaluation of: tumor stage, residual

tumor, grading, and number of lymph nodes involved. The

specimens were fixed in 5% formaldehyde and set in

paraffin. The lymph nodes were counted and assessed by a

pathologist. A series of sections from each node were

selected and stained with hematoxylin and eosin (H&E) as

well as with periodic acid-Schiff (PAS). All dissected

lymph nodes were microscopically analyzed for metastatic

disease. Nodal status (N0, N1) was evaluated in accordance

with the 6th edition of the TNM classification, but for the

purpose of this study the number of metastatic lymph nodes

and their site were also analyzed.21

Statistical Analysis Data were collected prospectively in

accordance with a standardized prospective protocol that

began in 1980. All statistical analyses were performed

using the SAS for Windows version 9.1 (SAS Institute,

Cary, NC). A median (interquartile [IQ] range) or

frequency (%) was used for descriptive statistics, as

appropriate. Categorical data were compared using Fisher

exact test and McNemar test, as appropriate; continuous

data were compared using the Mann-Whitney U test and

the Kruskal-Wallis test, as appropriate. Survival estimates

were calculated using the Kaplan-Meier method, and a

comparison of survival rates was performed using log-rank

TABLE 1 Demographic and clinical characteristics of 402 patients

enrolled between 1992 and 2007 with locally advanced esophageal

cancer and R0 resection

Patients 402

Gender: M/F 327/75

Age: median (IQR) 63 (55.5–69.9)

Histotype

Adenocarcinoma 181 (45)

Squamous cell carcinoma 221 (55)

Tumor site

Upper thoracic 58 (14.4)

Mid thoracic 100 (24.9)

Lower thoracic 96 (23.9)

Esophagogastric junction 148 (36.8)

Clinical TN stage

T1N1 10 (2.5)

T2N1 55 (13.7)

T3N0 132 (32.8)

T3N1 205 (51)

Treatment

Surgery alone 248 (61.7)

Surgery ? neoadjuvant therapy 154 (38.3)

Neoadjuvant therapy

CT 48

CT-RT 106

Pathological TN stage

T0/Tis N0 45 (11.2)

T0N1 14 (3.5)

T1N0 12 (3)

T1N1 7 (1.7)

T2N0 55 (13.7)

T2N1 27 (6.7)

T3N0 74 (18.4)

T3N1 153 (38.1)

T4N0 8 (2)

T4N1 7 (1.7)

Number of examined lymph nodes: Median (IQR) 18 (14–25)

Number of metastatic lymph nodes: Median (IQR) 1 (0–3)

Site of metastatic lymph nodes:

Laterocervical 2 (0.5)

Supraclavicular 2 (0.5)

Paraesophageal 98 (24.4)

Paratracheal 15 (3.7)

Subcarinal 27 (6.7)

Recurrent nerve nodes 13 (3.2)

Inferior pulmonary vein nodes 8 (2)

Paracardial 91 (22.6)

Perigastric 86 (21.4)

Celiac axis 31 (7.7)

Post operative CT-RT 67 (16.7)

Data expressed as n (%)

Nodal Metastasis From Locally Advanced Esophageal Cancer 3745

test. All tests were 2-sided and P values less than .05 were

considered significant.

RESULTS

Patients

A total of 446 patients with locally advanced esophageal

tumors were eligible for inclusion in the study (Table 1).

However, 33 of these were excluded because their resec-

tion was not radical and 11 were excluded because they

received only neoadjuvant therapy.

There were 181 patients who underwent R0 resection for

locally advanced esophageal adenocarcinoma (AC)

(Table 2). One hundred thirty-two underwent surgery

alone, 32 underwent surgery ? CT-RT neoadjuvant ther-

apy, and 17 underwent surgery ? chemotherapy (CT)

neoadjuvant therapy. The gender rate was similarly dis-

tributed in the 3 groups, while the patients who underwent

surgery alone were significantly older (P = .002). All but

seven patients (who had a 3-field lymphadenectomy) had a

2-field lymphadenectomy. Tumor site distribution was

significantly different in the three groups: the patients who

underwent surgery and neoadjuvant therapy presented more

often with a low esophageal localization than those who had

surgery alone. A significant number of patients who

underwent neoadjuvant therapy presented with T0/T1-N0

stages at the pathological examination compared with those

who had surgery alone (P = .02).

A total of 221 patients underwent R0 resection for

locally advanced esophageal SCC. Of these, 116 under-

went surgery alone, 74 underwent surgery ? CT-RT

neoadjuvant therapy while 31 underwent surgery ? CT

neoadjuvant therapy. Tumor site distribution and gender

rate were similar in the three groups, and the median age

was not significantly different (P = .08). Patients who had

surgery alone presented more frequently with stage T3N0

and less frequently with stage T3N1 than the other groups

TABLE 2 Clinical characteristics of patients with adenocarcinoma

Surgery alone Surgery ? neoadjuvant therapy Surgery ? neoadjuvant CT-RT Surgery ? neoadjuvant CT

Patients 132 49 32 17

Sex: M/F 114/18 47/2 31/1 16/1

Age: median (IQR)a,b 66.6 (57.8–72.7) 59.9 (53.1–67.2) 60.4 (52.2–66.8) 59.7 (53.3–70.2)

Tumor sitea,b

Lower thoracic 15 (11.4) 20 (40.8) 15 (46.9) 5 (29.4)

Esophagogastric junction 117 (88.6) 29 (59.2) 17 (53.1) 12 (70.6)

Clinical stage

T1N1 3 (2.3) 1 (2) 0 1 (5.9)

T2N1 19 (14.4) 3 (6.1) 2 (6.3) 1 (5.9)

T3N0 54 (40.9) 5 (10.2) 4 (12.5) 1 (5.9)

T3N1 56 (42.4) 40 (81.7) 26 (81.2) 14 (82.3)

Clinical stage N 1a,b 78 (59.1) 44 (89.8) 28 (87.5) 16 (94.1)

Pathological TN stagea,b,c

T0/Tis N0 0 6 (12.2) 5 (15.6) 1 (5.9)

T0N1 0 5 (10.2) 5 (15.6) 0

T1N0 2 (1.5) 1 (2) 1 (3.1) 0

T1N1 2 (1.5) 1 (2) 1 (3.1) 0

T2N0 14 (10.6) 8 (16.3) 4 (12.5) 4 (23.5)

T2N1 10 (7.6) 6 (12.2) 5 (15.6) 1 (5.9)

T3N0 27 (20.5) 5 (10.2) 5 (15.6) 0

T3N1 73 (55.3) 15 (30.6) 5 (15.6) 10 (58.8)

T4N0 1 (0.8) 1 (2) 1 (3.1) 0

T4N1 3 (2.3) 1 (2) 0 1 (5.9)

Pathological stage N1 88 (66.7) 21 (42.9) 16 (50) 5 (29.4)

Data expressed as n (%)a P \ .05, surgery alone versus surgery ? neoadjuvant therapyb P \ .05, surgery alone versus surgery ? neoadjuvant CT-RT versus surgery ? neoadjuvant CTc Pathological stage: T0-1 vs T2-3-4

Clinical stage N1 versus pathological stage N1:surgery alone P = .22, surgery ? neoadjuvant therapy P = .0004

3746 C. Castoro et al.

(P \ .001). A significant number of patients who under-

went neoadjuvant therapy presented with T0/T1-N0 stages

at the pathological examination compared with those who

had surgery alone (P \ .001). The characteristics of

patients who were operated on for SCC are outlined in

Table 3.

The survival rate of the 402 patients who underwent R0

section ± neoadjuvant therapy for locally advanced

esophageal cancer is shown in Fig. 1a and b. In the group

of 154 patients who had neoadjuvant therapy, 41 patients

obtained a complete response (27%), 88 had a partial

response (57%), and 25 were classified as nonresponder

(16%). The overall survival of these patients correlated

with the response: 5-year survival was 67.5% in patients

with complete response, 49.2% in patients with partial

response, and 20.4% in nonresponders (P = .0003). Uni-

variate analysis for predictors of survival after treatment of

locally advanced esophageal adenocarcinoma and SCC

included, as possible predictors, treatment modality, age,

tumor site, clinical stage, pathological stage, number of

examined lymph nodes, number of nodal metastasis,

metastasis at the paraesophageal, subcarinal, paracardial

perigastric, or celiac trunk stations. With multivariate

analysis, only metastasis at paracardial (around the cardias)

and celiac trunk stations were revealed to be independent

predictors of survival in patients with locally advanced

esophageal adenocarcinoma. Moreover, multivariate anal-

ysis showed that only neoadjuvant therapy and pathologic

N0 status were independent predictors of better survival in

patients with esophageal SCC. Survival analysis in locally

advanced adenocarcinoma and SCC of the esophagus is

shown in Tables 4 and 5.

Metastatic Lymph Node Distribution Almost 30% of the

patients with AC and approximately 40% of the SCC

patients were found to have effective T downstaging

TABLE 3 Clinical characteristics of patients with SCC

Surgery alone Surgery ? neoadjuvant therapy Surgery ? neoadjuvant CT-RT Surgery ? neoadjuvant CT

Patients 116 105 74 31

Sex: M/F 88/28 78/27 53/21 25/6

Age: median (IQR)a 62.4 (55–70.1) 59.9 (53–66) 59.8 (53.7–66.6) 60 (50.6– 65.8)

Tumor site

Upper thoracic 25 (21.6) 33 (31.4) 19 (25.7) 14 (45.2)

Mid thoracic 50 (43.1) 50 (47.6) 39 (52.7) 11 (35.5)

Lower thoracic 41 (35.3) 22 (21) 16 (21.6) 6 (19.3)

Clinical stage

T1N1 2 (1.7) 4 (3.8) 4 (5.4) 0

T2N1 23 (19.8) 10 (9.5) 4 (5.4) 6 (19.4)

T3N0 53 (45.7) 20 (19.1) 7 (9.5) 13 (41.9)

T3N1 38 (32.8) 71 (67.6) 59 (38.7) 12 (38.7)

Clinical stage N1a,b 63 (54.3) 85 (81) 67 (90.5) 18 (58.1)

Pathological TN stagea,b,c

T0/ Tis N0 1 (0.9) 38 (36.2) 29 (39.2) 9 (29)

T0N1 0 9 (8.6) 8 (10.8) 1 (3.2)

T1N0 5 (4.3) 4 (3.8) 3 (4.1) 1 (3.2)

T1N1 2 81.7) 2 (1.9) 1 (1.4) 1 (3.2)

T2N0 12 (10.3) 21 (20) 16 (21.6) 5 (16.1)

T2N1 8 (6.9) 3 (2.9) 2 (2.7) 1 (3.2)

T3N0 31 (26.7) 11 (10.5) 6 (8.1) 5 (16.1)

T3N1 50 (43.1) 15 (14.3) 8 (10.8) 7 (22.6)

T4N0 4 (3.5) 2 81.9) 1 (1.4) 1 (3.29

T4N1 3 (2.6) 0 0 0

Pathological stage N1a,b 63 (54.3) 29 (27.6) 19 (25.7) 10 (32.3)

Data expressed as n (%)a P \ .05, surgery alone versus surgery ? neoadjuvant therapyb P \ .05, surgery alone versus surgery ? neoadjuvant CT-RT versus surgery ? neoadjuvant CTc Pathological stage: T0-1 versus T2-3-4

Clinical stage N1 versus pathological stage N1: surgery alone P = .99, surgery ? neoadjuvant therapy P \ .0001

Nodal Metastasis From Locally Advanced Esophageal Cancer 3747

(regression score 1 or 2 assessed using Mandard scoring)

after neoadjuvant therapy. In fact, a significantly higher

number of patients with pathological stage 0 or 1 had

undergone neoadjuvant therapy.

The median number of lymph nodes examined was 18

(IQ range 14–25). In the AC group the median number of

lymph nodes retrieved from the surgical specimens was

similar in the surgery-alone and in the surgery ? neoad-

juvant therapy groups. Those who underwent neoadjuvant

therapy had, instead, a significantly lower number of

metastatic lymph nodes (P = .03). This was particularly

evident in the patients who underwent CT-RT therapy.

100

80

60

40

20

Patients at risk

Surgery alone, pN0Surgery alone, pN1Surgery + Neoadjuvant therapy, pN0Surgery + Neoadjuvant therapy, pN1

600

Months

aPercentsurvival

Survival analysis afteresophagectomy for adenocarcinoma P = 0.0002

48362412

1410

4–

2319

64

3027

77

36381011

41591719

100

80

60

40

20

Patients at risk

Surgery alone, pN0Surgery alone, pN1Surgery + Neoadjuvant therapy, pN0Surgery + Neoadjuvant therapy, pN1

600

Months

Survival analysis afteresophagectomy for SCC

bPercentsurvival

48362412

95

192

171034

3

201240

5

252252

9

40466417

FIG. 1 Survival analysis after

esophagectomy for

a adenocarcinoma, b SCC

TABLE 4 Univariate and

multivariate survival analysis

after radical resection of locally

advanced esophageal

adenocarcinoma

Adenocarcinoma Univariate: log-rank test Cox regression model

Cumulative % 5 years surviving P value OR (95% CI) P value

Age group .09 .08

\65 years 42

[65 years 36.8

Treatment .19 .62

Surgery alone 36.9

Surgery ? neoadjuvant therapy 49.3

Pathological stage \.0001 .22

0–1–2 55

3–4 25.3

Pathological stage N .0002 .37

0 58.2

1 28

Paraesophageal nodes .03 .82

Nonmetastatic 43.8

Metastatic 27.1

Subcarinal nodes .01 .31

Nonmetastatic 40.6

Metastatic 17.4

Paracardial nodes \.0001 2.79 (1.86–4.18) \.0001

Nonmetastatic 52

Metastatic 12.5

Celiac axis nodes .003 1.77 (1.05–3.00) .03

Nonmetastatic 42.2

Metastatic 25.5

3748 C. Castoro et al.

There was no significant difference in the proportion of

clinical and pathological N1 patients (P = .22) in the

surgery-alone group. In the patients who underwent neo-

adjuvant therapy, however, 89% were clinical node

positive while the percent of pathological node positive

patients dropped to 42% (P = .0004). The distribution of

lymph node metastasis in the different stations was similar

in the surgery-alone and surgery ? neoadjuvant therapy

groups. There were, nevertheless, less frequent metastases

at the paracardial nodes (P = .002) in the group of patients

who underwent CT-RT therapy. Nodal metastasis distri-

bution in locally advanced AC is outlined in Table 6.

In the SCC patients, the median number of lymph nodes

retrieved from the surgical specimens was similar in the

surgery-alone and surgery ? neoadjuvant therapy patients.

Those who underwent neoadjuvant therapy had a signifi-

cantly lower number of metastatic lymph nodes (P \ .001).

In fact, in the surgery-alone patients there was no signifi-

cant difference in the proportion of clinical and

pathological N1 patients (54% were both clinical node

positive and pathological node positive P = .99). In the

group of patients who underwent neoadjuvant therapy,

instead, 81% were clinical node positive, while the number

of pathological node positive patients dramatically dropped

to 28% (P \ .0001). This was even more evident with

regard to the patients who underwent neoadjuvant CT-RT:

more than 75% were staged as N0 after therapy. The fre-

quency of metastasis in the various nodal stations was

different in the subgroups. While the periesophageal nodes

remained the most frequent site of metastasis after neoad-

juvant therapy, their frequency dropped significantly

(P \ .001), and the difference was even more evident in

the CT-RT group. The frequency of subcarinal node

metastasis was, likewise, significantly lower in the patients

who had neoadjuvant therapy (P = .007), and no patients

in the CT-RT group showed metastasis at that site. Para-

cardial nodes were the 2nd most frequent site of metastasis

in the patients who had surgery alone, while they were the

3rd site in patients who had neoadjuvant therapy

(P \ .001). Perigastric nodes became the 2nd most fre-

quent site of metastasis in that group. Nodal metastasis

distribution in locally advanced SCC after surgery alone

and after neoadjuvant therapy is outlined in Table 7.

In the group of patients with esophageal SCC originat-

ing from the superior or middle thoracic esophagus, the

frequency of metastasis at the periesophageal and subcar-

inal stations and at lymph nodes along the pulmonary vein

were significantly reduced in patients who had neoadjuvant

therapy. The periesophageal nodes were still the most

frequent site of metastasis in these patients, but the

TABLE 5 Multivariate

survival analysis after radical

resection of locally advanced

esophageal SCC

Squamous cell carcinoma Univariate: log rank test Cox regression model

Cumulative %

5 years surviving

P value OR (95% CI) P value

Age group .05 .11

\65 years 40.3

[65 years 31.9

Treatment .0004 (0.68 (0.47–0.98) .04

Surgery alone 26.7

Surgery ? neoadjuvant therapy 49.8

Pathological stage .0004 .69

0–1–2 45.1

3–4 22

Pathological stage N \.0001 2 (1.4–2.9) .0002

0 51.2

1 17.1

Paraesophageal nodes .0005 .93

Nonmetastatic 43.6

Metastatic 16.1

Subcarinal nodes .001 .18

Nonmetastatic 39.2

Metastatic 10

Perigastric nodes .0003 .18

Nonmetastatic 41

Metastatic 11.5

Nodal Metastasis From Locally Advanced Esophageal Cancer 3749

subcarinal station shifted from second to fourth place and

the paracardial nodes were completely free of metastasis.

Nodal metastasis distribution in locally advanced SCC

originating from the superior or middle thoracic esophagus

is outlined in Table 8.

The frequency of metastasis at the periesophageal and

paracardial nodes in the patients with esophageal SCC

originating from the lower third of the esophagus was

significantly lower in patients who had neoadjuvant ther-

apy compared with those who had surgery alone. Nodal

TABLE 6 Metastatic lymph node distribution in esophageal adenocarcinoma

Surgery

alone

Surgery ? neoadjuvant

therapy

Surgery ? neoadjuvant

CT-RT

Surgery ? neoadjuvant

CT

Patients 132 49 32 17

Number of examined lymph nodes:

median (IQR)

19.5 (15–27) 20 (15–25) 17 (14–24.5) 22 (18–26)

Number of metastatic lymph nodes:a,b

median (IQR)

2 (0–5.5) 1 (0–2) 0.5 (0–1) 2 (0–4)

Site of metastatic lymph nodes:

Laterocervical 0 0 0 0

Supraclavicular 0 0 0 0

Periesophageal 39 (29.6) 10 (20.4) 7 (21.9) 3 (17.7)

Paratracheal 4 (3) 2 (4.1) 1 (3.1) 1 (5.9)

Subcarinal 7 (5.3) 5 (10.2) 3 (9.4) 2 (11.8)

Recurrent nerve nodes 1 (0.8) 0 0 0

Inferior pulmonary vein 3 (2.3) 0 0 0

Paracardialb 49 (37.1) 14 (28.6) 4 (12.5) 10 (58.8)

Perigastric 47 (35.6) 12 (24.5) 6 (18.8) 6 (35.3)

Celiac axis 19 (14.4) 8 (16.3) 6 (18.8) 2 (11.8

Data expressed as n (%)a P \ .05, surgery alone versus surgery ? neoadjuvant therapyb P \ .05, surgery alone versus surgery ? neoadjuvant CT-RT versus surgery ? neoadjuvant CT

TABLE 7 Metastatic lymph node distribution in esophageal SCC

Surgery

alone

Surgery ? neoadjuvant

therapy

Surgery ? neoadjuvant

CT-RT

Surgery ? neoadjuvant

CT

Patients 116 105 74 31

Number of examined lymph nodes: median (IQR) 16 (12–21) 18 (13–23) 18 (15–24) 18 (12–19)

Number of metastatic lymph nodes:a,b median (IQR) 1 (0–3) 0 (0–1) 0 (0–0) 0 (0–1)

Site of metastatic lymph nodes:

Laterocervical 2 (1.7) 0 0 0

Supraclavicular 0 2 (1.9) 2 (2.7) 0

Periesophageala,b 37 (31.9) 12 (11.4) 7 (9.5) 5 (16.1)

Paratracheal 5 (4.3) 4 (3.8) 3 (4.1) 1 (3.2)

Subcarinala,b 13 (11.2) 2 (1.9) 0 2 (6.5)

Recurrent nerve nodes 7 (6) 5 (4.8) 3 (4.1) 2 (6.5)

Inferior pulmonary vein n 5 (4.3) 0 0 0

Paracardiala,b 23 (19.8) 5 (4.8) 4 (5.4) 1 (3.2)

Perigastric 19 (16.4) 8 (7.6) 6 (8.1) 2 (6.5)

Celiac axis 2 (1.7) 2 (1.9) 2 (2.7) 0

Data expressed as n (%)a P \ .05, surgery alone versus surgery ? neoadjuvant therapyb P \ .05, surgery alone versus surgery ? neoadjuvant CT-RT versus surgery ? neoadjuvant CT

3750 C. Castoro et al.

metastasis distribution in locally advanced SCC originating

from the lower esophagus is outlined in Table 9.

DISCUSSION

Nodal stage is considered the most reliable predictor of

survival after esophagectomy with lymphadenectomy in

esophageal cancer patients without systemic metastases, and

the presence of nodal metastases is indicative of high risk for

disease recurrence.2–4 Our data (Fig. 1a, b) have confirmed

these hypotheses. The number of lymph nodes removed, in

addition to tumor depth and the number of lymph nodes

involved, have recently been found to be independent pre-

dictors of survival.1 Several investigators, in fact, consider

the current AJCC staging system for esophageal cancer,

largely based on depth of invasion, inadequate when applied

to patients receiving neoadjuvant therapy.10,26 In fact,

despite conflicting results concerning neoadjuvant CT

before surgical resection, multimodal neoadjuvant therapy

has emerged as a potential paradigm for the management of

locally advanced esophageal cancer.27–32 Achieving a

pathologic complete response and a node-negative status are

the major determinant of outcome following neoadjuvant

CT-RT.9 In those cases in which pathologic response is not

complete, distribution and frequency of nodal metastasis

have been found to be extensively modified by CT-RT. The

aim of this study is to define how neoadjuvant chemoradio-

therapy can affect distribution of nodal metastasis in order to

provide surgeons with a more precise map in preparation for

adequate lymphadenectomy.

TABLE 8 Metastatic lymph

node distribution in esophageal

SCC originating from the

superior or middle esophagus

Data expressed as n (%)a P \ .05, surgery alone vs

surgery ? neoadjuvant therapy

Surgery alone Surgery ? neoadjuvant

therapy

N 75 83

Number of examined lymph nodes: median (IQR) 15.5 (12–21) 18 (12.5–23)

Number of metastatic lymph nodes:a median (IQR) 0 (0–2) 0 (0–1)

Site of metastatic lymph nodes:

Laterocervical 2 (6.7) 0

Supraclavicular 0 2 (2.4)

Periesophageala 21 (28) 10 (12.1)

Paratracheal 4 (5.3) 2 (2.4)

Subcarinala 9 (12) 2 (2.4)

Recurrent nerve nodes 7 (9.3) 5 (6)

Inferior pulmonary veina 4 (5.3) 0

Paracardial 10 (13.3) 4 (4.8)

Perigastric 7 (9.3) 6 (7.2)

Celiac axis 0 1 (1.2)

TABLE 9 Metastatic lymph

node distribution in esophageal

SCC originating from the lower

esophagus and the

esophagogastric junction

Data expressed as n (%)a P \ .05, surgery alone vs

surgery ? neoadjuvant therapy

Surgery alone Surgery ? neoadjuvant

therapy

N 41 22

Number of examined lymph nodes: median (IQR) 17 (12–20) 18 (14–21)

Number of metastatic lymph nodes:a Median (IQR) 1 (0–3) 0 (0–0)

Site of metastatic lymph nodes:

Laterocervical 0 0

Supraclavicular 0 0

Periesophageala 16 (39) 2 (9.1)

Paratracheal 1 (2.4) 2 (9.1)

Subcarinal 4 (9.8) 0

Recurrent nerve nodes 0 0

Inferior pulmonary vein 1 (2.4) 0

Paracardiala 13 (31.7) 1 (4.6)

Perigastric 12 (29.3) 2 (9.1)

Celiac axis 2 (4.9) 1 (4.6)

Nodal Metastasis From Locally Advanced Esophageal Cancer 3751

The impact of neoadjuvant therapy on the number of

metastatic nodes has been described by several studies

and has been confirmed by the present one.5–9 The

frequency of metastatic lymph nodes was lower in the

neoadjuvant therapy ? R0 resection patients than in

those who had surgery alone. This data is even more

remarkable considering that neoadjuvant therapy did not

decrease the number of lymph nodes retrieved. In fact,

although the number of examined lymph nodes was

lower than that reported by Hulsher et al. it was similar

in all the groups and more than 75% of the patients had

15 or more lymph nodes removed, indicating that the

extent of lymphadenectomy had been adequate.3,33 This

was true regardless of the histotype, but it was more

pronounced in the SCC patients. In fact, while in the AC

patients the overall survival of those staged N0 after

neoadjuvant therapy was similar to that in the patients

with the same stage who had surgery alone, in the SCC

patients the improvement in terms of overall survival was

significantly greater in the patients who staged N0 after

neoadjuvant therapy than in those who had surgery alone.

The frequency of nodal metastasis in the various stations

in the AC patients who had surgery alone was similar to

what reported by Dresner et al. and by Van de Val

et al.11,12 On the contrary, the AC patients who underwent

CT-RT neoadjuvant therapy had less frequent metastasis

at the paracardial nodes. The most frequently involved

nodal stations in patients who had surgery alone was the

paracardial, while in patients who underwent neoadjuvant

CT-RT the most frequent metastatic nodal station was

the periesophageal followed by the perigastric. Postneo-

adjuvant therapy nodal metastasis map could help define

the prognosis of AC. In fact, some authors reported that

metastases at the celiac nodes were one of most important

parameters of a new nomogram to assess the prognosis of

esophageal adenocarcinoma.34 Figure 2a illustrates the

modifications in the patterns of lymph node metastasis in

patients with AC who underwent CT-RT neoadjuvant

therapy.

In our SCC patients who had surgery alone the nodal

metastatic distribution was quite similar to what was

reported by Akiyama et al. in 1981 and 1994.13,14 On the

other hand, in the group of patients with esophageal SCC

originating in the superior or middle thoracic esophagus

who underwent neoadjuvant therapy, metastasis at the

periesophageal nodes was less frequent than that reported

by Altorki et al. and by Kato et al.15,35 The frequency of

metastasis at the subcarinal station and at the lymph nodes

along the pulmonary vein was significantly lower in the

patients with upper or middle esophagus SCC who

underwent neoadjuvant therapy. Periesophageal nodes

were still the most frequent site of metastasis in this group

of patients, but the subcarinal station was less frequently

involved and the paracardial nodes were completely free of

metastasis. The frequency of metastasis to the periesoph-

ageal and paracardial nodes in SCC originating from the

29.6%

p = 0.49

Adenocarcinoma

Neoadjuvant CT-RT therapySurgery alone

p = 0.002

p = 0.20

21.9%

12.5%

18.8%

37.1%

35.6%

31.7%

29.3%

9.8%

39.0% 9.8%

4.8%

9.1%

0%p = 0.29

p = 0.05

SCC

Neoadjuvant therapySurgery alone

p = 0.02

p = 0.11

5.3%

13.3% 4.8%

12.0%

28.0%

2.4%

0%

12.1%

p = 0.02

p = 0.03

p = 0.05

SCC

Neoadjuvant therapySurgery alone

p = 0.09

a

b

c

FIG. 2 a Main metastatic lymph nodes sites in esophageal adeno-

carcinoma. The area of the circles is proportional to the frequency of

nodal metastasis. b Main metastatic lymph nodes sites in esophageal

SCC originating from upper or mid esophagus. The area of the circles

is proportional to the frequency of nodal metastasis. c Main metastatic

lymph nodes sites in esophageal SCC originating from lower

esophagus and esophagogastric junction. The area of the circles is

proportional to the frequency of nodal metastasis

3752 C. Castoro et al.

lower third of the esophagus was significantly lower in

patients who had neoadjuvant therapy compared with those

who did not. As suggested by several investigators, these

findings indicate that the probability of finding metastatic

nodes in a particular nodal station can change significantly

not only in relation to the tumor’s histotype or to its pri-

mary localization, but also depending on neoadjuvant

therapy.13–15,35 Changes in nodal metastasis sites in

patients with upper and middle thoracic esophagus and

in those with lower thoracic esophagus SCC are illustrated

in Fig. 2b and c.

The present study is based on data recorded in a

prospectively collected database, but nevertheless it is a

retrospective study and patient selection bias could have

an impact on the results obtained. One of the limits of

this study is that the distribution of tumor sites and

clinical stages were not identical in the surgery-alone and

surgery ? neoadjuvant therapy groups of patients both

for SCC and AC. The fact that there were more T3N0

patients in the surgery-alone group could indicate a

selection bias. Nonetheless, in our opinion, the decrease

in the proportion of N ? patients in the neoadjuvant

therapy groups was so marked that a possible selection

bias could be considered not relevant. Moreover, only

SCC patients who had neoadjuvant therapy seemed to

have benefitted, while in the AC group the number of

nodal metastasis was similar to that observed in patients

who had surgery alone. These patients were, nonetheless,

equally distributed in the two groups receiving neoadju-

vant therapy, but to impede influencing data concerning

the distribution of nodal metastasis they were considered

apart. Secondly, the number of patients who were

excluded from this study because they had incomplete

resection (R1, R2) or only neoadjuvant therapy without

surgery was quite small (33 and 11 patients, respec-

tively), and excluding them from the study did not, we

feel, affect our analysis. In fact, their inclusion would

add patients for whom nodal situation could not be

completely assessed since part of the tumor was neces-

sarily left behind. However, we are conscious that this

might cause a selection bias as neoadjuvant therapy

increases R0 rate. Another limit concerns the lack of

information about the radiation field in our prospective

database. Information on positive lymph node basins

inside and outside the field of radiation could have been

very useful.

In conclusion, this study shows that not only did nodal

metastasis frequency decrease but even nodal metastasis

localization was altered after neoadjuvant therapy. The

map of the distribution of nodal metastasis after neoadju-

vant therapy might be useful information to plan the

operative technique and adequate lymphadenectomy.

ACKNOWLEDGMENT The authors are extremely grateful to

Linda Inverso for her kind help in the revision of the English language

and for editing the final version of the paper.

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