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Surgical Oncology 23 (2014) 140e146
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Surgical Oncology
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Review
Status and prognosis of lymph node metastasis in patients with cardia
cancer e A systematic review
Cecilie Okholm*, Lars Bo Svendsen, Michael P. Achiam
Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 København Ø, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Accepted 1 June 2014
Background: Adenocarcinoma of the gastroesophageal junction (GEJ) has a poor prognosis and survival
rates significantly decreases if lymph node metastasis is present. An extensive lymphadenectomy may
increase chances of cure, but may also lead to further postoperative morbidity and mortality. Therefore,
the optimal treatment of cardia cancer remains controversial. A systematic review of English publications
dealing with adenocarcinoma of the cardia was conducted to elucidate patterns of nodal spread and
prognostic implications.
Methods: A systematic literature search based on PRISMA guidelines identifying relevant studies
describing lymph node metastasis and the associated prognosis. Lymph node stations were classified
according to the Japanese Gastric Cancer Association guidelines.
Results: The highest incidence of metastasis is seen in the nearest regional lymph nodes, station no. 1e3
and additionally in no. 7, 9 and 11. Correspondingly the best survival is seen when metastasis remain in
the most locoregional nodes and survival equally tends to decrease as the metastasis become more
distant. Furthermore, the presence of lymph node metastasis significantly correlates to the TNM-stage.
Incidences of metastasis in mediastinal lymph nodes are associated with poor survival.
Conclusion: The best survival rates is seen when lymph node metastasis remains locoregional and survival rates decreases when distant lymph node metastasis is present. The dissection of locoregional
lymph nodes offers significantly therapeutic benefit, but larger and prospective studies are needed to
evaluate the effect of dissecting distant and mediastinal lymph nodes.
© 2014 Elsevier Ltd. All rights reserved.
Keywords:
Adenocarcinoma
Cardia cancer
Gastroesophageal junction
Lymphadenectomy
Lymph node metastasis
Prognosis
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Classifications of cardia cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Siewert's classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Classifications of lymph node stations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
The Japanese Gastric Cancer Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Pattern of nodal spread in cardia cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Five-year survival related to each lymph node station . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Additional findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Morbidity and mortality related to D1/D2 dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Number of lymph nodes removed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
* Corresponding author. Tel.: þ45 25114720.
E-mail address: [email protected] (C. Okholm).
http://dx.doi.org/10.1016/j.suronc.2014.06.001
0960-7404/© 2014 Elsevier Ltd. All rights reserved.
C. Okholm et al. / Surgical Oncology 23 (2014) 140e146
141
Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Sentinel node for gastric cardia cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Introduction
Adenocarcinoma of the gastroesophageal junction (GEJ) is an
important clinical entity due to the increasing incidence in the
West [1,2]. Arising from the gastric cardia, the cancer has a poor
prognosis with five-year survival rates of 24e36% after curative
resection [3,4]. Located in the borderline between the stomach and
esophagus it shares many similarities with both regions, although
the optimal characterization and treatment of cardia cancer remains controversial.
Studies have shown, that lymph node involvement is a strong
prognostic predictor of survival [5], and five-year survival rates
significantly decreases from 53% to 11% when lymph node metastasis is present [6]. Lymphadenectomy is considered essential in
addition to the surgical treatment, since lymph node involvement
is a major determinant of locoregional recurrence [7,8].
The standard treatment in Asia for gastric cancer is surgical
resection combined with the extensive D2 lymph node dissection,
whereas most of the European countries perform a less extensive
D1þ dissection [5]. The extended lymph node dissection has been
associated with an increased chance for cure in some studies, but
may also lead to a higher incidence of postoperative morbidity and
mortality [9e11]. Given the different clinicopathological characteristics in patients with cardia cancer, the need and extent of
lymphadenectomy remain controversial in the West.
We conducted a systematic review of English publications
dealing with adenocarcinoma of the cardia to elucidate patterns of
nodal spread and prognostic implications.
Materials and methods
Search strategy
The databases PubMed and EMBASE were searched strategically
for terms according to the PRISMA guidelines on the 15th of April
2014 [12]. The search was limited to English language. The identified titles and abstracts were scanned for relevant topics, and the
full texts of the potentially relevant articles were obtained. In
addition, review articles were scanned for missed articles. Potentially relevant studies were identified through hand searching of
the reference lists of the acquired studies. There were no restrictions on the year of publication.
The search string used was: ((Gastric cardia cancer OR gastric
cardia carcinoma OR gastric cardia adenocarcinoma OR esophagogastric junction cancer OR esophageal cancer OR siewert type II
OR siewert type 2 OR siewerts type II OR siewerts type 2)) AND
(lymphatic metastasis OR nodal spread).
Siewert's classification will be presented below.
The results from the search are presented in Fig. 1.
Eligibility criteria
Relevant papers were included in the review based on the
following eligibility criteria. There were no restrictions on
study design, since no RCT's has been made to date to our
knowledge.
Participants: Patients with cardia cancer undergoing surgery
primarily focused on Siewert's type II or junctional adenocarcinomas. If the article was based on several gastric or esophageal
cancers, the results for cardia cancer patients had to be presented separately.
Interventions: Patients undergoing lymphadenectomy with
retrieval of involved lymph nodes and estimation of lymph node
status. Additionally, records of the incidences of node metastasis
to each Japanese Gastric Cancer Association (JGCA) lymph node
station for node positive patients. Of particular interest were
articles estimating the associated five-year survival (5-Y-S) to
each lymph node station.
Outcome: Incidence of lymph node metastasis to JGCA lymph
node stations. In cases where studies presented data from all
three Siewert's types combined, we still included the studies
since no difference between the three types has been observed.
Data extraction: Lymph node metastasis in percent associated to
each lymph node station and median and range of the correlated 5-Y-S to each station if presented. Additionally, the prognosis and correlation to the TNM-stage was extracted. Only
available lymph node stations relevant to the different classifications for D1, D2 and D3 dissections were analyzed. Thus,
distant lymph node stations and some upper thoracic and cervical stations were not included in this review.
Exclusion: Exclusion criteria were articles with non-cardia cancer, esophagus cancer, subcardia or gastric cancer, and articles
with results not distinguished from esophagus or gastric cancer.
Additionally gastric carcinosarcoma, stromal tumors and squamous cell tumors were excluded. Furthermore, articles focusing
on biological markers for lymph node retrieval, patients
receiving neoadjuvant chemotherapy and studies without linkage to lymph node stations were considered irrelevant. If the
results were combined for squamous cell and adenocarcinoma
they were excluded in addition.
Classifications of cardia cancer
Siewert's classification
In 1998 Siewert et al. [13] introduced a classification for adenocarcinomas of the GEJ, defining them as tumors having their
epicenter within five cm proximal or distal of the anatomical cardia.
Three distinct tumors were differentiated: Type I: Adenocarcinoma
of the distal esophagus which usually arises from an area with
specialized intestinal metaplasia of the esophagus and which may
infiltrate the gastroesophageal junction from above. Type II: True
carcinoma of the cardia, arising from the cardia epithelium or short
segments with intestinal metaplasia at the gastroesophageal
junction. Type III: Subcardial gastric carcinoma, which infiltrates
the gastroesophageal junction and distal esophagus from below.
142
C. Okholm et al. / Surgical Oncology 23 (2014) 140e146
lymphatic flow and observed survival associated with metastasis in
each station (Fig. 1).
The third English edition from JGCA (2011) [16] defined lymph
node stations 1e12 and 19, 20, 110 and 111 for tumors with
esophageal invasion as regional lymph node metastasis; others
were classified as distant metastasis. Moreover, an edition with
special focus on treatment guidelines was published, in which the
extent of lymphadenectomy was defined according to the type of
gastrectomy [17].
In principle, a D1 or a D1þ lymphadenectomy was indicated for
node negative tumors, and D2 was indicated for node positive or
T2eT4 tumors. Since the pre- and perioperative diagnosis of lymph
node metastases remains unreliable, it was recommended that a D2
lymphadenectomy should be performed whenever nodal involvement was suspected. Although it is not prerequisite, the examination of 16 or more regional lymph nodes was recommended for Nstatus determination [17].
Since most of the included studies describe lymph node stations
and dissections according to the JGCA 1998 edition [15], the results
in this review will be presented according to this edition.
Results
Based on the search methods described, a total of 17 articles
were identified describing the pattern of lymph node spread and
six articles were identified describing the associated five-year
survival (5-Y-S). The six articles comprised of retrospective cohorts with a number of included patients ranging from 62 to 225
(Table 1).
Pattern of nodal spread in cardia cancer
Figure 1. Station numbers of regional lymph nodes. Reprinted with permission from
the Japan Esophageal Society, from the article “Japanese Classification of Esophageal
Cancer, tenth edition: printed in part I”, printed in Esophagus (2009) 6: 1e25.
Cardia cancer was defined as adenocarcinoma of the GEJ. The
search was specified to Siewert's type II, since this was considered
the true cardia carcinoma [13]. Siewert type I is mainly treated like
esophagus cancer, since most tumors arise from areas of intestinal
metaplasia in Barrett's epithelium as a consequence of reflux. In
contrast, type III tumors represent proximal gastric cancer and
should be approached in accordance with gastric cancer guidelines
[14]. The characterization and optimal treatment for Siewert's type
II cardia cancer remains debatable, and is therefore the primary
focus of this review.
Classifications of lymph node stations
The Japanese Gastric Cancer Association
Classification guidelines published by JGCA for gastric cancer
including definitions of the lymph node stations, aimed at
providing a common language for the clinical and pathological
description of gastric cancer. In 1998, the second English edition
from JGCA classified lymph nodes into three groups depending on
the location of the primary tumor [15]. These three groups were
subdivided into 33 stations based on the results of studies of
In Fig. 2, the incidence of lymph node metastases is presented
according to the JGCA lymph node stations divided into D1eD3
dissections [3,18e33].
The highest incidence of lymph node metastasis is seen in
regional lymph nodes, especially station no. 1e3, with a range from
13.7 to 72.7%. The incidence in station no.4 is lower, ranging from
0 to 31.8%. In the D2 stations the highest incidence of metastasis is
observed in no. 7, 9 and 11, ranging from 0 to 45.5%. The incidences
in D3 stations are remarkably lower with fewer than 20% of nodes
involved.
Incidences and survival rates associated with mediastinal
lymph node involvement is poorly reported and few are classified
Table 1
Included studies.
Yamashita et al. [30]
Hoskokawa et al. [20]
Mine et al. [25]
Fujitani et al. [19]
Saito et al. [3]
Wang et al. [28]
Fang et al. [18]
Matsumoto et al. [23]
Nakamura et al. [26]
Ichikura et al. [21]
Feith et al. [14]
Mattioli et al. [24]
Yamamoto et al. [29]
Kakeji et al. [22]
Pedrazzani et al. [36]
Gertler et al. [32]
Meier et al. [31]
Yuasa et al. [33]
n
Siewert
n of LN stations
5-Y-S
225
179
150
86
110
42
51
58
30
31
485
116
67
129
62
224
167
40
II
I,II,III
II
II
II
II
II
I,II,III
II
II
II
II
II
I,II,III
I,II,III
I,II,III
II,III
II
19
17
15
13
16
17
16
16
11
10
6
8
4
15
14
7
9
8
x
x
x
x
x
x
C. Okholm et al. / Surgical Oncology 23 (2014) 140e146
143
Figure 2. Lymph node metastasis according to JGCA stations in % with median and range.
according to stations (data is not presented) [3,20,21,24e26,29].
Node metastasis in the lower mediastinal stations ranged from 7.5
to 23.8%, whereas patients with upper mediastinal node involvement were below 4%. Patients with lymph node involvement
extending to the proximal field of the chest (no. 106, 107) tended
to have a higher ratio of involved to total lymph nodes [34]. One
study found positive nodes in the chest in 24% of the patients [35].
Five-year survival related to each lymph node station
In Fig. 3 the 5-Y-S is shown in percent with median and range
according to each lymph node station [3,19,20,25,30,36].
Stations in D1 has the best 5-Y-S rates overall, ranging from 0 to
50%. Involvement of no. 4sb reduced the survival rate, although the
incidence of metastasis was correspondingly low.
In D2 stations the 5-Y-S ranges from 0 to 53%. The best survival
rate is seen in station no. 7, the station with the highest lymph node
involvement in this group. The lowest survival rate is seen in station
no. 9, with survival rates below 14.7%.
Metastasis to the lymph node stations in D3 shows overall very
poor survival. Data is not presented due to insufficiency of reported
data. No patients with involvement of station no. 5, 12 and 111
survived after five years. Only one study found patients alive after
five years with involvement of station 6 [19]. Few studies reported
survival in station 16 and 110, ranging from 0 to 23.8%
[3,20,25,30,36].
Additional findings
The presence of lymph node metastasis seems to be significantly
correlated to the depth of tumor invasion [28,36e38]. Ielpo et al.
found an increasing rate of distal nodal involvement as the T-stage
increases [35]. Furthermore, lymph node metastases were significantly correlated to the size of the tumor, where large tumors
(>4 cm) had significantly greater risk of lymph node involvement
[37].
Some studies have investigated the influence of lymph node
metastasis on prognosis. The majority concluded that the presence
of lymph node metastasis (Nþ) was an independent prognostic
factor, and was associated with poor survival [3,25,27,37,39,40]. Only
one study found no significantly difference between Nþ/N [29].
A limited number of studies investigated survival rates when the
frequency of lymph node involvement was divided into N-stage
(Table 2). There was an observable correlation between higher Nstage and poorer survival, with 5-Y-S rates from 2 to 17.4% in N3
tumors compared to 5-Y-S in N0 up to 82.7% [5,19,30].
Figure 3. 5-Y-S according to JGCA lymph node stations in % with median and range.
144
C. Okholm et al. / Surgical Oncology 23 (2014) 140e146
Table 2
Prognosis to N-stage in %.
Yamashita
et al. [30]
5-Y-S
Fujitani
et al. [19]
5-Y-S
Zhang
et al. [5]
5-Y-S
N0
N1
N2
N3
82.7
65.1
35.9
17.4
p < 0.0001
N0
N1
N2
N3
64.7
54.4
31.6
10.7
p < 0.0001
N0
N1
N2
N3
47.4
29.4
5.5
2.0
p < 0.001
Discussion
The highest incidences of lymph node metastasis in patients
with cardia cancer are located in the locoregional nodes; especially
station no. 1e3 and no. 7, 9 and 11. Aikou et al. reported in 1989 [41]
that lymph node metastasis from cardia cancer preferentially make
their way to the upper gastric lymph nodes located at the right and
left cardia and along the lesser curvature of the stomach, and in
addition various involvement of the coeliac axis, the splenic hilum
and the para-aortic lymph nodes [41]. A more recent review confirms the spread to the paracardial and lesser curvature regions
[42]. This is in line with our results, although the incidence of paraaortic lymph involvement was below 19%.
The best prognosis is correspondingly seen when metastasis
remain in the nearest regional lymph nodes, which indicate that
dissection here offers significantly therapeutic benefits. Station 1e3
are included in D1 dissection in both gastric classifications [15,16].
In D2 dissection the best survival is seen in patients with metastasis
in station no. 7, which in the most recent classification (JGCA 2011)
now is a part of D1 dissection. Station no. 10 with lymph node
metastasis up to 22.7%, has 5-Y-S ranging from 0 to 50%. In both
JGCA station no. 10 is a part of D2 dissection. Earlier recommendations were spleenectomy when dissecting no. 10 in order to
properly dissect the nodes [43], but recently spleen- and pancreas
preserving D2 dissections has been recommended in high-volume
centers for western patients [44].
In general, the survival rates decrease along with an increased
distal lymph node involvement, and might indicate a cancer in the
advanced stage. Dissection of station no. 5 and 6 (D3 dissection)
may offer marginal therapeutic benefit, and these stations might
represent distant rather than locoregional metastasis [19,30]. All
stations in D3 (except no 5 and 6) were in 2011 upgraded to a D1þ
or D2 dissection.
When interpreting the results, it is important to consider that
survival associated to lymph node stations is interdependent. It is
difficult to determine patient survival correlated to one isolated
station, since metastasis most likely will be present in other stations as well. Also, studies have shown a decreasing survival when
N-stage is increasing (Table 2). Therefore, it is difficult to conclude
on survival outcome from one isolated lymph node. To our
knowledge, no studies investigating survival adjusted for this factor
has been made to date.
The results of this review summarize survival rates correlated to
lymph node stations of D1, D2 or D3 dissection. Overall, survival
rates seem consistent in D1 and station no. 7 and 10. The decreasing
survival rates in D2 and D3 stations may represent advanced
disease.
Morbidity and mortality related to D1/D2 dissection
The definitions of D1 and D2 dissection have changed over the
years, but the optimal treatment is still debatable.
A study of 110 patients with cardia cancer found D2 morbidity
and mortality rates higher than D1, although not significantly [37].
One study with 123 patients compared D4 (D3þ paraaortic station
no. 15,16) and D2 dissection and concluded that in node positive
patients where invasion was deeper than T2, the D4 dissection
showed superior survival than D2 (p < 0.05) [40]. It has been stated
that the D2 dissection allows more adequate staging and more
lymph nodes examined [9,45], and Lerut et al. found that an
extended three-field lymphadenectomy (D2þ posterior mediastinum) could be performed with low mortality and acceptable
morbidity [46]. However, many of these studies suffered from a low
number of patients and a non-randomized design.
In patients with gastric cancer, large RCT's comparing the
morbidity and mortality rates of D1 and D2 dissection has been
performed [10,11,43]. All concluded that D2 dissection was associated with worse morbidity and mortality than D1 dissection. In
contrast, patients undergoing D2 dissection experienced lower
locoregional recurrence and gastric cancer related deaths [11]. The
increased morbidity and mortality rates associated with the D2
dissection has been criticized to be a result of the invasive distal
pancreatectomy and the removal of the spleen in order to dissect
station no. 10 [11]. Degiuli et al. found no difference in morbidity
and mortality rates comparing D1 and D2 dissection when performing a spleen and pancreas preserving D2 dissection in gastric
cancer patients, although he did not find an increased survival [44].
According to the Danish Gastroesophageal Cancer Group
(DECG), the standard approach is a D1þ dissection combined with
removal of a minimum of 15 lymph nodes, always including
abdominal station 7 and 9 and standard lymphadenectomy in
thorax (lymph nodes no. 20,107,108,110,111) [47]. The five-year
survival rate after curative resection was 32% (95% CI 28e36) in
2011 which is comparable to international studies where overall 5Y-S rates range from 21.9% to 27.2% [5,24,36,46].
The depth of tumor invasion seems to reflect the incidence and
extent of lymph node metastasis, and it has been suggested that a
predetermination of the T-stage may help to indicate the relevant
lymph node dissection [28]. The correlation between the TNMstage and the involvement of lymph nodes indicate and confirm
that TNM-staging with adequate lymphadenectomy should be the
goal of the curative surgical approach.
In contrast, it is difficult to predetermine the presence of
mediastinal and thoracic lymph node metastasis and the removal of
these stations is still controversial. Station no. 110 were in 1998
included in D3 dissection, but were in 2011 upgraded to D1þ. This
indicates that the significance of mediastinal lymph node involvement may have increased. Involvement of these nodes may
represent distant rather than regional metastasis and might indicate a cancer in the advanced stage [26,34,48]. The frequency of
lymph node metastasis in mediastinum was low, and dissection of
these nodes is suggested to have minimal or no survival benefits
[26,49]. Since the number of studies is limited and the mediastinal
and thoracic lymph node stations are inadequately defined, it is
difficult to conclude any beneficial effect of dissection these
stations.
Number of lymph nodes removed
Another question is whether the removal of specific lymph node
stations or the amount of lymph nodes removed is the most
important prognostic factor. A large international multicenter
study with more than 2300 esophagus cancer patients concluded
that the number of lymph nodes removed was a prognostic factor,
even when adjusted for lymph node status and number of involved
lymph nodes [50]. There was no relation to stage migration, but
simply a correlation between the number of lymph node harvest
and increased prognosis. They recommended that a minimum of 23
lymph nodes should be removed in order to achieve the best
outcome.
C. Okholm et al. / Surgical Oncology 23 (2014) 140e146
145
Studies investigating this approach in cardia cancer are limited,
although it has been stated that adequate dissection over 15 lymph
nodes is necessary to permit a sufficient staging [9,35,51]. The
improved prognosis when performing an increased lymph node
harvest may be due to a better diagnosis, but it could also represent
better surgical techniques. Larger and prospective studies are
needed to investigate this field further.
lymph node metastasis remains locoregional and only involves
those in the D1 dissection (JGCA 1998 edition) and no. 7 and 10.
Survival rates decrease when lymph node involvement become
distant but the beneficial effect of dissecting these is debatable.
Larger and prospective studies are needed to validate the optimal
lymphadenectomy and further investigate the significance of predetermination of T-stage and the concept of sentinel node.
Future perspectives
Conflict of interest statement
Sentinel node for gastric cardia cancer
Limited publications are available concerning sentinel node
techniques for cardia cancer. In a small study of 20 patients with
adenocarcinoma of the gastroesophageal junction; sentinel node
were able to correctly predict lymph node status in overall 85% of
the early stage carcinomas [52].
In gastric cancer, sentinel node is a promising concept and has
shown high sensitivities in early stage cancers [53,54].
The presence of skip metastasis in gastric cancer, which has
been observed in 10% of the cases [55] may be an obstacle [53]. In
cardia cancer incidences of skip nodes is more rarely observed, one
study found no cases, and another study had one incidence of skip
metastasis in 22 patients [28,56]. Since the frequency of skip metastases in cardia cancer seems lower, sentinel node might have
increased clinical significance due to the borderline location and
varying lymphatic drainage of cardia cancer [57]. Especially in the
context of the need to perform a limited lymphadenectomy
including only involved stations, it is attractive to consider the use
of a sentinel node technique in order to determine the extent of
lymphadenectomy [58].
Limitations
This review summarizes the existing literature of lymph node
metastasis and prognosis in cardia cancer patients. However,
studies are limited and suffer from retrospective designs. Furthermore, the studies are not exclusively comparable in relation to
lymph node stations, since they describe metastasis in different
numbers of lymph node stations. In addition, some authors
combine stations, e.g. 8a, 8b and 8p as station 8, or do not define it
in detail. Because of this, there may be some bias when investigating the exact lymph node spread. Moreover, in the results presenting lymph node spread some stations are described by all
included studies and some are only described by few of the
included studies. As mentioned before, some studies present results combined for all Siewert's types, and bias may exist when
concluding lymphatic pathways from Siewert's type II. Also, the
number of patients in the included studies is low. Furthermore,
studies comparing D1 and D2 dissection regimes may be prone to
selection bias, since some studies may have chosen D2 lymphadenectomy to patients that are younger and healthier.
Despite an extensive reviewing of the search results, it is
possible that valuable articles have been missed. Furthermore, due
to language restrictions, some potential relevant articles published
in Chinese or Japanese are not included in this review.
The retrospective design of the studies is a major limitation,
which must be adjusted for when interpreting the results. This
indicates that this field needs further investigation.
Conclusion
This review confirms that the spread of cardia cancer preferentially involves the locoregional gastric lymph node stations, followed by station 7, 9 and 11. The best survival rates are seen when
The authors have no conflict of interests to declare.
Acknowledgments
The authors have no conflict of interests to declare.
Authorship statement
Guarantor of the integrity of the study: Lars Bo Svendsen,
Michael P. Achiam.
Study concepts: Cecilie Okholm, Michael P. Achiam.
Study design: Cecilie Okholm, Lars Bo Svendsen, Michael P.
Achiam.
Definition of intellectual content: Cecilie Okholm, Lars Bo
Svendsen, Michael P. Achiam.
Literature research: Cecilie Okholm.
Data acquisition: Cecilie Okholm.
Data analysis: Cecilie Okholm, Lars Bo Svendsen, Michael P.
Achiam.
Statistical analysis: Cecilie Okholm, Lars Bo Svendsen, Michael P.
Achiam.
Manuscript preparation: Cecilie Okholm.
Manuscript editing: Cecilie Okholm, Lars Bo Svendsen, Michael
P. Achiam.
Manuscript review: Cecilie Okholm, Lars Bo Svendsen, Michael
P. Achiam.
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