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Lymphadenectomy for Gastric Adenocarcinoma: Should West
Meet East?SAM S. YOON,a HAN-KWANG YANGb
aDepartment of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,
USA; bDepartment of Surgery, Seoul National University Hospital, Seoul University College of Medicine,
Seoul, South Korea
Key Words. Gastric cancer Surgery Lymphadenectomy Outcomes Review
Disclosures: Sam S. Yoon: None; Han-Kwang Yang: None.Section editors Richard M. Goldberg, Patrick G. Johnston, and Peter J. ODwyer have disclosed no financial
relationships relevant to the content of this article.The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free
from commercial bias.
LEARNING OBJECTIVES
After completing this course, the reader will be able to:
1. Calculate the lymph node drainage patterns of gastric adenocarcinoma based on the location of the tumor.
2. Differentiate and explain the extent of lymphadenectomies performed in different countries.
3. Analyze the risks and benefits of performing more extensive lymphadenectomies for gastric adenocarcinoma.
This article is available for continuing medical education credit at CME.TheOncologist.com.CMECME
ABSTRACT
The extent of lymphadenectomy that should be performed
for gastric adenocarcinoma has been a topic of persistent
debate. In countries such as Japan and Korea, where the
incidence of gastric adenocarcinoma is high, more exten-
sive (e.g., D2) lymphadenectomies are routinely per-
formed, usually by experienced surgeons with low
morbidity and mortality. In western countries such as the
U.S., where the incidenceof gastric adenocarcinoma is ten-fold lower, the performance of more extensive lymphade-
nectomies is generally limited to specialized centers, and
quite possibly the majority of patients are treated at non-
referral centers with less than a D1 lymphadenectomy.
There is little disagreement among gastric cancer experts
that the minimum lymphadenectomy that should be per-
formed for gastric adenocarcinoma shouldbe at least a D1
lymphadenectomy. Two large, prospective randomized
trials performed in the United Kingdom and the Nether-
lands failed to demonstrate a survival benefit of D2 over
D1 lymphadenectomy, but these trials have been criticized
for high surgical morbidity and mortality rates in the D2
group. More recent studies have demonstrated that west-
ern surgeons can be trained to perform D2 lymphadenec-
tomies on western patients with low morbidity andmortality. Retrospective analyses and one prospective,
randomized trial suggest that there may be some benefits
to more extensive lymphadenectomies when performed
safely, but this assertion requires further validation. This
article provides an update on the current literature re-
garding the extent of lymphadenectomy for gastric adeno-
carcinoma. The Oncologist 2009;14:871882
Correspondence: Sam S. Yoon, M.D., Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Yawkey7B-7926, 55 Fruit Street, Boston, MA 02114, USA. Telephone: 617-726-4241; Fax: 617-724-895; e-mail: [email protected] Received April 6, 2009; accepted for publication August 6, 2009; first published online in The Oncologist Express onSeptember 8, 2009. AlphaMed Press 1083-7159/2009/$30.00/0 doi: 10.1634/theoncologist.2009-0070
TheOncologistThe Oncologist CME Program is located online at http://cme.theoncologist.com/.
To take the CME activity related to this article, you must be a registered user.
GastrointestinalCancer
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INTRODUCTION
Gastric cancer is one of the leading worldwide causes of
cancer death, with about 803,000 deaths each year [1]. The
incidence of gastric adenocarcinoma varies tremendouslythroughout the world, with the highest incidence occurring
in South Korea at 66.572.5 per 100,000 males and 19.5
30.4 per 100,000 females [2]. The incidence of gastric can-
cer in the U.S. is only one tenth that of South Korea. The
estimated number of new gastric cancer cases in the U.S. in
2008 was 21,500, and the estimated number of deaths was
10,880 [3].
Gastric adenocarcinoma frequently metastasizes to re-
gional lymph nodes. For T1 lesions invading the submu-
cosa, lymph node involvement is found in about 19% of
patients [4]. For T2 lesions (invading the muscularis pro-pria or submucosa), the lymph node metastasis rate in-
creases to 50%. There is also significant evidence that
some patients with lymph node metastases beyond the im-
mediate perigastric lymph nodes can be cured with surgical
resection alone [5]. Whether this group of patients repre-
sents a significant percentage of patients with resectable
gastric cancer is a matter of debate, and thus the optimal ex-
tent of lymphadenectomy for adenocarcinoma of the stom-
ach continues to be controversial.
There are significant differences in the extent of lymph-
adenectomy performed by surgeons in different countries.To broadly generalize, surgeons in Japan and Korea rou-
tinely perform more extensive lymphadenectomies (D2
lymphadenectomy or greater) whereas most surgeons in the
U.S. and many other western countries perform more lim-
ited lymphadenectomies (D1 lymphadenectomy or less).
Two large, prospective randomized trials performed in The
Netherlands and the United Kingdom found no survival
benefit for D2 over D1 lymphadenectomy [6, 7]. However,
there were significant problems with these studies, includ-
ing a high morbidity and mortality rate in the D2 group,
which was associated with inadequate surgical training, and
with the frequent performance of a distal pancreatectomy
and splenectomy in the D2 group, which is now considered
unnecessary [8, 9].
Several studies since these randomized trials have sug-
gested that more extensive lymphadenectomies may be
beneficial in certain patients with gastric adenocarcinoma.
These studies have demonstrated that: (a) D2 lymphadenec-
tomies can be performed in specialized western centers
without distal pancreatectomy or splenectomy and with low
morbidity and mortality [1, 10, 11], (b) there may be a sur-
vival benefit for D2 lymphadenectomy if performed with
low morbidity and mortality [12], and (c) there may be a
survival benefit if lymph node stations that are predicted to
have metastatic disease preoperatively are removed [13,
14].
This article examines important historical trials andcontemporary studies regarding lymphadenectomy for gas-
tric adenocarcinoma. Regional differences in the extent of
lymphadenectomy are reviewed. Hypothetical advantages
of more extensive lymphadenectomies are discussed fol-
lowed by an analysis of the available studies supporting or
disclaiming these potential advantages. Barriers to the per-
formance of more extended lymphadenectomies in western
countries are also examined, followed by a discussion of
how these barriers may be overcome.
NODAL STATION ANDLYMPHADENECTOMY DEFINITIONS
Prior to a discussion of lymph node dissections for gastric
adenocarcinoma, one must define the terms to be used. The
lymph node stations surrounding the stomach have been
precisely defined by the Japanese Research Society for
Gastric Cancer (JRSGC) [15] (Fig. 1, Table 1). The JRSGC
defines four levels of lymph node stations, N1N4. The
designation of N1N4 nodes varies according to the site of
the primary tumor (i.e., upper, middle, or lower third of the
stomach). The D level of lymphadenectomy (formerly
known as the R level of lymphadenectomy) is based on theJRSGC definitions of lymph node station level [16]. A D1
lymphadenectomy is defined as removal of all N1 level
nodes, and a D2 dissection is defined as removal of all N1
and N2 level nodes. Table 2 shows the lymph node stations
that should be removed for a D1 and D2 lymphadenectomy
(based on the location of the primary tumor) as recom-
mended by the Japanese Gastric Cancer Association.
REGIONAL DIFFERENCES IN LYMPHADENECTOMY
FOR GASTRIC ADENOCARCINOMA
As noted earlier, South Korea has the highest incidence of
gastric adenocarcinoma in the world. Despite the high inci-
dence of gastric adenocarcinoma in Korea, patients are of-
ten referred to tertiary care centers for treatment. Two thirds
of all gastric cancer surgeries in South Korea are performed
at 16 high-volume institutions, which perform at least 200
gastric cancer surgeries per year. Thus, gastric cancer sur-
geons at high-volume institutions in Korea gain tremendous
experience in the surgical management of gastric cancer.
The minimum lymphadenectomy performed by Korean
surgeons for gastric adenocarcinoma is generally a D2
lymphadenectomy. Despite performing extensive lymph-
adenectomies, the morbidity and mortality rates are quite
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low. For example, Seoul National University Hospital,
which performs almost 1,000 gastric cancer operations per
year, recently reported a morbidity rate of 18% and mortal-
ity rate of 0.5% [17]. Japanese patients with gastric cancer
are also frequently treated at high-volume institutions with
low complication rates. In a prospective, randomized trial
from 24 Japanese institutions of D2 versus extended para-
aortic lymphadenectomy, the morbidity rate was 20.9%
28.1%, and the mortality rate was 0.8% [18].
Unlike in Korea and Japan, the majority of gastric can-
cer surgeries in the U.S. are performed at nonreferral cen-
ters, and thus a high-volume institution in the U.S. has
been reported in some studies to be centers with only 1520
or more cases per year [19, 20]. Birkmeyer et al. [19] re-
viewed a database of Medicare patients and found that hos-
pitals that performed 20 gastrectomies per year had
significantly lower mortality rates, yet 80% of patients
were operated on at centers that performed 20 gastrecto-
mies per year. Given that most U.S. general surgeons see
few gastric cancer patients, these surgeons likely err on the
side of more limited lymphadenectomies in order to avoid
excess morbidity and mortality. The American College of
Surgeons performed a survey study in 1993 of18,000 pa-
tients treated at 700 institutions [21]. Of the 77% of pa-
tients that underwent gastric resection, perigastric lymph
nodes were resected in 50% of patients. The overall sur-
vival rate in resected patients at 5 years was 19%, and the
first site of recurrence was local or regional in 41% of pa-
tients that recurred. In the Intergroup 0116 trial, in which
patients were randomized after gastric cancer surgery to no
further therapy or chemoradiation, 50% of patients en-
rolled received less than a D1 lymphadenectomy [22, 23].
Most gastric cancer experts in both the east and west would
agree that a D1 lymphadenectomy is the minimum lymph-
Figure 1. Locations of lymph node stations. Adapted from Japanese Gastric Cancer Association. Japanese classification of gas-tric carcinoma2nd English editionresponse assessment of chemotherapy and radiotherapy for gastric carcinoma: Clinicalcriteria. Gastric Cancer 2001;4:18, with permission.
873Yoon, Yang
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adenectomy that should be performed for gastric adenocar-
cinoma beyond an early T1 lesion [24].
Despite the performance of less extensive lymphade-
nectomies in the U.S., surgical morbidity and mortality
rates for gastric adenocarcinoma are generally much higher
in the U.S. than in South Korea and Japan. A recent analysis
of the Nationwide Inpatient Sample from 19982003 of
50,000 patents with gastric cancer found that the overallmortality rate following gastric surgery was 6% [25]. Sin-
gle-institution series have reported morbidity rates follow-
ing gastrectomy of up to 40% [26]. Certain factors in
Japanese and Korean patients, such as less advanced gastric
cancer and fewer comorbidities such as cardiovascular dis-
ease and obesity, allow for lower morbidity and mortality
rates, but almost certainly the surgical expertise and better
perioperative care that comes with a higher volume play a
significant role. Thus, in order for western surgeons to con-
sider performing more extended lymphadenectomies with
low morbidity and mortality, volume at referral centersneeds to be increased and some additional surgical training
is likely needed. The learning curve for training general sur-
geons for D2 lymphadenectomy has been estimated to be at
least 23 cases [27]. Following adequate training, D2 lymph-
adenectomies can be performed by western surgeons on
western patients with low morbidity and mortality rates
similar to high-volume centers in the east [10, 11].
POTENTIAL BENEFITS OF MORE
EXTENSIVE LYMPHADENECTOMIES
Lymphadenectomy for cancer can serve three primary pur-
poses: staging of disease, prevention of locoregional recur-
Table 1. Regional lymph nodes of the stomach
Number Description
1 Right paracardial
2 Left paracardial
3 Lesser curvature
4 Greater curvature
sa Along short gastric vessels
sb Along left gastroepiploic vessels
d Along right gastroepiploic vessels
5 Suprapyloric
6 Infrapyloric
7 Along left gastric artery
8 Along common hepatic artery
a Anterosuperior group
p Posterior group
9 Around celiac artery
10 Splenic hilum
11 Along splenic artery
p Along proximal splenic artery
d Along distal splenic artery
12 Hepatoduodenal ligament
a Along hepatic artery
b Along bile duct
p Along portal vein
13 Posterior surface of pancreatic head
14 Along superior mesenteric vesselsv Along superior mesenteric vein
a Along superior mesenteric artery
15 Along middle colic vessels
16
a1 Aortic hiatus
a2 Abdominal aorta (from upper margin of celiactrunk to lower margin left renal vein)
b1 Abdominal aorta (from lower margin leftrenal vein to upper margin inferior mesentericartery)
b2 Abdominal aorta (from upper margin inferior
mesenteric artery to aortic bifurcation)17 On anterior surface of pancreatic head
18 Along inferior margin of pancreas
19 Infradiaphragmatic
20 In esophageal hiatus of diaphragm
110 Paraesophageal in lower thorax
111 Supradiaphragmatic
112 Posterior mediastinal
Table 2. Extent of lymphadenectomy
Location D1 dissection D2 dissection
LMU 16 7, 8a, 9, 10, 11p, 11d,12a, 14v
LD/L 3, 4d, 5, 6 1, 7, 8a, 9, 11p, 12a,14v
LM, M, ML 1, 3, 4sb, 4d, 5, 6 7, 8a, 9, 11p, 12a
MU, UM 16 7, 8a, 9, 10, 11p, 11d,12a
U 1, 2, 3, 4sa, 4sb 4d, 7, 8a, 9, 10, 11p,11d
When the tumor involves only one of the three portions ofthe stomach, this is expressed by U, M, or L.If the lesions involves more than one of the three portionsof the stomach, this is expressed by listing the primarilyinvolved portion first followed by the less involvedportion(s).
Abbreviations: D, duodenum; L, lower; M, middle; U,upper.Adapted from Japanese Gastric Cancer Association.Japanese classification of gastric carcinoma2nd Englisheditionresponse assessment of chemotherapy andradiotherapy for gastric carcinoma: Clinical criteria.Gastric Cancer 2001;4:1 8.
874 Lymphadenectomy for Gastric Cancer
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rence, and improvement in overall survival. There is little
doubt that more extensive lymphadenectomies for gastric
adenocarcinoma lead to better staging of disease. The 2002
Sixth Edition of the American Joint Committee on Cancer
Staging Manual for gastric adenocarcinoma recommends
that at least 15 lymph nodes be examined for correct assess-
ment of the N category [28]. An analysis of6,000 gastric
cancer patients treated at 691 U.S. hospitals found that
40% of patients undergoing surgical resection had the
requisite 15 lymph nodes examined [29]. Using the Surveil-
lance, Epidemiology, and End Results database, Coburn et
al. [30] found that only 29% of 10,807 resected gastric can-
cer patients had 15 lymph nodes examined. In a study
from the United Kingdom analyzing 18 hospitals, only 31%
of the 699 surgical resections resulted in15 lymph nodes
analyzed [31]. Thus, many western patients are understaged
following surgical resection of their gastric cancers becauseof inadequate lymph node sampling.
Significant variability in the extent of lymphadenec-
tomy and number of lymph nodes examined pathologically
leads to difficulty in comparing the outcomes of patients
from different regions based on stage of disease as well as
stage migration. It is difficult to be confident that a tumor is
truly node negative when 10 lymph nodes are examined
[32, 33], and N1 tumors can be upstaged to N2 or even N3
tumors as more lymph nodes are harvested [33, 34]. Fur-
thermore, it is impossible to be categorized as N3 if15
lymph nodes are harvested. Several studies have demon-strated that examination of even more than 15 lymph nodes
improves the ability to predict prognosis in patients with
gastric adenocarcinoma [33, 35]. Shen et al. [35] found that
increasing the total lymph nodes examined to 30 im-
proved the accuracy of staging for patients with T3 disease.
Several authors have found that the ratio of involved lymph
nodes to resected lymph nodes may be a better predictor of
prognosis than the absolute number of positive lymph
nodes. In one study of 9,058 patients who underwent resec-
tion for gastric cancer, the ratio of involved lymph nodes to
resected lymph nodes was a more precise predictor of prog-
nosis than the absolute number of positive lymph nodes
[36]. Similar findings were reported by the German Gastric
Cancer Study [37] and the Italian Research Group for Gas-
tric Cancer [38]. Thus, there is little debate that more exten-
sive lymphadenectomies improve staging for patients with
gastric adenocarcinoma.
One must also recognize that, even if a surgeon per-
forms an extensive lymphadenectomy, the pathologist is
usually the one who finds and examines the dissected
lymph nodes. Thus, a coordinated effort is required be-
tween the surgeon and pathologist if more extensive lymph-
adenectomies are to result in better staging of patients. In
Japan and Korea, following the en bloc dissection of the
stomach and lymph nodes, the surgeon dissects out the in-
dividual nodal stations from the surgical specimen, allow-
ing the pathologist to examine and report the number of
positive and negative lymph nodes for each nodal station.
At Massachusetts General Hospital, where one author has
been routinely been performing D2 lymphadenectomies,
the institution of a protocol of dissecting out the individual
nodal stations from the resected surgical specimen has in-
creased the average number of lymph nodes examined per
specimen from 35 to 42.
There is some indirect evidence that more extensive
lymphadenectomies result in lower rates of locoregional re-
currence. Locoregional recurrence after potentially cura-
tive surgery for gastric adenocarcinoma can be quite high.
In a 1982 series from the University of Minnesota, 107 pa-
tients with gastric adenocarcinoma underwent second-looklaparotomy, and 80% had a recurrence [39]. Of these recur-
rences, 88% were locoregional, 54% were peritoneal, and
29% were distant. More recently, in the U.S. Intergroup
0116 trial, 177 of 275 patients (64%) in the surgery-only
group developed recurrent disease [22]. In terms of the site
of first relapse, 29% had local recurrence, 72% had regional
recurrence, and only 18% had distant recurrence. Rates of
locoregional recurrence are generally lower in reports from
both western and Asian institutions that perform more ex-
tensive lymphadenectomies. In a series of 367 patients with
recurrent gastric adenocarcinoma from Memorial Sloan-Kettering Cancer Center over 15 years, 81% of patients had
a D2 or greater lymphadenectomy, and the median number
of lymph nodes removed was 22 [40]. Of patients who re-
curred, locoregional recurrence was the initial and only site
of recurrence in 26% of patients and was a component of
initial recurrence in 54% of patients. Yoo et al. [41] exam-
ined 508 patients who developed recurrent disease after
curative gastrectomy at Yonsei University in South Korea.
Nineteen percent of patients had locoregional recurrence
only as the first site of recurrence, and 32.5% of patients had
locoregional recurrence combined with peritoneal or dis-
tant recurrence as the initial site of recurrent disease. In the
patients with only locoregional disease as the site of first
recurrence, the anastamosis was the most common location
of recurrence, followed by the lymph nodes. In a Japanese
prospective randomized trial of adjuvant S-1 chemother-
apy, 188 (35.5%) of 530 patients treated with surgery suf-
fered a recurrence [42]. The site of first recurrence in those
188 patients was local in 7.9% and in lymph nodes in
24.5%.
The effect of more extensive lymphadenectomies on
overall survival for gastric cancer is still quite controver-
sial. The majority of gastric surgeons in Korea and Japan
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its 1,024 patient accrual goal. A D2 lymphadenectomy is
required for that trial, and survival results are pending.
SPLEEN, PANCREAS, AND
D2 LYMPHADENECTOMIES
Tumors of the upper and middle stomach are known to me-
tastasize to the splenic artery (station 11) and splenic hilar
(station 10) lymph nodes, and distal pancreatectomy and
splenectomy were historically routinely performed to clear
these nodal stations [52]. Pancreatic fistula rates were high,
thus significantly increasing the morbidity of the D2
lymphadenectomy procedure. Maruyama et al. [47] de-
scribed a pancreas-preserving D2 lymphadenectomy that
resected the spleen and splenic artery along with the station
10 and 11 lymph nodes. A retrospective study from Japan of
nearly 400 patients found that there was no survival benefit
in patients undergoing total gastrectomy combined withdistal pancreatectomy and splenectomy over patients un-
dergoing total gastrectomy with splenectomy only [53].
Distal pancreatectomy is now generally considered to be
unwarranted in the routine performance of a D2 lymphad-
enectomy until there is direct extension of the tumor. A ret-
rospective Japanese study of 224 patients with proximal
gastric cancer found no survival benefit in patients who
received pancreaticosplenectomy or splenectomy over
pancreas and spleen preservation, but morbidity was signif-
icantly greater in the pancreaticosplenectomy group [54].
As shown in Table 3, Sasako et al.[55]estimatedthe benefitof dissecting the station 10 and 11 lymph nodes for a prox-
imal gastric cancer at 5.6%. Hartgrink et al. [56] analyzed
the patients in the Dutch Gastric Cancer Trial who had
lymph node metastases at stations 10 and 11. Of the 18 pa-
tients with station 10 metastases, the 11-year survival rate
was 11%. Of the 24 patients with station 11 metastases, the
11-year survival rate was 8%. The authors concluded that
the relevance of the dissection of these nodes has to be
questioned as the survival benefit is small and morbidity
and hospital mortality are significantly increased.
Although most expert gastric cancer surgeons no longer
resect the distal pancreas as part of a D2 lymphadenectomy
unless there is direct tumor extension, the resection of the
spleen continues to be controversial. Two prospective ran-
domized trials of total gastrectomy and lymphadenectomy
with or without splenectomy have been performed in Chile
and South Korea [57, 58]. Both studies found no difference
in overall survival, and the Chilean study found a signifi-
cantly higher rate of infectious complications in the sple-
nectomy group. However, the number of patients in these
studies was 187207, and thus the power of these studies to
determine a modest improvement in survival for splenec-
tomy is limited. A multicenter randomized trial to evaluate
the role of splenectomy for proximal gastric cancers is cur-
rently under way in Japan [59].
Taking lymph node stations beyond those incorporatedin a D2 lymphadenectomy (D2 lymphadenectomy) likely
does not improve survival, given that disease at such distant
nodal stations is unlikely to be cured by surgical therapy
alone. Based on data from the National Cancer Center
(NCC) in Japan, the station 13 lymph nodes posterior to the
head of the pancreas are rarely involved, and their involve-
ment predicts a 5-year survival rate close to 0% [52]. Add-
ing dissection of station 16 para-aortic nodes to a D2
lymphadenectomy was studied in a multicenter, prospec-
tive randomized trial in Japan. In that study, 523 patients
were randomized to D2 lymphadenectomy or D2 lymphad-
enectomy plus additional para-aortic lymph node dissection
(D2) [18]. The surgical morbidity rate was slightly higher
in the D2 group (28.1% versus 24.5%), but the mortality
rate was only 0.8% in both groups. The 5-year overall
survival rate was 69%70% in both groups [60]. Thus,
performing lymphadenectomies beyond a D2 lymphade-
nectomy is not warranted.
CAN WESTERN SURGEONS PERFORM MORE
EXTENSIVE LYMPHADENECTOMIES SAFELY?
Dr. Maurizio Degiuli and colleagues in Turin, Italy, ap-
proached the issue of western surgeons performing more
Table 3. Estimated benefit from lymph node dissectionat each nodal station, according to tumor location (%)
StationLowerthird
Middlethird
Upperthird
Entirestomach
1 1.6b
7.9a
12.0a
3.7a
2 0.0c 0.9b 5.1a 1.5a
3 17.3a 26.3a 17.1a 11.7a
4 14.5a 13.0a 3.0a 10.1a
5 3.9a 0.8a 0.0b 2.7a
6 21.3a 3.9a 0.4b 7.0a
7 8.2b 10.5b 5.3b 8.2b
8 7.5b 4.6b 2.0b 5.9b
9 3.9b 5.2b 3.3b 3.8b
10 0.0c 4.0b 3.8b 1.6b
11 1.0c 1.3b 1.8b 0.8b
12 2.7c
0.5c
0.0c
0.0c
13 0.0c 0.0c 0.0c 0.0c
14 2.1c 0.0c 0.0c 0.0c
16 2.4d 0.0d 0.0d 2.9d
aFirst level (N1).bSecond level (N2).cThird level (N3).dFourth level (N4).
877Yoon, Yang
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extensive lymphadenectomies in western patients in a se-
ries of two prospective clinical trials [10]. Dr. Degiuli
learned the D2 lymphadenectomy method at the NCC Hos-
pital in Tokyo, Japan, from Dr. Mitsuru Sasako, a well-known Japanese gastric surgeon. He was also given
didactic videos and manuscripts. Dr. Degiuli then orga-
nized meetings for 16 surgeons from eight university or
general hospitals in northern Italy (Italian Gastric Cancer
Study Group). At those meetings, the terminology was ex-
plained and indications and technique were agreed upon for
the trials. At least one of the two surgeons from each center
attended the first 10 procedures of the trial, which were per-
formed at Dr. Degiulis hospital. Dr. Degiuli then attended
the first three operations performed at each of the remaining
seven centers. Following this advanced training of surgeons
in gastric surgery, a phase II trial of D2 lymphadenectomy
was instituted. At each institution, all surgeries were per-
formed by the same two attending surgeons. Of the 191 pa-
tients enrolled in the study, 106 (55%) were ultimately
found to be ineligible, usually as a result of more extensive
disease. The mean number of lymph nodes removed was 39
(range, 2293). The overall postoperative morbidity and
mortality rates were impressively low, at 20.9% and 3.1%,
respectively. Subsequent to this study, the surgeons from
the five highest volume centers performed a randomized
trial of D1 versus D2 lymphadenectomy [11]. Of 296 pa-
tients registered, 134 patients (45%) were ineligible, with
the most common causes of ineligibility being N2 or N3
nodal spread (25.2%), peritoneal disease (19.3%), and T4
disease (18.4%). Of 162 randomized patients, the total mor-
bidity rate was 10.5% in the D1 group and 16.3% in the D2group. Only one postoperative death occurred, and that pa-
tient received a D1 dissection. Survival results are pending.
The experience of the Italian Gastric Cancer Study Group
clearly demonstrates that, following a period of fairly rig-
orous training, western surgeons can perform D2 lymphad-
enectomies on western patients with morbidity and
mortality results similar to those of high-volume centers in
Korea and Japan.
LOW MARUYAMA INDEX SURGERY
Many centers in Japan and Korea have been performing ex-
tended lymphadenectomies for gastric cancer for decades.
At the NCC in Japan, gastric cancer surgeons routinely per-
form D2 or greater lymphadenectomies and meticulously
dissect out and label each station of lymph nodes following
removal of the surgical specimen. NCC pathologists then
examine each nodal station separately and document posi-
tive and negative nodes in each nodal station. Using a large
database of patients treated with D2 or greater lymphade-
nectomy, Maruyama et al. [61] calculated the riskfor lymph
node metastasis in each lymph node station by location of
the primary tumor (Table 4). In 1989, the NCC database of
3,843 cases was used to create the Maruyama computer
Table 4. Incidence of lymph node metastasis and 5-year survival rates of those having nodal metastasis in each station,according to tumor location
Station
Lower third Middle third Upper third Entire stomach
Incidence
5-yr
survival Incidence
5-yr
survival Incidence
5-yr
survival Incidence
5-yr
survival
1 6.2 25.0 15.0 52.6 38.0 31.7 32.7 11.3
2 7.1 0.0 3.4 25.0 22.0 23.2 18.2 8.0
3 40.9 42.2 44.8 58.7 45.1 37.9 66.0 17.8
4 34.2 42.3 26.8 48.4 14.5 20.5 53.1 19.0
5 10.5 37.5 2.4 33.3 3.0 0.0 14.2 18.8
6 46.3 46.0 14.6 26.8 6.8 6.3 37.7 18.7
7 23.4 34.9 22.6 46.5 26.9 19.7 44.4 18.5
8 24.5 30.6 11.0 41.5 10.2 20.0 30.6 19.2
9 12.8 30.4 11.0 47.5 16.0 20.5 18.5 20.7
10 3.8 0.0 11.9 33.3 17.4 21.6 21.6 7.4
11 6.7 15.4 6.3 21.4 16.1 11.4 20.6 3.7
12 9.0 29.6 1.6 33.3 2.5 0.0 4.4 0.0
13 8.3 0.0 0.0 0.0 2.5 0.0 5.6 0.0
14 14.6 14.3 8.7 0.0 10.0 0.0 4.5 0.0
16 13.1 18.2 7.4 0.0 12.1 0.0 26.5 11.1
878 Lymphadenectomy for Gastric Cancer
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program [62]. This program estimates the risk for lymph
node metastasis for each lymph node station based on the
input of eight variables: sex, age, endoscopic or Bormanns
classification, depth of invasion, maximal diameter, loca-
tion (upper, middle, or lower third), position (lesser or
greater curvature, anterior or posterior wall, or circumfer-
ential), and World Health Organization histological classi-
fication. The Maruyama computer program was later
expanded to include 4,302 cases (WinEstimate 2.5) [63].
By matching input variables to this large database of pa-
tients, the program gives a percent likelihood of disease in
each of the 16 lymph node stations defined by the JRSGC.
The accuracy of this program was analyzed in 222 patients
treated at the Technical University in Munich, Germany.
The accuracies for lymph node stations 16, 712, and
1316 were 82%, 89%, and 96%, respectively [64]. Guad-
agni et al. [65] subsequently analyzed 282 Italian patientswith gastric cancer who underwent at least a D2 lymphad-
enectomy and found the Maruyama program to be 83% ac-
curate for stations 16, 82% accurate for stations 712, and
72% accurate for stations 1316. Moreover, if an absolute
cutoff point of 0% was used to direct the subsequent har-
vesting of lymph nodes, only six patients (3.4%) would
have had lymph node metastases left undissected.
Using the NCC database, Sasako et al. [52] were able to
not only determine the incidence of lymph node metastasis
in each nodal station based on location but to also determine
the 5-year survival rate of patients who had lymph node me-tastasis to any given stationstratifiedby tumor location (Ta-
ble 4). Using these data, the estimated benefit from lymph
node dissection of each nodal station was calculated strati-
fied by tumor location (Table 3). When one compares the
likelihood of involvement of lymph node stations (Table 4)
with the nodal stations resected in a D1 versus D2 lymph-
adenectomy (Table 2), one can see that there is a significant
risk of leaving involved lymph nodes undissected when
performing a D1 dissection for a tumor in any stomach lo-
cation. Performing less than a D1 lymphadenectomy leaves
even more positive lymph nodes behind. Hundahl et al. [66]
went on to define the Maruyama Index (MI) of unresected
disease as the sum of the regional nodal disease (stations
112) percentages, as estimated by the Maruyama program,
not removed by the surgeon. That study calculated the MI
for 553 patients who enrolled in the Intergroup 0116 pro-
spective, randomized trial of 5-FUbased chemoradiation
versus surgery alone. Only 10% of patients in that study un-
derwent the recommended D2 lymphadenectomy. Thus,
the median MI for 553 analyzed patients was 70, and MI
proved to be an independent prognostic factor for overall
survival (p .005) and recurrence-free survival (p .002).
The authors concluded that surgical undertreatment of pa-
tients in this study clearly underminedsurvival. Peeters et
al. [14] calculated the MI for 648 patients enrolled in the
Dutch trial and found the median MI to be 26. MI5 was
found to be an independent predictor of longer overall and
recurrence-free survival times on univariate and multivari-
ate analysis. Moreover, a doseresponse relationship was
demonstrated, with longer survival times as the MI de-
creased. The authors concluded that MI was a quantitative
yardstick for assessing the adequacy of lymphadenectomy
in gastric cancer.
Performing less than a D2 lymphadenectomy can result
in leaving positive lymph nodes behind. The Maruyama
computer program thus allows one to prospectively know
with fairly high accuracy which nodal stations have any
likelihood of harboring metastatic disease. Retrospective
analyses suggest that removal of all nodal stations that are
predicted to harbor metastases results in superior survival,but a prospective trial of this approach is needed to confirm
any validity.
BARRIERS TO PERFORMANCE OF MORE EXTENSIVE
LYMPHADENECTOMIES IN WESTERN COUNTRIES
Several tertiary referral centers in western countries rou-
tinely perform D2 lymphadenectomies for gastric cancer
[40], but as noted earlier, lymphadenectomies for gastric
cancer in western countries are limited and often do not
even reach the D1 threshold. There are several reasons why
more extensive lymphadenectomies are not more com-monly performed. First and foremost is the lack of a proven
benefit in terms of overall survival for D2 over D1 lymph-
adenectomy based on the Dutch and United Kingdom trials.
Unfortunately, many western surgeons have interpreted the
results of these trials to mean any lymphadenectomy does
not improve overall survival. Certainly some patients with
lymph node positivedisease are cured by surgical resec-
tion alone, and these patients would undoubtedly not have
been cured if diseased lymph nodes were left undissected
without additional therapy. Another significant obstacle to
the performance of more extensive lymphadenectomies is
the relative paucity of gastric adenocarcinomas seen at any
given institution. In order for more extensive lymphadenec-
tomies to benefit gastric cancer patients, they must be per-
formed without excess morbidity and mortality, and this
can be achieved only with adequate surgical training and
adequate case volume. Contributing to the lack of high-
volume centers for gastric cancer surgery is a significant re-
luctance of general surgeons to refer gastric cancer patients
to tertiary referral centers, given that gastric surgery has
historically been the realm of the general surgeon [67]. Fi-
nally, there are geographical and language barriers between
different countries that make dissemination of information
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and techniques on the surgical treatment of gastric cancer
difficult.
SUMMARY
The Dutch and United Kingdom trials of D1 versus D2
lymphadenectomy demonstrated that when D2 lymphad-
enectomy is performed with excess morbidity and
mortality there is no survival benefit over D1 lymphad-
enectomy. What have we learned since these trials?
Many, and perhaps the majority, of patients in the U.S.
receive an inadequate lymphadenectomy (i.e., less than a
D1 lymphadenectomy). Distal pancreatectomy is not re-
quired to perform an adequate D2 lymphadenectomy and
likely should be performed only when there is direct tu-
mor invasion. Splenectomy is not required for distal tu-
mors, but the role of splenectomy for mid or proximal
tumors is currently being investigated in a prospective,
randomized trial in Japan. D2 lymphadenectomy can be
taught to western surgeons such that the procedure can be
performed on western patients with low morbidity and
mortality [10]. When a more extensive lymphadenec-
tomy is performed, there is clearly a benefit in terms of
staging, and possibly in terms of less locoregional recur-
rence. If D2 lymphadenectomy is performed with low
morbidity and mortality, there also may be a benefit in
terms of overall survival [12], but this potential benefit
needs to be demonstrated by prospective, randomized tri-
als in western patients. D1 lymphadenectomies incor-
porating only lymph node stations beyond the N1 level
that are predicted to harbor metastatic disease by the Ma-
ruyama computer program may optimize resection of
disease and minimize complications, but this has not
been proven. There exist several barriers to the perfor-
mance of more extensive lymphadenectomies in western
countries. Future collaborations and clinical trials will
hopefully answer whether west should meet east, east
should meet west, or there exists some utopian Shan-
gri-La in between.
AUTHOR CONTRIBUTIONSConception/Design: Sam S. Yoon, Han-Kwang YangAdministrative support: Sam S. YoonProvision of study materials: Sam S. Yoon, Han-Kwang YangCollection/assembly of data: Sam S. Yoon, Han-Kwang YangData analysis: Sam S. Yoon, Han-Kwang YangManuscript writing: Sam S. Yoon, Han-Kwang YangFinal approval of manuscript: Sam S. Yoon, Han-Kwang Yang
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882 Lymphadenectomy for Gastric Cancer
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DOI: 10.1634/theoncologist.2009-00702009;14;871-882; originally published online September 8, 2009;The Oncologist
Sam S. Yoon and Han-Kwang YangLymphadenectomy for Gastric Adenocarcinoma: Should West Meet East?
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