Available online at www.sciencedirect.com
Journal of the Chinese Medical Association 75 (2012) 573e580
www.jcma-online.com
Original Article
Number of involved lymph nodes is important in the prediction of prognosis
for primary duodenal adenocarcinoma
Tsung-Jung Liang a,b, Being-Whey Wang b,c, Shiuh-Inn Liu b,c, Nan-Hua Chou b,
Cheng-Chung Tsai b, I-Shu Chen b, Ming-Hsin Yeh b, Yu-Chia Chen b, Po-Min Chang b,
King-Tong Mok b,c,*
a
b
Department of Surgery, Kaohsiung Veterans General Hospital, Pingtung Branch, Pingtung, Taiwan, ROC
Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC
c
National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
Received December 22, 2011; accepted April 16, 2012
Abstract
Background: The significance of lymph node involvement regarding the prognosis of primary duodenal adenocarcinoma remains controversial.
This study aims to evaluate the prognostic accuracy of nodal metastasis using the seventh edition American Joint Committee on Cancer staging
system in patients with primary duodenal adenocarcinoma.
Methods: Between 1993 and 2010, 36 patients who had undergone surgical resection for primary duodenal adenocarcinoma at the Kaohsiung
Veterans General Hospital were retrospectively reviewed.
Results: The median disease-free survival for all patients was 19 months and the median overall survival was 21 months. Lymph node metastases
were found in 26 (72%) of the patients, and 14 patients (39%) patients had in excess of three positive lymph nodes (N2). Patients with N2 disease
had significantly reduced overall survival, as compared to patients with three or fewer positive lymph nodes (N1; p ¼ 0.036). In univariate
analysis, factors including age >75 years, body weight loss, tumor size 4 cm, N2 disease and lymph node ratio >0.4 predicted shorter overall
survival. Multivariate analysis demonstrated that N2 and lymph node ratio >0.4 are significant risk factors associated with overall survival
( p ¼ 0.026 and p ¼ 0.042 respectively). N2 is also the only independent predictive factor for disease-free survival ( p ¼ 0.023).
Conclusion: Subdivision of metastatic lymph nodes into N1 and N2 improves predictive ability. The seventh edition American Joint Committee
on Cancer staging system is applicable in the present study with regard to the prediction of the prognosis for primary duodenal adenocarcinoma.
Copyright Ó 2012 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved.
Keywords: American Joint Committee on Cancer; duodenal adenocarcinoma; lymph node metastasis; small bowel
1. Introduction
Primary duodenal adenocarcinoma is an uncommon tumor
that accounts for less than 0.5% of all gastrointestinal malignancies.1 Because of the rarity of this type of cancer, it has
typically been reported together with jejunal and ileal tumors
as a small bowel cancer, or in some cases grouped with periampullary malignancy, along with pancreatic, ampullary, and
* Corresponding author. Dr. King-Tong Mok, Division of General Surgery,
Department of Surgery, Kaohsiung Veterans General Hospital, 386, Ta-Chung
First Road, Kaohsiung 813, Taiwan, ROC.
E-mail address: [email protected] (K.-T. Mok).
distal bile duct cancers.2e4 Studies that focus only on
duodenal adenocarcinoma are scarce.5,6 Correspondingly,
many questions regarding disease pathogenesis, natural
history, ideal medical management, and prognostic factors are
still unanswered.
Until now, the significance of lymph node involvement
regarding the prognosis of primary duodenal adenocarcinoma
remains controversial.7 However, some studies show a strong
negative impact on survival in lymph node metastatic
disease.6,8 The most common tool used to evaluate lymph
node metastasis is the American Joint Committee on Cancer
(AJCC) tumor-node-metatasis (TNM) staging system. Lymph
node staging is divided into two groups: no regional lymph
1726-4901/$ - see front matter Copyright Ó 2012 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved.
http://dx.doi.org/10.1016/j.jcma.2012.08.002
574
T.-J. Liang et al. / Journal of the Chinese Medical Association 75 (2012) 573e580
node metastasis (N0) and positive lymph node metastasis (N1)
according to the sixth edition of the AJCC TNM classification
system for small intestinal cancer published in 2002.9 In 2010,
the release of the seventh edition of AJCC classification
included major modifications to the lymph node staging
system.10 The previous N1 group is further subdivided into
new N1 (metastasis in 1e3 nodes) and N2 (metastasis in 4 or
more nodes). As a result, the Stage III disease is subclassified
into Stage IIIA (TxN1M0) and Stage IIIB (TxN2M0).
However, the clinical correlation of this change has yet to be
determined.
Apart from the involved lymph node, studies from other
cancers have suggested that the total number of lymph nodes
harvested is also an important indicator for prognosis because
an insufficient number evaluated may not provide an accurate
node staging.11e13 Consequently, the idea of lymph node ratio
(LNR) was introduced to eliminate the variation of dissection
techniques by different surgeons and the number of lymph
node harvested. This ratio is defined as the ratio of metastatic
nodes to the total number of lymph node examined. Evidence
presented in existing literature has demonstrated that the LNR
is inversely related to survival in esophageal, gastric, and
colon cancers.14e16
In this study, we aimed to clarify the prognostic impact of
lymph node status, including AJCC node staging, the total
number of lymph node examined, and the lymph node ratio in
patients with primary duodenal adenocarcinoma treated with
curative resection at a single medical center.
2. Methods
The medical records of all patients with primary duodenal
adenocarcinoma who had undergone surgical resection at
Kaohsiung Veterans General Hospital between 1993 and 2010
were reviewed retrospectively. All patients enrolled in this
study had primary tumor located in the duodenum, and
histologically proven adenocarcinoma. Tumors arising from
ampulla of Vater, bile duct, and pancreas were excluded.
Patients whose pathologic reports were not available were also
excluded from the study.
A total of 36 patients met the inclusion criteria. Data for
each patient were collected, including age at diagnosis, clinical presentation, type of surgery, postoperative course, and the
use of adjuvant therapy. Anemia was defined as hemoglobin
level <130 g/L in males, and <110 g/L in females. Pathologic
specimens were reviewed for tumor location, size, tumor
depth, histology, grade, surgical margin, pancreatic invasion,
number of metastatic lymph node, and number of lymph nodes
harvested. The lymph node ratio was calculated by dividing
the number of metastatic lymph nodes by the total number of
lymph nodes assessed. Patients were then subclassified into
four groups based on LNR (LNR ¼ 0; 0 < LNR 0.2;
0.2 < LNR 0.4; 0.4 < LNR). The cutoff value for each
group was determined by previous studies.3,17,18 The seventh
edition of AJCC classification for malignant neoplasms of the
small intestine was used for staging.
Patients had regular postoperative follow-up examinations.
Tumor recurrence was identified using various diagnostic tools
such as sonography, computed tomography, magnetic resonance imaging, positron emission tomography scan, and whole
body bone scan. Survival time and pattern of recurrence were
recorded. Distant metastasis was suspected if the distal lesion
was newly detected and did not appear in the preoperative
survey. Biopsy might be considered if the lesion was not in
any of the customary metastatic sites where duodenal adenocarcinoma is found (e.g. liver, peritoneum, lung). Informed
consent was obtained from all patients before operation. The
study complied with institutional review board protocols.
Statistical analyses were performed using SPSS 18.0 for
Windows (SPSS, Inc., Chicago, IL, USA). Disease-free
survival and overall survival were estimated by use of the
Kaplan-Meier method and differences were compared by logrank test. Multivariate comparisons were conducted using the
Cox proportional hazards model. Statistical significance was
considered at p < 0.05.
3. Results
3.1. Patient characteristics
The clinicopathological data of enrolled patients were
shown in Table 1. Of the 36 patients reviewed, 24 (67%) were
men and 12 (33%) were women. The median age at diagnosis
was 66 years (range 35e88). Most of the tumors were located
at the secondary portion of the duodenum (70%), followed by
eight (22%) at the first portion, two (5%) at the third portion,
and one case was found at the fourth portion. Also, 29 (80%)
patients underwent classic pancreaticoduodenectomy (Whipple procedure) and two (6%) patients received pyloruspreserving pancreaticoduodenectomy (PPPD). Segmental
duodenal resections were performed in five (14%) patients,
four of whom had a tumor at the first portion, and one patient
had a tumor at the fourth portion of the duodenum. All patient
surgical margins were disease-free, except for one patient in
the Whipple procedure group. Grossly, this patient’s resection
margins were free of tumor, but tumor cells were found
microscopically in the distal pancreatic cut end. The AJCC
nodal staging of this male patient was N2 and his LNR was
0.686 (11/16). He suffered from local recurrence 8 months
later.
The median tumor size was 4 cm in diameter and the depth
of tumor invasion was T4 in 72% of all patients. The median
number of lymph nodes harvested was 16 (range 5e38), and
10 (28%) patients had no metastatic lymph nodes with an LNR
of zero. Among the 26 patients who had positive lymph nodes,
12 patients had one to three positive lymph nodes (N1) and
were classified as Stage IIIA. The other 14 patients had more
than three positive lymph nodes (N2) and were classified as
Stage IIIB. When categorized by LNR, there were 11 (30%)
patients with LNR from 0 to 0.2, nine (25%) patients with
LNR from 0.2 to 0.4 and six (17%) with LNR > 0.4. All of the
eight (22%) patients who received adjuvant chemotherapy had
node-positive disease.
T.-J. Liang et al. / Journal of the Chinese Medical Association 75 (2012) 573e580
Table 1
Clinicopathologic
adenocarcinoma.
features
of
36
patients
with
primary
duodenal
Feature
n (%)
Age, y, median (range)
Male sex
Tumor location
First
Second
Third
Fourth
Type of surgery
Whipple
PPPD
Segmental resection
Surgical margin
Positive
Negative
Tumor size, cm, median (range)
Tumor depth (T-stage)
T1
T2
T3
T4
Nodal statusa
N0
N1
N2
TNM stageb
I
IIA
IIB
IIIA
IIIB
IV
Lymph node harvested, median (range)
Lymph node ratio (LNR)
0
0 < LNR 0.2
0.2 < LNR 0.4
<0.4
Grade
Well
Moderate
Poor
Adjuvant chemotherapy
Yes
No
Recurrence
No
Local
Distant
Local þ Distant
66 (35e88)
24 (67)
8
25
2
1
(22)
(70)
(5)
(3)
29 (80)
2 (6)
5 (14)
1 (3)
35 (97)
4 (1.0e9.0)
1
4
5
26
(3)
(11)
(14)
(72)
10 (28)
12 (33)
14 (39)
4
2
4
12
14
0
16
(11)
(6)
(11)
(33)
(39)
(0)
(5e38)
10
11
9
6
(28)
(30)
(25)
(17)
575
(according to the current AJCC staging system) was 50%, 45%
and 0%, respectively, ( p < 0.001; Fig. 1). Patients with N2
disease had a significantly shorter overall survival rate
compared with patients with N0 and N1 disease ( p < 0.001 and
p ¼ 0.036, respectively). However, no significant difference was
detected in the overall survival between N0 and N1 disease
( p ¼ 0.238). Additionally, LNR is shown to be inversely
associated with overall survival when categorized into four
groups (LNR ¼ 0; 0 < LNR 0.2; 0.2 < LNR 0.4;
0.4 < LNR). Their 3- and 5-year overall survival rate were 90%,
31%, 29%, 0%, 50%, 31%, 0%, and 0%, ( p ¼ 0.011). However,
there is no one distinctive LNR group that has a significant
difference in overall survival in comparison with the other three
groups (Fig. 2).
Nineteen out of the 36 patients (53%) had recurrence of
their cancer. The median time to recurrence after operation
was 9 months (range 3e46). Local recurrence occurred in
five (14%) cases and distant metastasis in six (17%) cases.
Concurrent local and distant metastases were documented in
the remaining eight (22%) cases. The liver was the most
common site of distant metastasis followed by the peritoneum, lung, and bone. Palliative chemotherapy was given to
three of the 19 recurrent patients (16%). Disease-free survival
rates at 3 and 5 years for all 36 patients were 39% and 35%,
respectively. Both the AJCC node classification and LNR
were significantly associated with disease-free survival
( p ¼ 0.021 and 0.040, respectively; Fig. 3 and Fig. 4). In
subgroup analysis, N2 disease had shorter median diseasefree survival compared with N1 disease, but it did not
reach statistical significance (8 months vs. 13 months,
p ¼ 0.174).
3 (8)
20 (56)
13 (36)
8 (22)
28 (78)
17
5
6
8
(47)
(14)
(17)
(22)
PPPD ¼ pylorus-preserving pancreaticoduodenectomy.
a
N0, no positive lymph node; N1, 1e3 positive lymph nodes; N2, >3
positive lymph nodes.
b
TNM stage: American Joint Committee on Cancer TNM staging system,
seventh edition.
3.2. Survival stratified by AJCC N classification and
lymph node ratio
The median follow-up duration was 41 months for patients
who survived and 17 months for patients who died. The 5-year
overall survival rate of patients with N0, N1, and N2 disease
Fig. 1. Overall survival stratified by seventh edition American Joint Committee
on Cancer (AJCC) N stage. ( p < 0.001). N0 ¼ node negative; N1 ¼ 1e3
positive nodes; N2 ¼ >3 positive nodes.
576
T.-J. Liang et al. / Journal of the Chinese Medical Association 75 (2012) 573e580
Fig. 2. Overall survival stratified by lymph node ratio ( p ¼ 0.011).
LNR ¼ lymph node ratio.
Fig. 4. Disease-free survival stratified by lymph node ratio ( p ¼ 0.040).
LNR ¼ lymph node ratio.
3.3. Prognostic factors associated with survival
Univariate analysis showed that patient factors including
age >75 years ( p ¼ 0.020), body weight loss ( p ¼ 0.037),
tumor size 4 cm ( p ¼ 0.041), AJCC N2 disease ( p < 0.001)
(Fig. 5) and LNR > 0.4 ( p ¼ 0.014) were associated with
decreased overall survival (Table 2). Gender, anemia, tumor
grade, T stage, tumor location, total lymph node examined,
LNR > 2, pancreatic invasion, and the use of adjuvant
chemotherapy had no significant influence on overall survival.
Subsequent multivariate analysis using 2 different models
were performed to avoid a confounding effect by putting the
two lymph node factors (N2 disease, LNR > 0.4) together.
The results demonstrated that N2 disease (hazard ratio ¼ 3.48,
Fig. 3. Disease-free survival stratified by seventh edition American Joint
Committee on Cancer (AJCC) N stage ( p ¼ 0.021). N0 ¼ node negative;
N1 ¼ 1e3 positive nodes; N2 ¼ >3 positive nodes.
Fig. 5. Overall survival stratified by positive lymph node > 3 and 3
( p < 0.001).
T.-J. Liang et al. / Journal of the Chinese Medical Association 75 (2012) 573e580
Table 2
Univariate analysis for factors associated with overall survival.
Factors
Age (y)
75
>75
Gender
Male
Female
Anemiaa
Yes
No
Body weight loss
Yes
No
Grade
Well þ Moderate
Poor
T stage
T1 þ T2 þ T3
T4
Tumor size (cm)
4
>4
Tumor location
Second portion
Other portion (first, third,fourth)
Lymph node metastasis, n
0e3 (N0, N1)
>3 (N2)
Total lymph nodes examined
<12
12
Lymph node ratio
0.2
>0.2
Lymph node ratio
0.4
>0.4
Pancreatic invasion
Yes
No
Adjuvant chemotherapy
Yes
No
N
577
Table 3
Multivariate analysis for factors associated with overall survival.
Median
survival
(mo)
Survival
(%)
p
Factors
Hazard ratio
95% CI
p
3-y
5-y
Model 1
Age >75 y
Body weight loss
Tumor size 4 cm
>3 LN metastases (N2)
2.79
2.06
1.48
3.48
0.89e8.77
0.87e4.85
0.56e3.90
1.18e10.22
0.079
0.100
0.432
0.024
29
7
23
5
50
17
30
17
0.020
24
12
18
21
45
42
25
31
0.886
Model 2
Age >75 y
Body weight loss
Tumor size 4 cm
LNR > 0.4
4.78
2.60
2.20
4.25
1.58e14.50
1.12e6.06
0.91e5.28
1.38e13.10
0.006
0.026
0.078
0.012
22
14
23
18
49
35
38
9
0.291
12
24
10
46
18
57
9
35
0.037
24
12
21
18
45
44
35
0
0.199
remained as an independent factor predicting tumor recurrence
(hazard ratio ¼ 3.36, p ¼ 0.023; Table 5).
10
26
56
18
70
33
35
22
0.296
4. Discussion
21
15
18
61
30
66
10
55
0.040
25
11
18
23
43
47
22
35
0.743
22
14
56
13
67
8
43
0
<0.001
9
27
18
21
50
43
50
21
0.296
21
15
55
17
57
24
34
12
0.286
30
6
41
13
51
0
31
0
0.014
18
18
16
55
28
64
17
37
0.224
8
28
16
46
25
50
13
32
0.218
LN ¼ lymph node; LNR ¼ lymph node ratio; CI ¼ confidence interval.
The principal goal of this study was to determine whether
LN status, especially the new AJCC N-stage was associated
with survival. Lymph node metastasis is a well-known prognostic factor for many gastrointestinal and periampullary
malignancies.19e22 When LN assessment occurs in the context
of duodenal adenocarcinoma, however, there is some
disagreement in this area.7 Our data, in accordance with many
other reports, have shown that patients with nodal metastases
have diminished survival ( p < 0.001).6e8,23e25 However,
other studies have found no such relationship.1,26,27 The
incidence of lymph node metastasis in patients with duodenal
adenocarcinoma has been reported to range from 22% to
a
Anemia was defined as hemoglobin level <130 g/L in male and <110 g/L
in female respectively.
p ¼ 0.024) and LNR > 0.4 (hazard ratio ¼ 4.25, p ¼ 0.012)
were significant prognostic predictors (Table 3).
With respect to recurrence, anemia ( p ¼ 0.004), poor tumor
grade ( p ¼ 0.017), tumor size 4 cm ( p ¼ 0.008), AJCC N2
disease ( p ¼ 0.010; Fig. 6), LNR > 0.4 ( p ¼ 0.026) and
pancreatic invasion ( p ¼ 0.028) were found to have a significant negative impact on disease-free survival by univariate
analysis (Table 4). Similarly, 2 separate models were constructed using the Cox proportional hazards model to assess
the influence of lymph node evaluation in disease-free
survival. When multivariate analysis was employed,
LNR > 0.4, along with anemia, tumor grade, and pancreatic
invasion lost their prognostic significance. Only N2 disease
Fig. 6. Disease-free survival stratified by positive lymph node >3 and 3
( p ¼ 0.010).
578
T.-J. Liang et al. / Journal of the Chinese Medical Association 75 (2012) 573e580
Table 4
Univariate analysis for factors associated with disease-free survival.
Factors
Age (y)
75
>75
Gender
Male
Female
Anemia
Yes
No
Body weight loss
Yes
No
Grade
Well þ Moderate
Poor
T stage
T1 þ T2 þ T3
T4
Tumor size (cm)
4
>4
Tumor location
Second portion
Other portion (first, third,fourth)
Lymph node metastases, n
0e3 (N0, N1)
>3 (N2)
Total lymph nodes examined
<12
12
Lymph node ratio
0.2
>0.2
Lymph node ratio
0.4
>0.4
Pancreatic invasion
Yes
No
Adjuvant chemotherapy
Yes
No
N
Median
survival (mo)
Survival
(%)
3-y
5-y
Table 5
Multivariate analysis for factors associated with disease-free survival.
p
29
7
14
19
41
33
37
33
0.801
24
12
27
13
43
33
37
33
0.644
22
14
NR
10
58
15
58
8
0.004
12
24
12
27
33
42
33
36
0.638
24
12
34
9
50
20
50
0
0.017
10
26
46
13
63
31
47
31
0.248
21
15
11
NR
19
68
13
68
0.008
25
11
19
13
37
44
31
44
0.661
22
14
NR
8
56
0
51
0
0.010
9
27
14
19
50
36
50
31
0.564
21
15
27
14
47
17
42
17
0.528
30
6
34
5
46
0
41
0
0.026
18
18
11
NR
28
54
21
54
0.028
8
28
12
46
13
51
13
45
0.159
Factors
Hazard ratio
95% CI
p
Model 1
Anemia
Grade, poor
Tumor size 4 cm
>3 LN metastasis (N2)
Pancreatic invasion
2.31
1.56
1.07
3.36
1.87
0.61e8.69
0.48e5.07
0.25e4.49
1.18e9.55
0.60e5.75
0.216
0.459
0.928
0.023
0.278
Model 2
Anemia
Grade, poor
Tumor size 4 cm
LNR > 0.4
Pancreatic invasion
1.70
1.44
1.88
2.23
1.47
0.42e6.88
0.44e4.75
0.43e8.27
0.66e7.53
0.47e4.65
0.461
0.549
0.406
0.199
0.508
LN ¼ lymph node; LNR ¼ lymph node ratio.
NR ¼ not reached median survival rates of 50.0%.
76%,6,7,28 and 72% of our patients had lymph node involvement. Given the relatively high percentage of nodal metastasis
in our study, it is reasonable that our 5-year survival rate of
26% appeared to be lower in compared with other series
(25e75%).7
In this study, we found that the overall survival rate of
patients with one to three positive lymph nodes (N1) did not
differ significantly from that of patients without lymph node
metastasis (N0; p ¼ 0.238). On the contrary, more than three
lymph nodes involved (N2) was an independent predictor of
overall and disease-free survival ( p ¼ 0.024 and p ¼ 0.023,
respectively). Similar results had been found in patients with
pancreatic carcinoma.22,29e31 Zacharias et al31 reported no
statistically significant difference in survival between patients
with a single metastatic node and patients with negative lymph
nodes. However, they did find that patients with no more than
one metastatic lymph node survived significantly longer than
patients with two or more involved lymph nodes. They
concluded that the presence of two or more positive lymph
nodes was a major prognostic factor after resection of
pancreatic carcinoma. These results also implied that a small
number of positive lymph nodes might not affect clinical
outcome, and that a subdivision according to the number of
metastatic lymph nodes should be considered to provide better
prognostic value.
Regarding small bowel adenocarcinoma, Overman et al.32
demonstrated evident improvement in prognostic efficacy by
stratifying patients with nodal metastasis into those patients
with fewer than three positive lymph nodes and those with
three or more positive lymph nodes (hazard ratio 1.44; 95%
confidence interval 1.12e1.86). The 5-year disease-specific
survival rates of the two subgroups were 58% and 37%
respectively. The selected cutoff point for the number of
positive lymph node in their study was slightly different
compared with the seventh edition of AJCC N-staging (3 vs.
>3 positive lymph nodes). Because in Overman’s study,
patients with tumors located in jejunum, ileum, and nonspecified locations were all included. When all circumstances
were factored in, it could not be determined whether more
than three positive lymph nodes is the cutoff value that has the
best prognostic success in patients with duodenal adenocarcinoma. Based on our study, we clearly demonstrated that
having more than three lymph node metastases (N2) is the
most important factor to predict survival after curative resection. To our knowledge, this study is the first to validate the
significant association between survival and N-staging of the
seventh edition AJCC classification in patients with duodenal
adenocarcinoma.
There were five (14%) patients in our series who received
segmental resection of the duodenum. Some investigators have
proposed a pancreaticoduodenectomy procedure for all
duodenal adenocarcinoma regardless of tumor location.1
Others suggest duodenal segmentectomy as a less morbid
choice for tumors located in the first, third, or fourth portions
T.-J. Liang et al. / Journal of the Chinese Medical Association 75 (2012) 573e580
of the duodenum.8,25,33 Inadequate surgical margins and
lymph node clearance are the two major concerns for limited
resection.34 Kaklamanos et al23 justified the use of segmental
resection by showing a comparable number of lymph nodes
removed, whether a pancreaticoduodenectomy or a duodenal
segmentectomy was performed. A similar result was also
found in our study ( p ¼ 0.436). Furthermore, no patient in our
limited resection group had surgical margins involved by
tumor. In all, our data support the use of the segmental
resection procedure in selected patients with duodenal
adenocarcinoma.
The total number of lymph nodes examined did not affect
survival in our study (overall survival, p ¼ 0.296; disease-free
survival, p ¼ 0.564) and in a small series reported by Struck
et al.35 Nevertheless, several investigators proposed that an
inadequate number of lymph nodes removed may impair
prognostic discrimination due to inaccurate assessment of
lymph node metastasis, which might understage cancer
patients.3,24,32 The correlation between survival and the
number of total lymph node evaluated have also been shown in
esophageal, gastric, pancreatic, and colorectal cancers.11e13,36
However, the exact number of lymph nodes that needed to be
removed varied from study to study. For example, in pancreatic adenocarcinoma, the proposed number of lymph nodes
that should be collected was reported to be 10, 12, or 15
nodes.13,17,37
In a retrospective review of 522 patients with resected
periampullary malignancies, Hurtuk et al3 found that LNR is
inversely associated with survival in pancreatic and ampullary
cancer, but not in bile duct and duodenal cancer. In contrast,
our results showed that LNR is predictive of disease-free
survival and overall survival in patients with primary
duodenal adenocarcinoma by categorizing patients into four
groups using the same LNR cutoff values of 0, 0.2, and 0.4
( p ¼ 0.011 and p ¼ 0.040 respectively). Besides, LNR > 0.4
was identified as an independent prognostic factor for overall
survival ( p ¼ 0.012). Two studies of small bowel adenocarcinoma also reported significantly reduced survival rates in
patients with LNR 0.5 and LNR 0.75, respectively.4,38
Theoretically, LNR is more discriminative than the number
of positive lymph nodes (N-stage) in prognostic prediction
because it incorporates the extent of lymphadenectomy.
Furthermore, LNR may also eliminate the variation on specimen examination by different pathologists (e.g., the number
of lymph nodes harvested).17 Certain reports of cases of
gastric and breast cancer have already demonstrated the
prognostic efficacy of LNR and its superiority over current
AJCC nodal staging categories.15,39 In the current study, more
than three positive lymph nodes (N2 disease) exhibited prognostic value in both disease-free and overall survival rates,
while LNR >0.4 failed to influence disease-free survival using
multivariate analysis. Based on our findings, the number of
metastatic lymph nodes was the more potent prognostic factor
after resection of primary duodenal adenocarcinoma.
Another interesting finding of the present study was that
smaller tumors (4 cm) were associated with a significantly
poorer outcome than were larger ones (>4 cm) in univariate
579
analysis (overall survival, p ¼ 0.040; disease-free survival,
p ¼ 0.008). This seemingly counterintuitive result has also
been observed by Hurtuk et al,40 who found that larger tumors
were less likely to behave aggressively. On the contrary,
smaller tumors had a predilection to invade periduodenal fat or
nearby structures. Furthermore, when they focused on tumors
that invaded nearby structures, patients with larger tumors still
showed better prognosis than those with smaller tumors. The
authors explained those results by hypothesizing that there
were differences in biological behaviors between duodenal
adenocarcionomas and some tumors that tend to be less
aggressive. Further study is required to clarify the biologic
nature of this tumor. However, in the meantime, the authors
suggested patients undergo aggressive surgical resection
regardless of the tumor size.40
In conclusion, our data validate the predictive power of
nodal metastasis using N classification of the seventh edition
AJCC staging system. More than three positive lymph nodes
(N2 disease) is the most important prognostic factor in patients
with primary duodenal adenocarcinoma after curative resection. The prognostic efficacy of LNR is promising and worthy
of further larger scale research.
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