The Site of Lymph Node Metastasis: A Significant Prognostic Factor in Pancreatic Ductal Adenocarcinoma
Anil AYSAL1, Cihan AGALAR2, Sumru CAGAPTAY1, Turugsan SAFAK2, Tufan EGELI2, Mucahit OZBILGIN2, Tugba UNEK3, Tarkan UNEK3, Ozgul SAGOL1
1Department of Pathology, Dokuz Eylul University, Faculty of Medicine, IZMIR, TURKEY
2Department of General Surgery, Dokuz Eylul University, Faculty of Medicine, IZMIR, TURKEY
3Department of Medical Oncology, Dokuz Eylul University, Faculty of Medicine, IZMIR, TURKEY
Keywords: Pancreatic ductal adenocarcinoma, Regional lymph node site, Metastasis
While the presence and number of metastatic lymph nodes (LNs) are important prognostic factors for pancreatic ductal adenocarcinoma
(PDAC), there is no recommendation to specify metastatic regional LN localization in the current staging system. The aim of this study was to
evaluate the prognostic effect of regional metastatic LN localizations in PDAC.
Material and Method:Metastatic sites of 101 consecutive PDAC patients who underwent pancreaticoduodenectomy were classified as
peripancreatic, perigastric, hepatica communis, hepatoduodenal, and superior mesenteric artery. The frequency of metastasis in each region and
the association between the presence of metastasis in each site and overall and disease-free survival were statistically analyzed.
Results: Eighty cases (79.2%) had peripancreatic, 7 (6.9%) had perigastric, 6 (5.9%) had hepatica communis, 7 (6.9%) had hepatoduodenal,
and 4 (4%) had superior mesenteric artery LN metastasis. The overall and disease-free survival values were significantly shorter in patients
with hepatoduodenal LN metastasis (log rank; p= 0.001, p=0.017, respectively). The presence of metastatic superior mesenteric artery LN was
significantly associated with shorter disease-free survival in univariate analysis (p=0.017). Hepatoduodenal LN metastasis was an independent
predictor of mortality (p=0.005) in multivariate analysis.
Conclusion: The presence of hepatoduodenal LN metastasis is an independent poor prognostic factor for mortality. The presence of metastatic
LN in the superior mesenteric artery region was significantly associated with shorter disease-free survival time, although not an independent
predictor. We conclude that the metastatic regional LN sites, especially the hepatoduodenal region, have an impact on the prognosis, and should
be included in synoptic pathology reports.
Pancreatic ductal adenocarcinomas (PDACs) are aggressive
tumors with a 5-year survival rate around 10%. The most
important prognostic parameters for these tumors include
tumor size, pathological stage, presence of lymph node
metastasis, number of metastatic lymph nodes, and vascular
invasion. Regarding regional lymph node metastases, it is
recommended to specify the number of metastatic lymph
nodes and pN stage, while metastatic regional lymph
node localization does not have a place in the current
staging system 1
. According to the 2014 consensus of the
International Pancreatic Surgery Working Group, standard
lymphadenectomy for pancreatoduodenectomy covers the
lymph node regions of 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b,
14a, 14b, 17a, and 17b, while for distal pancreatectomy,
the dissection of lymph node regions of 10, 11, and 18
is considered as standard 2
. While regional lymphatic
metastases are initially expected to occur in primary lymph nodes (pancreaticoduodenal - regions 13 and 17), second
line lymph nodes (inferior pyloric, hepatica communis, and
hepatic pedicle/hepatoduodenal – regions 6, 8, and 12) are
involved as the disease progresses 3
. There are few studies
on the relationship between the presence of metastases in
non-pancreaticoduodenal regional lymph nodes and the
prognosis that demonstrate the association between various
metastatic lymph node localizations and the prognosis 3
. As the data on this issue are very limited, the aim of this
study was to evaluate the effect of regional metastatic lymph
node localization on the prognosis of PDAC.
The study protocol was approved by the institutional
ethics committee (Approval date and number: 2022/18-
15). One hundred and one patients who underwent
pancreaticoduodenectomy (Whipple procedure) between
2010 and 2020 with no history of neoadjuvant chemotherapy
and were diagnosed as PDAC at our institution were included. The cases that died within the first 3 months of the
surgery (i.e., perioperative period) were excluded. Patient
demographics, perioperative mortality, and oncological
follow-up info were retrieved from the patient records.
Survival status and dates of death were obtained from
the national population registry system and the hospital
registry system. The histopathologic features including
tumor differentiation, tumor size, pT, pN, metastatic lymph
node number, lymphovascular invasion, and perineural
invasion were obtained from pathology reports. Standard
lymphadenectomy protocols had been performed for
all cases 2
. The regional lymph node localizations were
classified as peripancreatic and perigastric lymph nodes
(dissected by the pathologist (A.A., S.C. and O.S.) from the
main specimen), and hepatica communis, hepatoduodenal/
hepatic pedicle and superior mesenteric artery lymph
nodes (separately resected and specified by the surgeons
during the operation). Lymph node dissection had been
performed from all these regions in each case in the
study. Peripancreatic lymph nodes had been sampled
without further categorization. Each lymph node had been
completely sampled and examined. Hematoxylin-eosin
stained slides were examined for the presence and number
of metastatic lymph nodes in each region. The associations
between the presence of metastasis in each metastatic
lymph node site and the histopathologic prognostic factors
and the overall and disease-free survival were determined
Statistical analyses were performed using the SPSS 24.0
statistical package (SPSS, Chicago, IL). Categorical data
were compared using the Chi-square test and Fisher
Exact test. The independent samples T-test was used for
comparing normally distributed continuous variables, and
the non-normally distributed variables were compared
using the Mann–Whitney U test. Overall survival (OS) was
determined as the duration between the operation date and
time of death or last follow-up, while the duration between
the operation date and time of recurrence was calculated to
determine disease-free survival (DFS). The Kaplan-Meier
(K-M) estimator was used to calculate the OS and DFS rates,
and the Log-rank test was used to compare the differences
between survival curves. The association between OS and
DFS, and the prognostic parameters were also analyzed by
multivariate analysis. Log and Cox regression tests were
used to analyze the association between the survival time
and potential predictors. A p value<0.05 was considered
The mean age was 63.7 ± 10.44 (range: 37-89) years. Sixtytwo
patients (61.3%) were male with a male:female ratio
of 1.58. The tumor was well differentiated in 68 (67.3%),
moderately differentiated in 26 (25.7%), and poorly
differentiated in 7 patients (7%). The surgical margin
was positive in 60 cases (59.4%), and the retroperitoneal
surgical margin was most commonly involved (n=43).
Lymphovascular invasion was present in 78 cases (77.2%),
whereas perineural invasion was detected in 87 (86.1%). pT
stage was pT1 in 7, pT2 in 25, and pT3 in 68 patients, and
pT4 in one patient. The mean number of dissected lymph
nodes was 24.8 ± 10.38 (range: 4-56), and the mean number
of metastatic lymph nodes was 3.08 ± 3.00 (range: 0-14).
Nineteen patients did not have lymph node metastasis,
while 62 were pN1 and 20 were pN2. Almost all of the cases
(97.5%) with lymph node metastasis had peripancreatic
lymph node metastasis.
Eighty cases (79.2%) had peripancreatic, 7 cases (6.9%) had
perigastric, 6 cases (5.9%) had hepatica communis, 7 cases
(6.9%) had hepatoduodenal/hepatic pedicle, and 4 cases
(4%) superior mesenteric artery lymph node metastasis
(Table I). All but one of the cases with hepatoduodenal
lymph node metastasis also had peripancreatic lymph node
metastasis. Almost all cases with extra-peripancreatic lymph
node metastases (except 2 cases) were already accompanied
by peripancreatic LN metastasis. The relationship between
all metastatic lymph node regions is shown in Figure 1
(together with the number of cases with metastasis in that
region). Extended lymphadenectomy had been performed
in six patients.
Click Here to Zoom
|Figure 1: Venn diagram showing the relationship between all
metastatic lymph node regions (with the number of cases with
metastasis in that region).
Positive surgical margin status was statistically associated
with the presence of peripancreatic lymph node metastasis
(68.3% vs. 86.7%, p=0.025), and hepatoduodenal lymph
node metastasis (0% vs. 11.7%, p=0.039). The presence of
lymphovascular invasion showed a statistically significant
association only with the presence of peripancreatic
lymph node metastasis (39.1% vs. 91%, p<0.001). The
site of the metastatic lymph node was not associated with
other histopathologic prognostic factors such as tumor
differentiation, pT, and perineural invasion.
Results of the Survival Analysis
The mean follow-up time was 21.3 ± 26.5 months. Seventyone
(70.3%) cases had recurrence, while 84 patients (83.2%)
died during follow-up. The average OS was 27.5 months (±
26.26). The average DFS was 9.6 months (± 9.9). The OS rates at 1, 3, 5 years were 68.7%, 31%, and 15%, respectively.
The DFS rate at 1 year was 26.8%.
The mortality and recurrence rates were not statistically
related to any of the metastatic lymph node regions.
In survival analysis, the estimated OS was significantly
shorter in patients with pN1 and pN2 stage compared to
patients without lymph node metastasis (56.42 vs. 31.36 vs.
16.40 months, log rank; p=0.002), and also with moderate
and poor tumor differentiation (40.24 vs. 23.84 vs. 8.79 months, log rank; p<0.001), positive surgical margin (46.05
vs. 26.37 months, log rank; p=0.008), lymphovascular
invasion (54.43 vs. 27.64 months, log rank; p=0.003), and
perineural invasion (55.88 vs. 29.48 months, log rank;
p=0.011). The DFS was also significantly shorter in patients
with moderate and poor tumor differentiation (19.27 vs.
13.52 vs. 5.66 months, log rank; p=0.025).
The OS (35.5 vs. 11.24 months) and DFS (10.17 vs.
2.6 months) were significantly shorter in patients with
hepatoduodenal/hepatic pedicle lymph node metastasis
(log rank; p=0.001, p=0.017, respectively). The OS (35.5
vs. 11.24 months) and DFS (10.17 vs. 2.6 months) were
significantly shorter in patients with hepatoduodenal/
hepatic pedicle lymph node metastasis (log rank; p=0.001,
p=0.017, respectively) (Figure 2). The DFS was significantly
shorter in patients with superior mesenteric artery lymph
node metastasis (9.8 vs. 1.8 months) (log rank; p=0.017)
(Figure 3). The OS was shorter in patients with hepatica
communis lymph node metastasis as well, albeit not
statistically significant (34.7 months vs. 20.5 months;
p=0.32) (Table I).
Click Here to Zoom
|Figure 2: Kaplan-Meier overall
survival curve of the hepatoduodenal/
hepatic pedicle lymph node metastasis,
with the risk table showing the number
of the cases at risk.
Click Here to Zoom
|Figure 3: Kaplan-Meier survival curves of the groups. A) Disease-free survival for superior mesenteric artery lymph node metastasis,
B) Disease-free survival for hepatoduodenal lymph node metastasis.
Click Here to Zoom
|Table I: The frequencies of metastatic regional lymph node sites and the results of univariate analysis for overall and disease-free
In multivariate analysis, hepatoduodenal/hepatic pedicle
lymph node metastasis was found to be an independent
predictor of mortality with the Cox regression analysis
(HR 3.27, 95% CI: 1.43 to 7.46, p=0.005) (Table II). No
independent predictors of recurrence were detected with
the Cox regression analysis.
Lymph node metastasis, specifically when present in the
hepatoduodenal/hepatic pedicle region, was found to be an
independent indicator of mortality in this study. Although
not an independent indicator, the DFS was significantly shorter in patients with superior mesenteric artery lymph
node metastasis. The presence of hepatica communis
lymph node metastasis was also found to be associated
with a shorter life expectancy of 14 months, which is a
very important period for these patients due to the low life
expectancy of PDAC, albeit without statistical significance.
All efforts for many years to improve the prognosis of
pancreatic ductal adenocarcinoma have yet to yield
satisfactory results. Late diagnosis, lack of effective
treatment options, and inadequate prediction of the
prognosis, which can be considered the main problems
related to this tumor, have been topics that have been studied
to date. A significant change that has occurred in recent
years as a result of studies on PDAC for better prognostic
classification is the transformation of PDAC pathological
staging into a tumor size-based staging system, which is a
more objective assessment, rather than tumor spread-based
staging, which was more prone to erroneous assessments
1,11. In addition, lymph node substaging has been added
to pN staging due to its significant prognostic contribution
1,12. On the other hand, the use of neoadjuvant therapy
and, albeit limited, targeted therapy options are among
the leading developments in treatment 13,14. Despite all
these developments, the 5-year survival is still reported as
11% according to current data 15. Our study showed a
slightly higher 5-year survival rate (15%), with an average
survival time of 27.5 months.
Numerous studies have shown that the assessment of the
number of metastatic lymph nodes contributes much
more to the prognostic classification than the previous
assessment based on the presence/absence of metastases
alone 12,16–18. The utility of the lymph node ratio
in predicting prognosis has also been emphasized in
the literature, although it has not yet been accepted as a
definitive prognostic determinant 17–19.
Regional lymph node metastases mostly occur in
pancreatoduodenal lymph nodes, with a high percentage
4–6 and extended lymphadenectomy does not improve
prognosis 2, as detected in our study. While the prognostic
effects of the number and the ratio of regional lymph
node metastasis have been highly emphasized, the studies
investigating the effect of metastatic lymph node sites
especially in non-pancreatoduodenal regions on prognosis are very limited and reveal conflicting data (Table III) 3–10.
Click Here to Zoom
|Table III: The summary of the findings in the studies investigating the effect of non-pancreatoduodenal metastatic lymph node
sites on prognosis in cases with PDAC who underwent pancreatoduodenectomy.
Wennerblom et al. have detected hepatica communis
lymph node metastasis in 21% of the cases that underwent
pancreatoduodenectomy and showed that the presence of
hepatica communis lymph node metastasis was associated
with significantly shorter survival in contrast to the patients
with no metastasis in this region 3. However, the study
group included periampullary adenocarcinomas as well as
pancreatic carcinomas, which caused heterogeneity in terms
of the case population 3. In two different studies of pure
pancreatic ductal adenocarcinoma cases that underwent
pancreatoduodenectomy, the negative prognostic effect of
the presence of hepatica communis lymph node metastasis
(with 18% and 16% detection rates) on survival were
demonstrated statistically 7,8. On the other hand, two
other studies showed that metastases in this region did
not have an effect on prognosis and survival, revealing
contrasting data on the subject 6,9. The common feature
of these studies is that, unlike our study, they evaluated
the prognostic effect of metastases only in the hepatica
communis lymph node region among the regional lymph
node sites. In our study, in which the prognostic value
of all regional lymph node localizations were separately
evaluated, hepatica communis lymph node metastasis was
interestingly detected at a lower rate (5.9%) than in these
studies. However, we found that the presence of hepatica
communis lymph node metastases was associated with a
shorter life expectancy of 14 months, in support of most of
these studies, although there was no statistical significance
probably due to the low detection rate.
In another study with a design similar to ours, Malleo
et al. investigated the prognostic effects of the presence
of hepatica communis, superior mesenteric artery, and
hepatoduodenal lymph node metastases, and found that
only the presence of superior mesenteric artery metastasis
was an independent prognostic factor in predicting shorter survival time 5. The authors have confirmed their findings
in another very recent study with a much larger number
of cases and prospective design, and have also added the
finding that jejunal mesenteric lymph node metastasis was
similarly associated with the prognosis 6. In our study,
which had a lower number of cases and where the jejunal
mesentery lymph nodes were not separately sampled, the
rate of superior mesenteric artery lymph node metastasis
was found to be quite low, and metastasis at this site was
significantly related to shorter disease-free survival time,
although not an independent predictor. Such a low rate is
probably due to populational differences. In a study from
France, with detection rates of SMA and hepatica communis
lymph node metastases were similar to ours and a case
number was close to ours despite a more heterogeneous
patient population (composed of PDAC and ampullary
carcinoma), Golse et al. showed that superior mesenteric
artery and hepatica communis lymph node metastasis
were significantly associated with shorter overall survival
in univariate analysis, although the significance was lost in
multivariate analysis 10. This, together with our findings,
may indicate that the rate of metastasis in these regions may be lower in the European population. In addition,
when they evaluated only the cases with PDAC, they found
that hepatica communis lymph node metastasis was an
independent prognostic factor for disease-free survival.
In a study also including patients who underwent distal
pancreatectomy, where only pancreatic head tumors were
examined, it was shown that only hepatoduodenal lymph
node metastasis among regional lymph node localizations
was associated with a very poor prognosis, with a 5-year
survival rate of 0% especially in uncinate process tumors,
although multivariate analysis was not performed 4. They
also stated that the prognostic value of jejunal mesenteric
lymph node metastasis is low. To the best of our knowledge,
that study is the first to indicate the negative prognostic effect
of the presence of hepatoduodenal lymph node metastasis
4, and our study is the second on this subject but the first
to demonstrate that hepatoduodenal lymph node metastasis
is an independent prognostic predictor for overall survival,
providing stronger evidence. No significance was detected
in the few other studies that evaluated the prognostic effect
of hepatoduodenal lymph node metastasis 5,6,10.
Twelve is an important number specified as the minimum
number of lymph nodes to be examined for pancreatoduodenectomy
specimens for optimal staging 20. The mean
number of evaluated lymph nodes was 24 in our study, with
a maximum number of 56, and more than 30 lymph nodes
were evaluated in almost one third of the patients. The reasons
for the high number of lymph nodes evaluated are the
total sampling of peripancreatic adipose tissue of the main
specimen in our pathology department, and the fact that all
regional lymph node stations are dissected separately and
meticulously with a standard approach in each case by our
surgeons. This approach may have a slight positive effect on
our survival rates; however, we think that the high number
of lymph nodes evaluated in our series and the complete
sampling of each lymph node are the features that increase
the reliability of the data we present here.
The major limitations of this study were its retrospective
design and the relatively low number of cases compared to
most studies evaluating the prognostic effects of various
regional lymph node sites. The peripancreatic lymph
nodes were not subcategorized due to the retrospective
nature of our study, and this may be considered as another
limitation. Nevertheless, we think that strong evidence that
can shed light on the topic has been obtained in this study
as we included a relatively homogeneous patient population
(including only the PDAC patients that had undergone
pancreatoduodenectomy without neoadjuvant therapy)
with the majority having a high lymph node count.
It is clear that there is confusion in the literature in terms
of the prognostic value of metastatic regional lymph node
localizations (Table III). On the other hand, it seems
undeniable that the presence of metastases in the hepatica
communis, superior mesenteric artery, and hepatoduodenal
lymph node regions has a negative effect on the prognosis,
according to the few studies providing strong evidence.
In our study, all but one of the cases with hepatoduodenal
lymph node metastasis also had peripancreatic lymph
node metastasis. Moreover, in multivariate analysis, the
presence of peripancreatic lymph node metastasis was not
statistically significant, while hepatoduodenal lymph node
metastasis was found to be a significant and an independent
prognostic factor. For these reasons, it can be assumed
that the prognostic effect of hepatoduodenal lymph node
metastasis is independent of the effect of peripancreatic
lymph node metastasis. Our finding and strong opinion
regarding hepatoduodenal lymph node metastasis is based
on these factors, although it was detected only in 7 cases.
In conclusion, this is the first study to show the presence
of hepatoduodenal/hepatic pedicle lymph node metastasis as an independent poor prognostic factor for mortality risk
in patients with PDAC, although it was detected in a low
number of cases. The presence of lymph node metastasis
in the superior mesenteric artery region is significantly
associated with shorter disease-free survival time, although
not an independent predictor. We conclude that the
metastatic lymph node site has an impact on the prognosis,
especially the hepatoduodenal region, and the inclusion
of the localization of the metastatic lymph nodes in the
synoptic reports is beneficial for the patients in terms of
better prognostic classification. Furthermore, the detection
of lymph node metastasis in specific sites associated
with adverse prognosis, such as the hepatoduodenal
region, may affect the treatment protocol when detected
postoperatively, or may indicate the candidates for
neoadjuvant chemotherapy when detected preoperatively,
and may be a topic for future studies.
Conflict of Interest
There is no conflict of interest.
Concept: AA, CA, OS, Design: AA, CA, OS, Data collection or
processing: CA, TE, MO, TS, SC, AA, OS, TU, TUn, Analysis or
Interpretation: AA, SC, OS, Literature search: AA, CA, SC, Writing:
AA, OS, Approval: OS, TUn.
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