Anatomia Chirurgica del Sistema Linfatico del Pancreas

Clinical Anatomy 00:00–00 (2014)
REVIEW
The Surgical Anatomy of the Lymphatic System
of the Pancreas
ALPER CESMEBASI,1,2 JASON MALEFANT,2 SWETAL D. PATEL,2,3 MAIRA DU PLESSIS,2
SARAH RENNA,2 R. SHANE TUBBS,2,4 AND MARIOS LOUKAS2,5*
1
Departments of Neurologic and Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
Department of Anatomical Sciences, School of Medicine, St George’s University, Grenada, West Indies
3
Department of Medicine, University of Nevada SOM, Las Vegas, Nevada
4
Section of Pediatric Neurosurgery, Children’s Hospital, Birmingham, Alabama
5
Department of Anatomy, Medical School Varmia and Mazuria, Olsztyn, Poland
2
The lymphatic system of the pancreas is a complex, intricate network of lymphatic vessels and nodes responsible for the drainage of the head, neck, body,
and tail of the pancreas. Its anatomical divisions and embryological development have been well described in the literature with emphasis on its clinical
relevance in regards to pancreatic pathologies. A thorough knowledge and
understanding of the lymphatic system surrounding the pancreas is critical for
physicians in providing diagnostic and treatment strategies for patients with
pancreatic cancer and pancreatitis. Pancreatic cancer has an extremely poor
prognosis and is a notable cause of morbidity and mortality worldwide.
Although a surgeon may try to predict the routes for metastasis for pancreatic
cancer, the complexity of this system presents difficulty due to variable drainage patterns. Pancreatitis also presents as another severe disease which has
been shown to have an association with the lymphatics. The aim of this article
is to review the literature on the lymphatics of the pancreas, pancreatic pathologies, and the available imaging methodologies used to study the pancreatic
lymphatics. Clin. Anat. 00:000–000, 2014. VC 2014 Wiley Periodicals, Inc.
Key
words:
pancreatitis;
pancreatic
pancreaticoduodenectomy
INTRODUCTION
Pancreatic cancer is one of the most aggressive
and lethal malignancies in humans. It is responsible
for approximately 38,460 deaths per year in the
United States alone, and has a very similar annual
incidence of 45,220 cases per year (Seigel et al.,
2013). It has a 5-year survival rate of only approximately 6% in the United States (Seigel et al.,
2013), and has been associated with the worst survival rate of all gastrointestinal malignancies worldwide (Beger et al., 2003). Pancreatitis is another
severe pancreatic pathology, associated with alcohol
and cholelithiasis (Gullo et al., 2002). With these
extreme insults, the lymphatic system of pancreas
plays an integral role in the body’s defense dealing
with pancreatic diseases. A comprehensive knowledge of the lymphatic structures associated with the
C
V
2014 Wiley Periodicals, Inc.
cancer;
EUS;
lymphatics;
pancreas is necessary when devising surgical treatment strategies for these patients. Furthermore,
defining the extent of the lymphatic network surrounding the pancreas may be a key factor in helping to explain the rapid lymphatic spreading of
pancreatic cancer (Regoli et al., 2001).
*Correspondence to: Marios Loukas, Department of Anatomical
Sciences, St George’s University, School of Medicine, Grenada,
West Indies. E-mail: [email protected]
Accepted under the editorship of Thomas R. Gest
Received 5 March 2014; Revised 22 July 2014; Accepted 16
August 2014
Published online in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ca.22461
2
Cesmebasi et al.
Fig. 1. The vasculature of the pancreas. The arterial
supply is derived from branches from both the superior
mesenteric artery and the celiac trunk. The splenic artery,
a branch from the celiac trunk, provides the dorsal pancreatic, inferior pancreatic and various other branches
along the neck, body, and tail of the pancreas. The gastroduodenal artery, a branch from the hepatic artery of the
celiac trunk, provides arterial supply to the head of the
pancreas via the anterior and posterior pancreaticoduodenal arteries, whereas the inferior pancreaticoduodenal
arteries, branches from the superior mesenteric artery,
provide for the uncinate process. The venous drainage of
the pancreas follows a similar pattern as the corresponding arterial supply, with the head of the pancreas being
drained by the pancreaticoduodenal veins into the portal
vein or the superior mesenteric vein (SMV), whereas the
neck, body, and tail of the pancreas drain into the splenic
vein prior to its merger with SMV to form the portal vein.
[Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
ANATOMY
is covered by peritoneum, whereas the posterior surface is in direct contact with the aorta, splenic vessels,
and inferior mesenteric vein as it joins the splenic
vein. The tail is the lateral termination of the pancreas, ranging from 1.5 to 3.5 cm in length in adults.
It lies between the layers of the splenorenal ligament
within the splenic hilum (Standring, 2008; Jensen
et al., 2012).
The arterial supply of the pancreas is derived from
branches from both the SMA and celiac trunk (Fig. 1).
The splenic artery, a branch of the celiac trunk, provides several small branches along the superior length
of the body and tail, while also giving rise to the multiple arcades of pancreatic arteries (Skandalakis et al.,
1979; Moore et al., 2010; Jensen et al., 2012). The
dorsal pancreatic artery is a branch of the splenic
artery, which provides for the neck and posterior surface of the body, before it becomes the inferior pancreatic artery, which terminates at the tail of the
pancreas. The superior pancreaticoduodenal arteries,
branches of the gastroduodenal artery, supply blood
flow for the superior portions of the head of the pancreas, whereas the inferior pancreaticoduodenal
arteries, branches from the SMA, provide vasculature
for the inferior portion of the head as well as the
The pancreas is a multifunctional organ with a firm,
lobulated smooth surface, measuring 10–20 cm in
length and 75–125 g in weight in an average adult
human (Jensen et al., 2012). Located retroperitoneal
at the level of L1 and L2 vertebrae, the pancreas
serves in producing both exocrine and endocrine
secretions as an accessory digestive organ. In most
textbooks, it can be anatomically divided into four
parts for descriptive purposes: head, neck, body, and
tail. The head is situated to the right of the midline
and sits in the C-shaped curvature of the duodenum
anterior to the inferior vena cava (IVC), giving off an
inferomedially extending projection known as the
uncinate process. The neck of the pancreas is a short
2-cm wide segment which connects the head with the
body. Its location is immediately anterior to where the
superior mesenteric artery (SMA) branches off the
abdominal aorta. The neck of the pancreas may also
be used as an anatomic landmark where the splenic
and superior mesenteric veins join to form the portal
vein. The body, the longest portion of the organ,
extends across the midline and becomes thinner as it
proceeds to the tail. The anterior surface of the body
The Surgical Anatomy of the Lymphatic System of the Pancreas
uncinate process (Moore et al., 2010; Jensen et al.,
2012). The venous drainage follows a similar pattern
as the corresponding arterial supply (Fig. 1). The head
of the pancreas is primarily drained by the four pancreaticoduodenal veins, whereas they drain into the
SMV or portal vein. The anterosuperior pancreaticoduodenal vein enters the right gastroepiploic vein
prior to joining the SMV, while the posterosuperior
pancreaticoduodenal vein drains directly into the portal vein near the superior aspect of the neck of the
pancreas. The anterior and posterior inferior pancreaticoduodenal veins enter the SMV near the inferior
border of the uncinate process. The neck, body, and
tail of the pancreas have venous drainage into the
splenic vein.
Lymphatic Anatomy
The lymphatic system of the pancreas is highly
complex due in part to the high vascularity of the
gland by anastomotic vessels. The function of the
lymphatics is to collect interstitial fluid containing
pathogens, immune cells, cell products, and cell
debris, which drain from vascular capillaries. The fluid
filters through a series of lymph nodes before being
returned to the venous circulation (Drake et al.,
2010). In general, the lymphatic vessels follow the
pancreatic blood vessels (Standring, 2008; Moore
et al., 2010).
There is still no widely used standard terminology
for classifying the pancreatic lymph nodes (Skandalakis and Gray, 1994; Skandalakis, 2004; Fischer,
2007). One classification system is outlined by Cubilla
et al. (1978) who described five main groups of nodes
in relation to their location around the pancreas:
superior, inferior, anterior, posterior, and splenic
nodes. Other authors have since followed this regional
grouping as well (Skandalakis and Gray, 1994; Borghi
et al., 1998; Skandalakis, 2004; Fischer, 2007).
The superior nodes have afferent vessels that come
from both the anterior and posterior portions of the
superior region of the pancreas (Fig. 2a). Lymph
nodes in this region are generally named accordingly
to the region and include the superior head nodes,
superior body nodes, and gastric nodes. Some of the
lymphatic vessels from this region of the pancreas
may also terminate into lymph nodes of the gastropancreatic fold or of the hepatic chain (Cubilla et al.,
1978; Skandalakis and Gray, 1994; Skandalakis,
2004; Fischer, 2007). The inferior pancreatic group of
nodes includes the inferior head and inferior body
nodes, also demarcated by their location along the
pancreas (Fig. 2b). Vessels from both the anterior and
posterior portions of the inferior halves of the head
and body drain mostly to these nodes. The vessels
can also extend into the superior mesenteric and left
lateroaortic lymph nodes in some cases (Cubilla et al.,
1978; Skandalakis and Gray, 1994; Skandalakis,
2004; Fischer, 2007).
The splenic nodes collect lymph from the tail of the
pancreas (Fig. 2c). They further drain to the nodes
found at the splenic hilum, splenorenal ligament, and
lymph nodes of the tail of the pancreas, and may also
3
lead into the nodes that lie either superior or inferior
to the body of the pancreas (Cubilla et al., 1978;
Skandalakis and Gray, 1994; Skandalakis, 2004;
Fischer, 2007).
The anterior group of nodes is comprised of the
pyloric, anterior pancreaticoduodenal, and mesenteric
lymph nodes found at the root of the mesentery of
the transverse colon (Fig. 2d). The afferent vessels
into these nodes form two collecting trunks that run
along the anterior surface of the superior and inferior
sections of the pancreatic head (Cubilla et al., 1978;
Skandalakis and Gray, 1994; Skandalakis, 2004;
Fischer, 2007). Similarly, the posterior lymph nodes
lie along the posterior surface of the superior and inferior parts of the head of the pancreas (Fig. 2e). These
include the posterior pancreaticoduodenal lymph
nodes, which are also a common site for drainage of
the (common) bile duct and the hepatopancreatic
ampulla (of Vater) lymphatic vessels. The group of
posterior nodes also includes (common) bile duct
lymph nodes, right lateral aortic lymph nodes, and
some nodes found at the origin of the SMA (Cubilla
et al., 1978; Skandalakis and Gray, 1994; Skandalakis, 2004; Fischer, 2007).
Standring (2008) offers a simplification of the
nomenclature of the lymphatic network by dividing
the pancreas into two main parts, head/neck region
and the body/tail region. Lymph vessels from the
body and tail of the pancreas mainly lead into the
pancreaticosplenic nodes, although some may also
lead directly to the preaortic lymph nodes. The neck
and head regions of the pancreas have a more extensive drainage system, as lymph can travel through the
nodes running alongside the pancreaticoduodenal,
superior mesenteric and hepatic arteries. Figures 3
and 4 show the extensive nature of the lymphatics in
a cadaveric dissection, while attempting to locate
nodes along the tail and near the splenic hilum posed
difficulties. Some lymphatics from these regions also
drain to the preaortic and celiac nodes (Standring,
2008).
Many authors have recognized the lymphatic plexus
surrounding the pancreas as complex and overlapping, thus studies have been done on the drainage
patterns and divisions of these nodes. Cubilla et al.
(1978) found that in the 44 patients with pancreatic
cancer, there was no sign of metastasis to lymph
nodes of the nearby greater or lesser curvatures of
the stomach. This corroborated previous findings that
no communication existed between the pancreas and
the gastric lymph nodes (Rouvière, 1938; Evans and
Ochsner, 1954; Cubilla et al., 1978). Furthermore,
lymphatics from the head and body of the pancreas
do not drain to the tail or to the splenic nodes. However, lymph from the tail has been found to drain to
the nodes of the superior or inferior body (i.e., the
superior and inferior groups) (Rouvière, 1938; Cubilla
et al., 1978; Skandalakis and Gray, 1994; Skandalakis, 2004; Fischer, 2007). Finally, Bartels (1907)
noted valves in the lymphatic vessels are arranged in
a manner so that lymph may flow from the pancreas
to the duodenal vessels, but not in a countercurrent
fashion laterally (Skandalakis and Gray, 1994; Skandalakis, 2004; Fischer, 2007). Other authors have
4
Cesmebasi et al.
Fig. 2. (a) The superior lymph nodes of the pancreas.
These lymph nodes are named as such due to their location along the superior border of the head, neck, and
body of the pancreas. (b) The inferior lymph nodes of the
pancreas. These lymph nodes are named as such due to
their location along the inferior border of the head, neck,
and body of the pancreas. (c) The splenic lymph nodes of
the pancreas. These lymph nodes drain the nodes along
the tail of the pancreas, hilum of the spleen, and splenorenal ligament. (d) The anterior lymph nodes of the
pancreas. These lymph nodes compromise of pyloric,
anterior pancreaticoduodenal, and mesenteric lymph
nodes. (e) The posterior lymph nodes of the pancreas.
These lymph nodes include the posterior pancreaticoduodenal lymph nodes, which are also a common site for
drainage of the (common) bile duct and hepatopancreatic
ampulla (of Vater) lymphatic vessels. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
described in detail three main lymphatic pathways
around the pancreatic head, which is the most common site for pancreatic adenocarcinoma (Deki and
Sato, 1988; Ungeheuer and Liebermann-Meffert,
1990; Kayahara et al., 1992; Sohn et al., 2000;
Cameron et al., 2006; Samra et al., 2008; Pavlidis
et al., 2011). Some lymphatic vessels from the pancreas have also been described to either directly lead
to the thoracic duct, or lead there indirectly through
the para-aortic lymph nodes (Hirai et al., 2001; Samra
et al., 2008).
All of these points are especially important for surgeons who are performing lymph nodal dissection for
pancreatic cancer patients whom shown metastasis to
surrounding lymph nodes.
life, and occurs concurrently with the development of
the vasculature (Moore and Persaud, 2008). By the
seventh week of intrauterine life, the pancreas is in
close relation with the developing lymphatic structures
lying anterior to the aorta. By the eighth week, one
may observe several lymphatic structures at the level
of the celiac artery, and note their origin is anterior to
the adrenal glands, kidney, and mesenteric vessels.
Between the 8th and 10th weeks of intrauterine life,
lymph nodes become evident with their surrounding
capsule. Borghi et al. (1998) reported that to the right
of the mesenteric artery, the lymph nodes are in association with the posterior section of the head of the
pancreas, whereas to the left of the artery, the nodes
go forward to the posterosuperior portion of the pancreatic body. The peritoneum lying over the pancreas
holds the lymphatic structures that sit lateral and posterior to the head of the pancreas in place (Borghi
et al., 1998).
Between the 12th and 20th weeks of intrauterine
life, the lymphatic structures develop into a complex
EMBRYOLOGY
The development of the pancreatic lymphatic system begins at the end of the sixth week of intrauterine
The Surgical Anatomy of the Lymphatic System of the Pancreas
5
Fig. 3. Cadaveric image of lymphatics (highlighted)
on the anterior surface of the pancreas noted upon gross
dissection near the head of the pancreas. The transverse
colon has been lifted to show the anterior pancreatic
lymph nodes near the head and neck of the pancreas and
in close proximity to the pancreaticoduodenal arteries
(not labeled). The pancreaticoduodenal arteries have not
been fully dissected as this would remove many of the
anterior lymph nodes. Some of the superior and inferior
pancreatic lymph nodes may also be noted, but cannot be
distinctly labeled. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
network. The lymph nodes at the level of the celiac
trunk are found within the dorsal mesogastrium and
are entwined with nervous structures. Lymphatic vessels attached to these nodes are seen to be in association with the superior portions of the head and body
of the pancreas. At the level of the SMA, the paraaortic lymph nodes are surrounded with nervous plexuses. Vessels from these nodes come from the posterior surface of the pancreatic body, along with some of
the nerve fibers. Other lymph nodes are present at
this level around the (common) bile duct inside the
hepatoduodenal ligament (Borghi et al., 1998). With
these observations, it may denote the lymphatic
development is closely related with the dual-bud
development of the pancreas.
Pavlidis et al., 2011; Seigel et al., 2013). While the
etiology of this disease is not yet fully established,
both genetic predispositions and environmental factors, such as smoking and chronic pancreatitis, have
been shown to play a role (Silverman et al., 1994,
1999; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2004; Parkin et al., 2005).
Due to its asymptomatic nature, pancreatic neoplasms are often discovered late in its course with a
higher stage (Wray et al., 2005). Common presenting
symptoms include jaundice, duodenal obstruction,
€ ninger et al., 2007; Michalski et al.,
and pain (Ko
2007b). Painless jaundice is the most common and
possibly only presenting feature of this disease, due
to the majority of pancreatic tumors arising at the
head. Pancreatic head tumors cause compression
and/or obstruction of the (common) bile duct, thus
leading to the painless jaundice presentation (Tan
et al., 1996; Yeo, 1998; Sohn et al., 2000; Cameron
€ ninger et al., 2007; Michalski et al.,
et al., 2006; Ko
2007b; Samra et al., 2008). If the patients do present
with pain, it is describe as diffuse and vague, with various intensities over the course of the disease (Kuhl€ ninger et al., 2007).
mann, 2004; Ko
The lymphatic system acts as a major route
through which the malignancy may metastasize.
Malignant cells migrate from the primary tumor site
through these vessels to form secondary tumors in
PANCREATIC NEOPLASMS
Pancreatic neoplasms are highly aggressive malignancies with an extremely poor prognosis as 5-year
survival is around 5–6% (Parkin et al., 2005; Loos
et al., 2008; Saif, 2008; Riediger et al., 2009; Badger
et al., 2010; Pavlidis et al., 2011; Seigel et al., 2013).
Despite recent advances in imaging, staging, and surgical treatment, there has been virtually no improvement in overall survival of these patients (Michaud,
2004; Takamori et al., 2008; Adams and Allen, 2009;
6
Cesmebasi et al.
Fig. 4. Cadaveric image of lymphatics on the posterior surface of the pancreas noted upon gross dissection
near the superior mesenteric artery. The intestines, stomach, and mesentery has been reflected to expose a close
up view of the posterior surface of the pancreas. The posterior pancreatic lymph nodes may be observed in close
proximity to the origin of the superior mesenteric artery
(SMA). Additionally, the celiac nodes may also be noted in
the image, which the posterior pancreatic lymph nodes
drain into. Intestinal lymph nodes may also be noted in
this image. A small group of splenic lymph nodes were
also found toward the tail of the pancreas and spleen (offimage). [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
distal regions (Drake et al., 2010). Several authors
have reported that the main factor for a poor prognosis of pancreatic cancer is positive lymph node
involvement (Geer and Brennan, 1993; Baumel et al.,
1994; Yeo and Cameron, 1996; Nakagohri et al.,
2006; Zacharias et al., 2007; Samra et al., 2008; Pavlidis et al., 2011). Others have suggested the lymph
node ratio is the strongest prognostic factor, where a
lower ratio equates to a greater patient survival
chance (Riediger et al., 2009). Some studies have
shown that the presence of two or more involved
lymph nodes correlates with a significantly decreased
survival rate (Zacharias et al., 2007; Riediger et al.,
2009).
Pancreatic cancer staging is classified according to
the TMN classification system published by the American Joint Committee on Cancer (AJCC) (Edge et al.,
2010; Jensen et al., 2012). The TNM classification
system applies to both endocrine and exocrine pancreatic neoplasms (Edge et al., 2010; Sobin et al.,
2010). Tumor size is classified on the range from T1
to T4. T1 classification denotes the tumor is limited to
the pancreas and is less than 2 cm, whereas T2 is
also limited to the pancreas, but is greater than 2 cm.
A T3 tumor is one that extends beyond the pancreas,
but does not involve the celiac axis or SMA, while T4
classification denotes involvement in either or both
celiac axis and SMA. The N and M classifications have
only two stages each. Lack of regional nodal involvement translates to N0 stage, while any regional nodal
involvement results in N1 staging. Similarly, M0 notes
no distant metastasis and M1 signifies the presence of
distant metastasis (Edge et al., 2010; Sobin et al.,
2010). Table 1 highlights the staging system outlined
by the AJCC.
The Japan Pancreas Society (JPS) (2003) has
developed another staging system for pancreatic cancer, which also utilizes the TNM classification method.
Although the M category describing metastasis is in
accordance with the UICC classification, the JPS differs from AJCC in their criteria for the other categories
(Neoptolemos et al., 2010). The N category in the
Japanese classification is more detailed, with a range
from N0 to N3. N1 corresponds to metastasis to adjacent lymph nodes that are unintentionally removed
during the pancreatectomy procedure, N2 represents
metastasis to regional nodes that are dissected intentionally for curative lymphadenectomy, and N3
describes metastasis to distant lymph nodes that
would normally not be removed in curative lymphadenectomy (Neoptolemos et al., 2010). Also in the Japanese classification, the T3 and T4 criteria differ as T3
signifies a tumor that has extended into peripancreatic
tissue, the bile duct, or duodenum, while T4 describes
a tumor that has expanded into any of the large adjacent vessels, extrapancreatic nerve plexus, or other
organs (Neoptolemos et al., 2010).
Lockhart et al. (2005) noted in their study, the TNM
classification system is beneficial in terms of determining the patient’s prognosis. For clinical management
The Surgical Anatomy of the Lymphatic System of the Pancreas
TABLE 1. AJCC Anatomical Staging of Pancreatic
Neoplasms
Stage 0
Stage
Stage
Stage
Stage
Stage
Stage
IA
IB
IIA
IIB
III
IV
T in situ
N0
M0
T1
T2
T3
T1–T3
T4
Any T
N0
N0
N0
N1
Any N
Any N
M0
M0
M0
M0
M0
M1
Adapted from Edge et al. (2010).
purposes, however, the cancer is simplified into one of
four categories: resectable, locally advanced, locally
unresectable, and metastatic (Lockhart et al., 2005;
Michalski et al., 2007b). Lockhart et al. (2005)
explained the definition of resectability of the cancer
can vary, and depends mostly on the surgeon’s skill
and experience, as well as the extent of the surgeon’s
resection of surrounding lymph nodes.
Though based on the anatomy of the pancreatic
lymphatics one may attempt to identify the drainage
route for cancer, it is crucial to understand that the
complex arrangement allows for numerous variations
in metastasis patterns. Due to this uncertainty, the
surgeon is unable to accurately predict an exact drainage route through which the cancer will spread
(O’Morchoe, 1997). Other factors may also cause variable or uncommon drainage patterns. Skandalakis
(2004) pointed out the cancer itself can alter typical
drainage routes by obstructing lymphatic vessels,
causing cancer to appear in unexpected nodes. Collateral lymphatic vessels may form and cause a shift in
regular lymph drainage routes (Skandalakis, 2004).
An additional factor that could pose as a challenge to
surgeons is the phenomenon known as skip metastasis, which is when metastasis occurs in an unusual
route (Nakao et al., 1989; Moriya, 2006). With skip
metastasis, a second-tier lymph node is found to be
involved while the sentinel node is negative; thus, it
may lead to inadequate lymphadenectomy and/or surgical margins (Tokunaga et al., 2009).
IMAGING OF THE PANCREATIC
LYMPHATICS
The visualization of the lymphatic system holds
important clinical value. Many studies have been done
to visualize the lymphatic vessels in order to obtain a
more clear understanding and knowledge of their
route and function. Dating back to Sappey (1874)
whom noted that the lymphatics could be marked by
the injection of silver nitrate into the arteries (Gray,
1937), there have been various injection-based studies which may be done to visualize the lymphatic system of the pancreas.
However, imaging techniques, such as computed
tomography (CT) and magnetic resonance imaging
(MRI) are the cornerstone technologies for diagnosing
pancreatic cancer in current practice (Von Hoff et al.,
2005). Other technologies are also helpful in visualizing the lymphatic system for diagnostic purposes.
7
Endoscopic ultrasonography (EUS) is a method used
by physicians to stage the cancer based on visualizing
the surrounding lymph nodes for signs of metastasis
(Fritscher-Ravens, 2004; Von Hoff et al., 2005). Akahoshi et al. (1998) described the use of EUS for staging pancreatic cancer. The authors looked for welldefined round or elliptical structures that were hypoechoic in comparison to other tissues surrounding the
pancreas and regarded these structures as lymph
nodes involved with cancer. If no such structures were
evident, the lymph nodes were considered nonmalignant (Akahoshi et al., 1992; Hamada et al., 1997;
Akahoshi et al., 1998). This procedure enables the
physician to make a classification of N0 or N1 according to lymph node involvement based on the AJCC
classification system (Akahoshi et al., 1998; Sobin
et al., 2010). It should be noted that in the study,
Akahoshi et al. (1998) reported the accuracy, sensitivity, and specificity for diagnosing lymph node metastasis to be 50, 28, and 76%, respectively. However,
other studies have reported better results, with
ranges of 50–74, 33–92, and 26–100% for accuracy,
sensitivity, and specificity, respectively (Tio et al.,
€ ller
1990; Palazzo et al., 1993; Yasuda et al., 1993; Mu
et al., 1994; Tio et al., 1996; Akahoshi et al., 1998).
In a study that compared EUS with multidetector
CT, DeWitt et al. (2004) found that although EUS
appeared to be superior to CT for tumor detection in
pancreatic cancer, both techniques had similar value
in assessing lymph node staging. The authors concluded that both EUS and CT were inaccurate in determining lymph node staging, mainly due to poor
detection of lymph nodes in the N1 stage. Other studies, however, have advocated the use of CT in the preoperative workup of patients with pancreatic cancer
for either staging or other purposes (Freeny et al.,
1988; Wray et al., 2005; Michalski et al., 2007b). In a
more recent study, Sakamoto et al. (2010) stated that
EUS provides detailed high-resolution images of the
pancreas that surpass those given by CT or MRI based
on the fact the close proximity of the high-frequency
transducers used to the pancreas provides a more
precise image (Sakamoto et al., 2010).
Normal and contrast-enhanced MR imaging with
magnetic resonance cholangiopancreatography (MRCP)
and magnetic resonance angiography may also be
used as a noninvasive technique for assessing patients
suspected or diagnosed with having pancreatic cancer.
€ nninen et al. (2002) used this method to clasLopez Ha
sify lymph nodes as metastatic if they had a short-axis
diameter on the MR image of greater than 1 cm. They
reported accuracy of lymph node metastasis to be
76%. However, they did also note in 21% of patients,
metastatic lymph nodes of normal size were missed.
In one patient, an enlarged abdominal lymph node was
recognized as being malignant when in fact it was
€ nninen et al., 2002).
benign (Lopez Ha
Recently, the use of nanoparticle enhanced magnetic resonance studies has begun to be evaluated as
a possible imaging modality for delineating pancreatic
cancer spread. McDermott et al. (2013) demonstrated
lymphotropic nanoparticle-enhanced MRI holds a high
sensitivity and specificity in identifying malignant nodal
involvement in pancreatic ductal adenocarcinoma
8
Cesmebasi et al.
patients. Using ultra-small superparamagnetic iron
oxide solution (ferumoxytol) to enhance T2 MRI studies, McDermott et al. (2013) showed an increase in
sensitivity to 83.3 and 76.5% on the patient and nodal
levels, respectively, in comparison to conventional
cross-sectional imaging. The specificity was noted to
increase to the 80 and 98.4% on the patient and nodal
levels, respectively (McDermott et al., 2013). Hedgire
et al. (2014) also evaluated the use of ferumoxytolenhanced MRI in evaluating the primary pancreatic
tumor patients receiving preoperative neoadjuvant
therapy. The results of their study supported McDermott et al. (2013) by showing nanoparticle-enhanced
MRI studies contributed to enhanced tumor delineation, achieving better surgical margins, and improving
the prognosis of pancreatic carcinoma patients undergoing surgical resection (Hedgire et al., 2014).
PANCREATICODUODENECTOMY FOR
PANCREATIC CANCER
Although preoperative staging for pancreatic adenocarcinoma has been improving with newer imaging
studies focused on nodal spread, it is not completely
reliable. Pathological staging may only be accomplished postoperatively. Although surgical resection
offers a low cure rate, several authors have emphasized the only potentially curative treatment of the
disease is complete removal of the tumor (Sohn et al.,
2000; Beger et al., 2003; Cameron et al., 2006;
Michalski et al., 2007b; Samra et al., 2008; Jensen
et al., 2012). Originally, the pancreaticoduodenectomy
(Whipple) procedure was associated with high morbidity and mortality in its early years, but it has now
become as a safe operation with lower morbidity and
mortality due to improvements in techniques. The
Whipple procedure consists of multiple integral steps:
exploration of the peritoneal surfaces for metastasis,
mobilization of the pancreas, cholecystectomy and
preparation of the common hepatic duct, resection of
the malignancy and metastasized tissues, and reconstruction of the biliary and intestinal continuity
(Michalski et al., 2007b; Jensen et al., 2012).
The extent of lymphadenectomy during the procedure has been a controversial topic for several years
(Michalski et al., 2007a,b; Jensen et al., 2012). A
standard lymphadenectomy is characterized as dissecting at least 15 lymph nodes (Farnell et al., 2005;
Schwarz and Smith, 2006; Pavlidis et al., 2011). The
logic of this dissection is that the majority of these
nodes will be negative for malignancy, and thereby
increase chances for cure of the disease (Schwarz and
Smith, 2006). Early studies performed in Japan
showed increased survival rates in patients undergoing radical extended lymphadenectomy, involving
resection of hilar and retroperitoneal nodes in addition
to the standard nodes with pancreatic cancer resection (Ishikawa et al., 1988; Manabe et al., 1989;
Miyazaki, 1989; Michalski et al., 2007a,b). However,
randomized controlled clinical trials have been performed and do not show radical extended lymphadenectomy procedures to be beneficial over the
standard lymphadenectomy procedure (Michalski
et al., 2007a,b; Farnell et al., 2008; Pavlidis et al.,
2011). Michalski et al. (2007a) described their metaanalysis study of three of these randomized clinical
trials (Pedrazzoli et al., 1998; Yeo et al., 2002; Farnell
et al., 2005) and showed increased morbidity rates
with radical extended lymphadenectomy. In addition,
it was noted the greatest postoperative complications
were delayed gastric emptying, pancreatic fistula formation, and dumping syndrome (Michalski et al.,
2007a,b; Farnell et al., 2008).
PANCREATITIS
The lymphatic system has been attributed to playing a role in pancreatitis. Dumont and Martelli (1968)
described how in instances of obstruction of the exocrine pancreatic duct, one will see an increase in protein leakage into the interstitial space from the
pancreatic juice. Several other authors have also commented on a similar association between the lymphatic system and both acute and chronic pancreatitis
(Dumont et al., 1960; Anderson and Schiller, 1968;
Dreiling, 1970; Papp et al., 1975; Pissas, 1984;
O’Morchoe, 1997). Many have speculated that aberrations in the lymphatics is linked with the pathogenesis
of the disease, as once the capacity of the lymphatic
system to drain fluid is surpassed, the proteolytic
enzymes can become trapped in the interstitial
spaces. Dumont et al. (1960) suggested that in
chronic pancreatitis the efficiency of lymph flow is
decreased or obstructed in heavily fibrosed regions.
With these peripancreatic fluid collections, it may lead
to pancreatic necrosis and the formation of pancreatic
pseudocysts and/or pancreatic fistulas. The occurrence of peripancreatic fluid collections may also give
way to infective pancreatic necrosis, in which the
definitive treatment should include surgical debridement with necrosectomy, closed continuous irrigation,
and open packing (Jensen et al., 2012)
Reynolds (1970) examined the lymphatic system of
the pancreas using three groups of patients: normal
patients, patients with acute pancreatitis, and patients
with chronic pancreatitis. During abdominal surgery, a
solution of 5.5% patent V dye injected into the anterior surface of the head and/or body of the pancreas
and time interval photos were taken. In the normal
patients, the lymphatic network surrounding the pancreas was easily visualized with the dye flowing cephalad (Reynolds, 1970) with complete clearing in 45
min. In the patients with acute pancreatitis, the time
of uptake of the dye was prolonged in these subjects
by 1.5 hr, and only partial clearing of the dye was
observed. In the chronic pancreatitis group, the
author saw a complete blockade in the lymphatic system, with no clearing of the dye occurring. O’Morchoe
(1977) commented that it is unknown whether the
reduced lymphatic drainage was directly a result from
the damage to the lymphatic vessels, or if it was due
to the fibrosis of the pancreas in its diseased state.
Regardless of etiology, the dysfunction of the lymphatics in pancreatitis is thought to be detrimental to
the patient, and potentially prolong recovery from
inflammatory processes (O’Morchoe, 1997).
The Surgical Anatomy of the Lymphatic System of the Pancreas
CONCLUSIONS
The lymphatic drainage of the pancreas involves a
complex arrangement of vessels and lymph nodes. A
firm understanding of the embryological development
plays a key role in understanding the lymphatic anatomy of the pancreas as it is closely related to the
dual-bud development of the pancreas. In addition, a
thorough knowledge of the pancreatic lymphatics
proves to be invaluable to surgeons treating patients
with pancreatic pathologies. When approaching pancreatic neoplasms, clinicians may be able to follow the
pathway of lymphatic drainage from the primary
tumor site to determine the appropriate course of
treatment and/or management. The identification of
positive lymph nodes correlates with a poorer prognosis even with aggressive surgical treatment. Additionally, variation in the metastasis of the tumor may
exist, especially with occurrence of lymph node
obstruction. Imaging of the pancreatic lymphatics provides a better understanding of these pathways, thus
simplifying the clinician’s decision on treatment
approach. The advent of lymphotropic nanoparticleenhanced imaging may prove very useful for surgeons
in determining the extent of lymphadenectomy and
pancreaticoduodenectomy. Pancreatic lymphatics also
play role in pancreatitis as lymphatic blockage may
lead to increased severity, poorer prognosis, and
recurrences with regards to chronic pancreatitis.
ACKNOWLEDGMENTS
The authors thank Jessica Holland, Medical Illustrator in the Department of Anatomical Sciences, St
Georges University, Grenada, West Indies, for the creation of her illustrations used in this publication. The
authors also gratefully thank the individuals who
donated their bodies to the Department of Anatomy.
This article was made possible by the selfless gift from
donor cadaver patients.
REFERENCES
Adams RB, Allen PJ. 2009. Surgical treatment of resectable and borderline resectable pancreatic cancer: Expert consensus statement by Evans et al. Ann Surg Oncol 16:1745–1750.
Akahoshi K, Misawa T, Fujishima H, Chijiiwa Y, Nawata H. 1992.
Regional lymph node metastasis in gastric cancer: Evaluation
with endoscopic US. Radiology 182:559–564.
Akahoshi K, Chijiiwa Y, Nakano I, Nawata H, Ogawa Y, Tanaka M,
Nagai E, Tsuneyoshi M. 1998. Diagnosis and staging of pancreatic cancer by endoscopic ultrasound. Br J Radiol 71:492–496.
Anderson MD, Schiller WR. 1968. Microcirculatory dynamics in the
normal and inflamed pancreas. Am J Surg 115:118–127.
Badger SA, Brant JL, Jones C, McClements J, Loughrey MB, Taylor
MA, Diamond T, McKie LD. 2010. The role of surgery for pancreatic cancer: A 12-year review of patient outcome. Ulster Med J
79:70–75.
Bartels P. 1907. Ueber die lymphage faesse des pankreas. III. Die
€ sen des pankreas beim menschen. Arch F Anat
regionaeren dru
Entw 267–279.
Baumel H, Huguier M, Manderscheid JC, Fabre JM, Houry S, Fagot H.
1994. Results of resection for cancer of the exocrine pancreas: A
study from the French Association of Surgery. Br J Surg 81:102–107.
9
Beger HG, Rau B, Gansauge F, Porch B, Link KH. 2003. Treatment of
pancreatic cancer: Challenge of the facts. World J Surg 27:1075–
1084.
Borghi F, Gattolin A, Garbossa D, Bogliatto F, Garavoglia M, Levi AC.
1998. Embryologic bases of extended radical resection in pancreatic cancer. Arch Surg 133:297–301.
Cameron JL, Riall TS, Coleman J, Belcher KA. 2006. One thousand
consecutive pancreaticoduodenectomies. Ann Surg 244:10–15.
Cubilla AL, Fortner J, Fitzgerald PJ. 1978. Lymph node involvement
in carcinoma of the head of the pancreas area. Cancer 41:880–
887.
Deki H, Sato T. 1988. An anatomic study of the peripancreatic lymphatics. Surg Radiol Anat 10:121–135.
DeWitt J, Devereaux B, Chriswell M, McGreevy K, Howard T,
Imperiale TF, Ciaccia D, Lane KA, Maglinte D, Kopecky K, LeBlanc
J, McHenry L, Madura J, Aisen A, Cramer H, Cummings O,
Sherman S. 2004. Comparison of endoscopic ultrasonography
and multidetector computed tomography for detecting and staging pancreatic cancer. Ann Intern Med 141:753–763.
Drake RL, Vogl AW, Mitchell AWM. 2010. Gray’s anatomy for students, second edition. Philadelphia: Churchill Livingstone. p 31–
32.
Dreiling DA. 1970. The lymphatics, pancreatic ascites, and pancreatic inflammatory disease. A new therapy for pancreatitis. Am J
Gastroenterol 53:119–131.
Dumont AE, Doubilet H, Mulholland JH. 1960. Lymphatic pathway of
pancreatic secretion in man. Ann Surg 152:403–409.
Dumont AE, Martelli AB. 1968. Pathogenesis of pancreatic edema
following exocrine duct obstruction. Ann Surg 168:302–309.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. 2010.
AJCC Cancer Staging Manual. 7th Ed. New York: Springer-Verlag,
p 117–26.
Evans BP, Ochsner A. 1954. The gross anatomy of the lymphatics of
the human pancreas. Surgery 36:177–191.
Farnell MB, Pearson RK, Sarr MG, DiMagno EP, Burgart LJ, Dahl TR,
Foster N, Sargent DJ, Pancreas Cancer Working Group. 2005. A
prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma.
Surgery 138:618–630.
Farnell MB, Aranha GV, Nimura Y, Michelassi F. 2008. The role of
extended lymphadenectomy for adenocarcinoma of the head of
the pancreas: Strength of the evidence. J Gastrointest Surg 12:
651–6.
Fischer JE. (ed.) 2007. Mastery of surgery volume two. Part VII: The
Gastrointestinal Tract. 5th Ed. Philadelphia: Lippincott Williams &
Wilkins. p 1237–1240.
Freeny PC, Marks WM, Ryan JA, Traverso LW. 1988. Pancreatic ductal adenocarcinoma: Diagnosis and staging with dynamic CT.
Radiology 166:125–133.
Fritscher-Ravens A. 2004. Endoscopic ultrasound and neuroendocrine tumours of the pancreas. JOP 5:273–281.
Geer RJ, Brennan MF. 1993. Prognostic indicators for survival after
resection of pancreatic adenocarcinoma. Am J Surg 165:68–73.
Gray JH. 1937. The lymphatics of the stomach. J Anat 71:492–496.
h A, Farkas G, Levy P, Arvanitakis C, Lankisch
Gullo L, Migliori M, Ola
P, Beger H. 2002. Acute pancreatitis in five European countries:
Etiology and mortality. Pancreas 24:223–227.
Hamada S, Akahoshi K, Chijiiwa Y, Nawata H, Sasaki I. 1997. Relationship between histological type and endosonographic detection of regional lymph node metastasis in gastric cancer. Br J
Radiol 70:697–702.
€ nninen, Amthauer H, Hosten N, Ricke J, Bo
€ hmig M,
Lopez Ha
Langrehr J, Hintze R, Neuhaus P, Wiedenmann B, Rosewicz S,
Felix R. 2002. Prospective evaluation of pancreatic tumors: Accuracy of MR imaging with MR cholangiopancreatography and MR
angiography. Radiology 224:34–41.
Hedgire SS, Mino-Kenudson M, Elmi A, Thayer S, Fernandez-Del
Castillo C, Harisinghani MG. 2014. Enhanced primary tumor
delineation in pancreatic adenocarcinoma using ultrasmall super
paramagnetic iron oxide nanoparticle-ferumoxytol: An initial
10
Cesmebasi et al.
experience with histopathologic correlation. Int J Nanomedicine
9: 1891–1896.
Hirai I, Murakami G, Kimura W, Nara T, Dodo Y. 2001. Long descending lymphatic pathway from the pancreaticoduodenal region to
the para-aortic nodes: Its laterality and topographical relationship with the celiac plexus. Okajimas Folia Anat Jpn 77:189–199.
IARC Working Group on the Evaluation of Carcinogenic Risks to
Humans. 2004. Tobacco smoke and involuntary smoking. IARC
Monogr Eval Carcinog Risks Hum 83: 1–1438.
Ishikawa O, Ohhigashi H, Sasaki Y, Kabuto T, Fukuda I, Furukawa H,
Imaoka S, Iwanaga T. 1988. Practical usefulness of lymphatic
and connective tissue clearance for the carcinoma of the pancreas head. Ann Surg 208:215–220.
Japan Pancreas Society. 2003. Classification of Pancreatic Carcinoma. 2nd English Ed. Tokyo: Kanehara.
Jensen EH, Borja-Cacho D, Al-Refaie WB, Vickers SM. 2012. Exocrine pancreas. In: Townsend CM, Beauchamp RD, Evers BM,
Mattox KL, editors. Sabiston Textbook of Surgery. 19th Ed. Philadelphia, PA: Saunders, p 1515–1547.
Kayahara M, Nagakawa T, Kobayashi H, Mori K, Nakano T, Kadoya N,
Ohta T, Ueno K, Miyazaki I. 1992. Lymphatic flow in carcinoma of
the head of the pancreas. Cancer 70:2061–2066.
€ ninger J, Wente MN, Mu
€ ller MW, Gutt CN, Friess H, Bu
€ chler MW.
Ko
2007. Surgical palliation in patients with pancreatic cancer. Langenbecks Arch Surg 392:13–21.
Kuhlmann KFD, De Castro SMM, Wesseling JG, ten Kate FJW,
Offerhaus GJA, Busch ORC, van Gulik TM, Obertop H, Gouma DJ.
2004. Surgical treatment of pancreatic adenocarcinoma: Actual
survival and prognostic factors in 343 patients. Eur J Cancer 40:
549–558.
Lockhart AC, Rothenberg ML, Berlin JD. 2005. Treatment for pancreatic cancer: Current therapy and continued progress. Gastroenterology 128:1642–1654.
€ chler MW. 2008. Surgical treatment of
Loos M, Kleeff J, Friess H, Bu
pancreatic cancer. Ann N Y Acad Sci 1138:169–180.
Manabe T, Ohshio G, Baba N, Miyashita T, Asano N, Tamura K,
Yamaki K, Nonaka A, Tobe T. 1989. Radical pancreatectomy for
ductal cell carcinoma of the head of the pancreas. Cancer 64:
1132–1137.
McDermott S, Thayer SP, Fernandez-Del Castillo C, Mino-Kenudson
M, Weissleder R, Harisinghani MG. 2013. Accurate prediction of
nodal status in preoperative patients with pancreatic ductal adenocarcinoma using next-gen nanoparticle. Transl Oncol 6: 670–
675.
€ chler MW, Friess H.
Michalski CW, Kleeff J, Wente MN, Diener MK, Bu
2007a. Systematic review and meta-analysis of standard and
extended lymphadenectomy in pancreaticoduodenectomy for
pancreatic cancer. Br J Surg 94:265–273.
€ chler MW. 2007b. Surgery insight: Surgical
Michalski CW, Weitz J, Bu
management of pancreatic cancer. Nat Clin Pract Oncol 4:526–
535.
Michaud DS. 2004. Epidemiology of pancreatic cancer. Minerva Chir
59:99–111.
Miyazaki I. 1989. Significance of extensive surgery in pancreatic
cancer. Gan To Kagaku Ryoho 16:1064–1069.
Moore KL, Dalley AF, Agur AMR. 2010. Clinically Oriented Anatomy.
6th Ed. Abdomen. Baltimore: Lippincott Williams & Wilkins. p 267.
Moore KL, Persaud TVN. 2008. Before we are born—Essentials of
embryology and birth defects. The Cardiovascular System. 7th
Ed. Philadelphia: Saunders. p 144, 219.
Moriya T, Kimura W, Hirai I, Mizutani M, Ma J, Kamiga M, Fuse A.
2006. Nodal involvement as an indicator of postoperative liver
metastasis in carcinoma of the papilla of Vater. J Hepatobiliary
Pancreat Surg 13:549–555.
€ ller MF, Meyenberger C, Bertschinger P, Schaer R, Marincek B.
Mu
1994. Pancreatic tumors: Evaluation with endoscopic US, CT, and
MR imaging. Radiology 190:745–751.
Nakagohri T, Kinoshita T, Konishi M, Takahashi S, Gotohda N. 2006.
Nodal involvement is strongest predictor of poor survival in
patients with invasive adenocarcinoma of the head of the pancreas. Hepatogastroenterology 53:447–451.
Nakao A, Ichihara T, Nonami T, Harada A, Koshikawa A, Nakashima
N, Nagura H, Takagi H. 1989. Clinicohistopathologic and immunohistochemical studies of intrapancreatic development of carcinoma of the head of the pancreas. Ann Surg 209:181–187.
€ chler MW. (eds.) 2010.
Neoptolemos JP, Urrutia R, Abbruzzese JL, Bu
Pancreatic cancer volume 2. New York: Springer Science1Business Media, LLC. p 1035–1050.
O’Morchoe CC. 1997. Lymphatic system of the pancreas. Microsc
Res Tech 37:456–477.
ke
te
F,
Palazzo L, Roseau G, Gayet B, Vilgrain V, Belghiti J, Fe
Paolaggi JA. 1993. Endoscopic ultrasonography in the diagnosis
and staging of pancreatic adenocarcinoma. Results of a prospective study with comparison to ultrasonography and CT scan.
Endoscopy 25:143–150.
Papp M, Makara GB, Folly G. 1975. Impeded interstitial fluid movement: A factor in pancreatic oedema. Lymphology 8:148–153.
Parkin DM, Bray F, Ferlay J, Pisani P. 2005. Global cancer statistics,
2002. CA Cancer J Clin 55:74–108.
Pavlidis TE, Pavlidis ET, Sakantamis AK. 2011. Current opinion on
lymphadenectomy in pancreatic cancer surgery. Hepatobiliary
Pancreat Dis Int 10:21–25.
Pedrazzoli S, DiCarlo V, Dionigi R, Mosca F, Pederzoli P, Pasquali C,
€ ppel G, Dhaene K, Michelassi F. 1998. Standard versus
Klo
extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the
head of the pancreas: A multicenter, prospective, randomized
study. Lymphadenectomy study group. Ann Surg 228:508–517.
Pissas A. 1984. Anatomoclinical and anatomosurgical essay on the
lymphatic circulation of the pancreas. Surg Radiol Anat 6:255–
280.
Regoli M, Bertelli E, Orazioli D, Fonzi L, Bastianini A. 2001. Pancreatic lymphatic system in rodents. Anat Rec 263:155–160.
Reynolds BM. 1970. Observations of subcapsular lymphatics in normal and diseased human pancreas. Ann Surg 171:559–566.
Riediger H, Keck T, Wellner U, zur Hausen A, Adam U, Hopt UT,
Makowiec F. 2009. The lymph node ratio is the strongest prognostic factor after resection of pancreatic cancer. J Gastrointest
Surg 13:1337–1344.
Rouvière H. 1938. Anatomy of the human lymphatic system. Lymphatics of the pancreas. Trans. by Tobias, MJ. Ann Arbor:
Edwards Brothers, Inc. p 203–205.
Saif MW. 2008. Is there a standard of care for the management of
advanced pancreatic cancer?. Highlights from the Gastrointestinal Cancers Symposium. Orlando, FL, USA. January 25–27,
2008. JOP 9:91–98.
Sakamoto H, Kitano M, Kamata K, El-Masry M, Kudo M. 2010. Diagnosis of pancreatic tumors by endoscopic ultrasonography. World
J Radiol 2:122–134.
Samra JS, Gananadha S, Hugh TJ. 2008. Surgical management of
carcinoma of the head of pancreas: Extended lymphadenectomy
or modified en bloc resection? ANZ J Surg 78:228–236.
Sappey MPC. 1874. Anatomie, physiologie, pathologie des vaisseaux
es chez l’homme et les verte
bres. Paris:
lymphatiques considere
A. DeLahaye and E. Lecrosnier.
Schwarz RE, Smith DD. 2006. Extent of lymph node retrieval and
pancreatic cancer survival: Information from a large US population database. Ann Surg Oncol 13:1189–1200.
Seigel R, Naishadham D, Jemal A. 2013. Cancer statistics, 2013. CA
Cancer J Clin 63:11–30.
Silverman DT, Dunn J, Hoover R, Schiffman M, Lillemoe KD,
Schoenberg JB, Brown LM, Greenberg RS, Hayes RB, Swanson
GM, Wacholder S, Schwartz AG, Liff JM, Pottern LM. 1994. Cigarette smoking and pancreas cancer: A case-control study based
on direct interviews. J Natl Cancer Inst 86:1510–1516.
Silverman DT, Schiffman M, Everhart J, Goldstein A, Lillemoe KD,
Swanson GM, Schwartz AG, Brown LM, Greenberg RS,
Schoenberg JB, Pottern LM, Hoover RN, Fraumeni JF Jr. 1999.
Diabetes mellitus, other medical conditions and familial history
of cancer as risk factors for pancreatic cancer. Br J Cancer 80:
1830–1837.
The Surgical Anatomy of the Lymphatic System of the Pancreas
Skandalakis JE, Gray SW, Rowe JS, Skandalakis LJ. 1979. Anatomical
complications of pancreatic surgery. Contemp Surg 15: 17–40.
Skandalakis JE, Gray SW. (eds.) 1994. Embryology for surgeons. 2nd
Ed. Pancreas. Baltimore: Williams & Wilkins. p 366, 397–399.
Skandalakis JE. (ed.) 2004. Surgical Anatomy: The Embryologic
and Anatomic Basis of Modern Surgery—Volume 2. Pancreas.
Athens: PMP (Paschalidis Medical Publications, Ltd.). p 736,
1191–1194.
Sobin L, Gospodarowicz M, Wittekind C. (eds.) 2010. UICC TNM
Classification of Malignant Tumors. 7th Ed. Oxford: Blackwell
Publishing. p 132–135.
Sohn TA, Yeo CJ, Cameron JL, Pitt HA, Lillemoe KD. 2000. Do preoperative biliary stents increase post pancreaticoduodenectomy
complications? J Gastrointest Surg 4:258–267.
Standring S. (ed.) 2008. Gray’s Anatomy. 40th Ed. Pancreas.
New York: Elsevier Churchill Livingstone. p 942, 1077, 1183–
1187.
Takamori H, Hiraoka T, Kanemitsu K, Tsuji T, Tanaka H, Chikamoto
A, Horino K, Beppu T, Hirota M, Baba H. 2008. Long-term outcomes of extended radical resection combined with intraoperative radiation therapy for pancreatic cancer. J Hepatobiliary
Pancreat Surg 15:603–607.
Tan HP, Smith J, Garberoglio CA. 1996. Pancreatic adenocarcinoma:
An update. J Am Coll Surg 183:164–184.
Tio TL, Tytgat GNJ, Cikot RJLM, Houthoff HJ, Sars PRA. 1990. Ampullopancreatic carcinoma: Preoperative TNM classification with
endosonography. Radiology 175:455–461.
Tio TL, Sie LH, Kallimanis G, Luiken GJHM, Kimmings AN, Huibregste
K, Tytgat GN. 1996. Staging of ampullary and pancreatic carcinoma: Comparison between endosonography and surgery. Gastrointest Endosc 44:706–713.
11
Tokunaga M, Ohyama S, Hiki N, Fukunaga T, Yamada K, Sano T,
Yamaguchi T. 2009. Investigation of the lymphatic stream of the
stomach in gastric cancer with solitary lymph node metastasis.
World J Surg 33:1235–1239.
Ungeheuer A, Liebermann-Meffert D. 1990. An anatomic study of
the pancreatic lymphatics. Review of the summary and an
abridged version of the original text (in German). Langenbecks
Arch Chir 375:303–307.
Von Hoff DD, Evans DB, Hruban RH. 2005. Pancreatic cancer. Endoscopic staging: EUS, ERCP. Sudbury: Jones and Bartlett Publishers. p 181–190.
Wray CJ, Ahmad SA, Matthews JB, Lowy AM. 2005. Surgery for pancreatic cancer: Recent controversies and current practice. Gastroenterology 128:1626–1641.
Yasuda K, Mukai H, Nakajima M, Kawai K. 1993. Staging of pancreatic
carcinoma by endoscopic ultrasonography. Endoscopy 25:151–155.
Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK,
Coleman J, Abrams RA, Hruban RH. 2002. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma,
part 2: Randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg 236:355–368.
Yeo CJ, Cameron JL. 1996. Pancreatic nodal metastases: Biologic
significance and therapeutic considerations. Surg Oncol Clin
North Am 5:145–157.
Yeo CJ. 1998. Pancreatic cancer: 1998 update. J Am Coll Surg 187:
429–442.
Zacharias T, Jaeck D, Oussoultzoglou E, Neuville A, Bachellier P.
2007. Impact of lymph node involvement on long-term survival
after R0 pancreaticoduodenectomy for ductal adenocarcinoma of
the pancreas. J Gastrointest Surg 11:350–356.