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. 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