The high propensity for lymphatic spread in gallbladder cancer[
6,8,10,15,23] renders adequate lymphadenectomy indispensable for improving patient outcomes after resection. However, what constitutes adequate lymph node dissection for these patients remains unresolved and prompted the current study. Since the 1980s, we have routinely harvested at least the first- and second-echelon nodes (Figure ) during curative-intent resection for pT2 or more advanced gallbladder cancer. As a result, and to the best of our knowledge, we report herein the largest single-institutional series of 5-year survivors (22 patients) with nodal disease ever analyzed. The study findings also indicated that a considerable proportion of node-positive patients could benefit from regional lymphadenectomy, providing that an R0 resection is feasible, and would seem to justify continuing our policy of aggressive lymphadenectomy for gallbladder cancer.
In this study cohort, initial nodal involvement occurred primarily in the cystic duct or pericholedochal nodes (Table ). Although these node groups are widely accepted as first-echelon nodes of the gallbladder, further possible routes of lymphatic spread have been poorly defined[
6,21-23]. In 1991, an autopsy study by Ito and colleagues[
21] implicated the cholecystoretropancreatic pathway, which descends along the common bile duct into the retroportal nodes, as the main lymphatic pathway of the gallbladder. Soon after, we identified the same pathway in a dye injection study and showed the second-echelon nodes located posterosuperior to the head of the pancreas or around the hepatic vessels; the dye solution finally drained into the interaortocaval nodes near the left renal vein[
6]. In 1996, Uesaka et al[
22] reported similar findings using vital staining. These studies therefore uniformly confirmed that lymph from the gallbladder first flows in a hepatofugal direction around the common bile duct and into the first-echelon nodes, before reaching the second-echelon nodes (other than the hilar nodes), and finally the paraaortic nodes[
6,21,22]. In addition, the prevalence of nodal disease in our series was high in both the first-echelon and second-echelon node groups (other than the hilar nodes), while the other node groups were only rarely involved (Table ). Thus, the rational extent of regional lymphadenectomy for gallbladder cancer should include at least the first- and second-echelon node groups as defined in the current study (Figure ).
Despite a number of 5-year survivors with nodal disease reported in the Japanese literature[
8,10,12,13], such survivors are exceptionally rare in the Western literature[
1,2,5,24]. Since the first proposal by Glenn et al[
17] in 1954, portal lymph node dissection has been regarded as the standard lymphadenectomy procedure for localized gallbladder cancer throughout the world[
15]. However, the scope of portal lymph node dissection differs considerably among institutions. In 2005, Dixon et al[
24] from the University of Toronto described “a complete portal lymph node dissection, with thorough skeletonization of the portal structures, down to and including the suprapyloric lymph node overlying the hepatic-gastroduodenal artery junction,” while Ito and colleagues from the Memorial Sloan-Kettering Cancer Center (MSKCC) in 2011[
5] reported a portal lymphadenectomy including “the lymph nodes in the hepatoduodenal ligament and those along with the common hepatic artery.” The NCCN guidelines[
11] described the extent of portal lymphadenectomy as “porta hepatis, gastrohepatic ligament, retroduodenal.” From the above descriptions, we thus assume that the portal lymphadenectomy performed in North America may leave behind some of the second-echelon nodes, particularly the retroportal, posterior superior pancreaticoduodenal, and right celiac node groups, which were frequently involved in the current series (Table ). This may explain, in part, why portal lymph node dissection only rarely achieves 5-year survival in cases of node-positive gallbladder cancer[
1,2,5,24].
Although the AJCC staging manual (6th edition)[
25] recommended “analysis of a minimum of three lymph nodes” for accurate staging of gallbladder cancer, a recent population-based study by Coburn et al[
26] disclosed that among patients in the United States with resectable T1-T3 disease, only 5.3% had retrieval of three or more lymph nodes. In addition, a recent report from MSKCC of 122 patients who underwent a portal lymph node dissection cited a median TLNC of only 3[
5]. In contrast, TLNC was much greater (median, 19) in the current series. Insufficient lymph node retrieval with portal lymphadenectomy may also explain, in part, the poor survival of node-positive patients in the Western literature[
5,26].
Thorough dissection of the second-echelon nodes is challenging even in the hands of expert hepatobiliary surgeons. In particular, complete removal of the posterior superior pancreaticoduodenal, retroportal, and right celiac node groups mandates a meticulous technique. As described in the Materials and Methods section, there are some measures that can be taken to facilitate adequate dissection of the second-echelon nodes: first, a full Kocher maneuver (Figure ) is essential for assessing the peripancreatic nodal status; second, identification of PSPDA (Figure ) ensures that dissection of the posterior superior pancreaticoduodenal nodes has been completed; and third, exposure of the superior border of the uncinate process (Figure ) ensures complete dissection of the retroportal nodes.
In our institution, we prefer to perform bile duct resection in fit patients with pT2 or more advanced gallbladder cancer; indeed, 66 (71%) of the 93 patients who underwent an extended cholecystectomy had a bile duct resection (Table ). Although the presence of ductal involvement is an absolute indication for such an approach, controversy exists regarding bile duct resection for tumors without clinically evident ductal involvement[
27]. Our rationale for bile duct resection for tumors with no evident ductal involvement is to facilitate regional lymphadenectomy, to remove the pericholedochal lymphatic vessels and nodes simultaneously, and to remove the possible presence of microscopic ductal (periductal) involvement as suggested by Shimizu et al[
28]. Another justification is to avoid the occurrence of ischemic biliary stricture after aggressive periductal nodal dissection[
29]. The suprapancreatic segment of the extrahepatic bile duct gets its arterial blood supply mainly from ductal branches of both PSPDA (“retroduodenal artery” by Northover et al[
30]) and the right hepatic artery[
30]. As described in the Materials and Methods section, during our extended portal lymph node dissection, the PSPDA (Figure ) was often sacrificed with division of the ductal branch of the right hepatic artery. In addition, skeletonization of the bile duct may inadvertently injure the periductal arterial plexus with “the 3 o’clock and 9 o’clock arteries”[
30]. Thus, we believe that simultaneous bile duct resection is a safer option if such aggressive periductal nodal dissection is required[
29].
Indications for pancreaticoduodenectomy for gallbladder cancer include direct invasion of the pancreaticoduodenal region and evident peripancreatic (head only) nodal disease (Figure )[
10,12,15]. While the former indication is widely accepted, it seems that most Western surgeons hesitate to undertake this procedure for the purpose of lymph node dissection because they believe that peripancreatic nodal disease is beyond the scope of resection[
1,11,16,27]. Shirai et al[
12] in 1997 and Sasaki et al[
13] in 2006 independently reported the effectiveness of pancreaticoduodenectomy for selected cases of peripancreatic nodal disease. This was also suggested by the current study. In 2002, Doty et al[
14] also suggested that the addition of pancreaticoduodenectomy could result in an R0 resection by removing extensive peripancreatic nodal disease in a select group of patients. Western surgeons should therefore be more open than ever to performing pancreaticoduodenectomy for gallbladder cancer.
The main limitations of the current study revolved around the retrospective nature of the analysis and considerable variability in the degree of nodal dissection among individual patients. However, the unique nature of this study has more clearly defined the role of regional lymphadenectomy for gallbladder cancer than earlier studies, although the survival of node-positive patients remains unsatisfactory (Figure ). Since 2009, we have therefore routinely administered adjuvant chemotherapy (using gemcitabine and/or S-1 for 6-12 mo) to patients with nodal disease (especially those with multiple positive nodes) to improve survival. In addition, we now use “extended” portal lymphadenectomy for both gallbladder and bile duct cancers, with the latter also showing some success (unpublished data). Thus, it seems that “extended” portal lymph node dissection is applicable to a wide range of biliary tract malignancies.
In conclusion, gallbladder cancer first spreads to the first-echelon nodes (cystic duct or pericholedochal nodes), then to the second-echelon nodes located posterosuperior to the head of the pancreas or around the portal vein/hepatic arteries, and finally to the paraaortic nodes. The rational extent of regional lymphadenectomy for pT2 or more advanced tumors should include the first- and second-echelon node groups. Such aggressive lymphadenectomy can achieve an acceptable rate of long-term survival even in patients with nodal metastasis, provided that a potentially curative (R0) resection is feasible. The addition of pancreaticoduodenectomy may also be beneficial in selected patients with peripancreatic (head only) nodal disease. This study confirmed that regional lymphadenectomy plays a key role in radical surgery for gallbladder cancer.
