Studies have demonstrated that the presence or absence of lymph node metastasis is an important prognostic factor in patients with curatively resected GBC[5,13,18-20
]. Patients with lymph node metastasis have significantly worse survival than those with negative nodes[1,21
]. With the increasing safety of hepatic and pancreatic surgery, various radical procedures have been advocated to improve the curative outcome for advanced GBC[22-24
]. Recent data also suggest that aggressive resection may improve long-term survival, even in patients with advanced stage disease[3,12,25
It had been confirmed that the main lymphatic pathway of the gallbladder descends along the common bile duct and into the retroportal nodes, then to the posterosuperior of the head of the pancreas or around the hepatic artery, and finally to the paraaortic nodes near the left renal vein[26-28
]. Based on these detailed anatomical studies, it has been suggested that lymphatic metastasis from GBC spreads widely through the hepatoduodenal ligament towards the peripancreatic region and beyond. In this study, initial nodal involvement occurred primarily in the cystic duct or pericholedochal nodes, followed by periportal and hepatic artery nodes. Posterosuperior pancreaticoduodenal and right celiac lymph nodes were involved in 16.22% of node-positive patients and were classified as N2 disease, according to the 7th
edition of AJCC classification. However, we observed that the categorization of patients as having N2 disease did not adversely influence DSS as compared to those with N1 disease. Hence, we believe that even patients with N2 lymph node metastasis can achieve an ideal survival if radical lymphadenectomy is performed. An addition of pancreaticoduodenectomy could result in an R0 resection by removing extensive peripancreatic nodal disease in a select group of patients[22,23,29
]. Furthermore, Murakami et al[30
] suggested that it is lymph node metastasis but not para-aortic lymph node metastasis that is associated independently with longer survival by multivariate analysis. In this study, six patients were treated with pancreaticoduodenectomy and two patients survived more than five years.
The high propensity for lymphatic spread in GBC renders adequate lymphadenectomy indispensable for improving patient outcomes after resection[8,19
]. However, because of the rarity of disease and low resectability rates, which limit the ability to perform large cohort studies or prospective randomized trials, the optimal extent of lymphadenectomy remains unresolved and there are no uniform evidence-based guidelines on the issue[9,10
]. Accuracy of nodal staging depends on a critical number of lymph nodes analyzed; insufficient number of nodes retrieved during surgery or examined pathologically leads to underestimation of disease stage[14
]. Although the 6th
edition of AJCC suggests a minimum of three lymph nodes to be assessed for appropriate pathologic nodal staging of gallbladder cancer, the basis of recommendation is not clear, and there are no established standards. A large population-based study on the SEER database demonstrated that of the 2835 resected patients with T1-T3 M0 GBC, only 5.3% had a lymphadenectomy of three or more lymph nodes[31
]. Also, Ito et al[14
] independently suggested that retrieval and evaluation of at least six lymph nodes improves risk stratification after resection in node-negative patients. These observations indicate that retrieval of a larger number of lymph nodes than previously practiced is warranted not only for accurately staging the nodal status, but also for improving survival due to better clearance of nodal disease[13
Although a greater number of examined nodes might improve the survival of the disease, the results of our study suggest that retrieval and evaluation of at least four nodes is perhaps optimal. Furthermore, TLNC significantly correlated with DSS in node-positive patients and allowed better prognostic substratification of these patients. For node-positive patients in this study, we can get a new cut-off value of six nodes for the number of TLNC that clearly stratifies them into 2 separate survival groups, which is more optimal than four nodes. But no definite cut-off value of TLNC could be identified for node-negative patients. Since the TLNC-survival relationship was observed only in node-positive patients and not in those node-negative patients, we believe that a higher count not only helps in stage purification but also helps improve therapeutic benefit, which is more serious in node-positive patients. These findings should heighten awareness about the importance of TLNC amongst surgeons performing lymphadenectomy for suspected node-positive patients. We believe that adequate lymphadenectomy is indispensable for improving the prognosis after radical resection in patients with GBC.
Endo et al[32
] first suggested that the PLNC is more useful in assessing nodal status than the location of positive nodes in GBC. Sakata et al[12
] additionally showed that the number, but not location, of positive nodes independently determined prognosis after resection. The burden of nodal disease (PLNC) also had an impact on prognosis; there was significantly reduced DSS observed in this study with involved nodes. The DSS progressively worsened with increasing PLNC; however, we were not able to identify any specific cut-off value. The use of PLNC as a prognostic factor might be limited by inherent bias of inadequate number of lymph nodes retrieved or histologically examined which leads to the phenomenon of “stage migration”. However, many recent studies (including this study) have reported a number of long-term survivors after resection for GBC with multiple positive lymph nodes[11,29,30,33
]. These observations indicate that regional lymph node dissection for GBC provides long term survival for selected patients with multiple positive lymph nodes, provided that R0 resection is feasible.
LNR has been shown to be an important predictor of survival for many gastrointestinal tract cancers after surgery because it is a better and reproducible method of stratifying nodal status which incorporates not only the burden and biology of disease (PLNC) but also the quality of lymphadenectomy and pathologic examination (TLNC)[34-36
]. Negi et al[16
] first found that LNR, and not PLNC, was an independent prognostic factor in their study cohort comprising 57 patients with a relatively small TLNC. Our study suggests that, along with tumor TNM staging, LNR is an independent prognostic factor and another important lymph nodal variable in patients undergoing curative resection for GBC. The prognostic impact of LNR was observed in the entire group, including the subgroup of patients with positive nodes, even though we could not find an optimal cut-off value in this study. LNR is of particular value in patients who cannot adequately be staged because of the limited number of lymph nodes evaluated. In the case of insufficient lymph node evaluation, LNR will more accurately reflect the nodal status than the number of positive nodes in GBC. Patients with high LNR after radical resection might need adjuvant chemoradiation therapy to improve their prognosis.
The strengths of our study include the reasonably sized cohort of patients managed in a single institution using a standardized treatment approach. The current study has several limitations: the retrospective nature of the analysis, the relatively small number of patients spanning a long period of time, some variability in the degree of nodal dissection, and the short follow-up time for some patients. The observations need to be confirmed in larger, especially population-based, cohort. We believe, however, that these limitations did not greatly affect the results of the study as the differences between groups were too marked to have resulted from bias. In addition, the role of TLNC and LNR in assessing the nodal status for GBC is now more clearly defined than previously, based on the current study. Our results thus provide useful information for accurately staging nodal disease, predicting prognosis after resection, and selecting candidates for adjuvant chemoradiation therapy after resection.
The results of the present study demonstrate that, rather than categorizing GBC patients based on PLNC or location of involved nodes, TLNC and LNR are more appropriate tools to stratify patients with regards to prognosis. Our data also suggest that removal and pathological examination of at least six lymph nodes can influence staging quality and disease-specific survival especially in node-positive patients. This knowledge should heighten awareness amongst surgeons about the importance of performing lymphadenectomy for suspected node-positive patients, aiming to retrieve and examine an adequate number of lymph nodes.