Key PointsQuestion
What is the prognostic association of the lymph node (LN) ratio with overall survival after liver resection for hilar cholangiocarcinoma?
Findings
In this Italian multicenter study, an LN ratio exceeding 0.20 was the only independent prognostic factor for overall survival in N1 patients after liver resection for hilar cholangiocarcinoma. However, overall survival of N0 patients was influenced by the total number of retrieved LNs, and removal of more than 5 LNs was the minimum number of LNs required for adequate staging.
Meaning
The LN ratio was an accurate prognostic factor after liver resection for hilar cholangiocarcinoma, but it was influenced by the total number of retrieved LNs.
Importance
The prognostic value of lymph node (LN) assessment after liver resection for hilar cholangiocarcinoma (HC) is still controversial, and the number of LNs required to be removed to obtain adequate staging is not well defined.
Objectives
To evaluate the LN status in patients after liver resection for HC and to clarify which prognostic factor (the number of positive LNs or the LN ratio [LNR]) was most accurate for staging and what minimum number of retrieved LNs was required for adequate staging.
Design, Setting, and Participants
Retrospective multicenter study of patients who underwent resection for HC between January 1, 1992, and December 31, 2007, at 8 hepatobiliary Italian centers. The last follow-up was assessed in July 2014.
Main Outcome and Measures
Differences in overall survival (OS) according to the LN status were analyzed. The OS results were defined as actual because all included patients completed a 5-year follow-up.
Results
One-hundred seventy-five patients with 1133 retrieved LNs were analyzed. The mean (SD) age of the cohort was 63 (10) years, and 42.9% (75 of 175) were female. The median number of LNs examined per patient was 6.5. Forty percent (70 of 175) had LN metastasis. An LNR exceeding 0.20 was associated with significantly lower 5-year OS than an LNR of 0.20 or less (10.6% vs 24.4%; odds ratio, 2.434; 95% CI, 1.020-5.810; P = .04). On multivariable analysis, the LNR was the only independent prognostic factor for OS but was influenced by the total number of retrieved LNs. The LNR was greater than 0.20 in all patients (30 of 30) with 1 to 4 retrieved LNs and in 52.5% (21 of 40) of patients with at least 5 retrieved LNs. Five-year OS in patients with 1 to 5 retrieved LNs was significantly lower than that in those with 6 to 7 retrieved LNs and those with at least 8 retrieved LNs (34.2%, 64.5%, and 62.7%, respectively; P = .047). Five-year OS did not significantly improve when the number of retrieved LNs was greater than 6. These results were confirmed in a receiver operating characteristic curve analysis performed among N0R0 patients, in whom 5 retrieved LNs was the most accurate cutoff to predict 5-year actual OS (area under the curve, 0.624; P = .004).
Conclusions and Relevance
An LNR exceeding 0.20 was the only independent prognostic factor for OS in N1 patients after liver resection for HC. However, the LNR was influenced by the total number of retrieved LNs, and removal of more than 5 LNs was the minimum number of LNs required for adequate staging.
Lymph node (LN) metastasis is one of the strongest prognostic factors associated with survival in several gastrointestinal tumors.1-3 Recently, particular interest has focused on the LN status by evaluating more than just LN positivity, including the number of positive LNs and the LN ratio (LNR), which is the number of positive LNs divided by the total number of harvested nodes. Several articles have shown that use of the LNR allowed investigators to better stratify the prognosis in patients with LN metastasis after resection of malignant neoplasms of the gastrointestinal tract.4-7 With respect to hilar cholangiocarcinoma (HC), negative resection margins and presence of LN metastasis represent the most significant independent prognostic factors.8-11 However, debate exists about whether the most accurate prognostic factor in N1 patients is the number of positive LNs or the LNR.12-16 Furthermore, lymphadenectomy has been shown to be beneficial for several gastrointestinal tumors.17,18 However, the prognostic value of LN assessment for HC is still controversial,19 and the number of nodes required to be removed to obtain adequate staging is not well defined.11,20,21
The objective of this Italian multicenter study was to evaluate the LN status in a large cohort of patients after liver resection for HC with a minimum follow-up of 5 years. We also aimed to clarify which prognostic factor (the number of positive LNs or the LNR) was most accurate for staging and what minimum number of retrieved LNs was required for adequate staging.
Data were collected from 8 hepatobiliary Italian centers. These centers were members of the Italian chapter of the International Hepato-Pancreato-Biliary Association. The study is a retrospective analysis that collected pathological data available in each center for resected patients. Patients did not undergo further examinations for this study. For this reason, ethical committee approval was waived.
The study included only patients who underwent major hepatectomy combined with resection of the main biliary confluence and regional lymphadenectomy for histologically proven HC between January 1, 1992, and December 31, 2007. Patients resected for intrahepatic cholangiocarcinoma involving the hepatic hilum were excluded.
Liver resections were defined according to International Hepato-Pancreato-Biliary Association terminology.22 Resections of 3 or more segments were classified as major hepatectomies. The extent of bile duct involvement was defined according to the classification by Bismuth and Corlette.23 Preoperative biliary drainage was usually performed in patients with jaundice.
Portal vein resection was not systematically performed according to the no-touch technique described by Neuhaus et al.24 All vascular resections were performed only when the portal vein or the hepatic artery could not be freed from the tumor during dissection of the hepatic pedicle.
Pathological tumor staging was based on the TNM classification of the sixth edition of the International Union Against Cancer25 staging system. Pathological data included histologic type (sclerosing or papillary), tumor size, grade, presence of perineural invasion, radicality of resection (biliary margin status), caudate lobe invasion of biliary ducts, and LN involvement. Data regarding LN metastasis were obtained from pathology reports. One section was usually cut from each LN, stained with hematoxylin-eosin, and examined for metastasis.
All patients underwent regional lymphadenectomy around the hepatic pedicle, including hilar, pericholedochal, cystic duct, hepatic artery, periportal, right celiac, and superior retropancreatic LN groups. The total LN count (TLNC) was defined as the total number of LNs retrieved in each patient.
Differences between subgroups were tested using the Pearson χ2 test. Statistical significance was defined as P < .05. Overall survival (OS) was defined as the time between the date of liver resection and the date of death or the last follow-up. In this study, the last follow-up was assessed in July 2014. All patients analyzed in the study had at least 5 years of follow-up. The primary outcome was 5-year actual OS, defined as the number of patients alive 5 years after liver resection. The Kaplan-Meier method was used to analyze actual OS. Differences between subgroups in OS were tested with the log-rank test. A Cox proportional hazards regression model was used for multivariable analysis. Results of these models were expressed as odds ratios with 95% CIs. Survival analyses were performed using different LNR cutoff values to identify which values had a statistically significant association with outcomes. To define the optimal cutoff point in the number of LNs required to be removed for adequate staging, the association of the TLNC among N0R0 patients with 5-year actual OS was tested in a receiver operating characteristic (ROC) curve analysis. The ROC curve coordinates were used to define and plot the probability of 5-year actual OS according to the TLNC removed and examined. The area under the curve with 95% CIs was reported. Statistical analysis was performed using a software program (SPSS for Windows, version 19; SPSS Inc).
Between January 1, 1992, and December 31, 2007, a total of 194 patients underwent major hepatectomy combined with resection of the main biliary confluence and regional lymphadenectomy for HC at 8 hebatobiliary Italian centers. Of the patients who underwent resection, 19 (9.8%) died during the postoperative course and were excluded from the study. The remaining 175 patients were enrolled in the study (Table 1). Right-sided hepatectomy was performed in 76 patients (43.4%), left-sided hepatectomy in 96 patients (54.9%), and mesohepatectomy in 3 patients (1.7%). Preoperative biliary drainage was performed in 111 patients (63.4%), by percutaneous approach in 64 patients and by endoscopic approach in 47 patients. The rate of preoperative biliary drainage was significantly higher before right-sided hepatectomies (55 of 76 [72.4%]) than before left-sided hepatectomies (55 of 96 [57.3%]) (P = .04). Preoperative right portal vein embolization was performed in 17 (22.4%) of the 76 right-sided hepatectomies. Among the cohort of 175, associated vascular resection with reconstruction was performed in 17 patients (9.7%), including portal vein resection in 14 patients, arterial resection in 2 patients, and resection of both in 1 patient.
Tumor characteristics for the cohort are listed in Table 1. An R0 resection was performed in 143 patients (81.7%). A total of 1133 LNs (median, 6.5 per patient; range, 1-25) were retrieved from the 175 patients. Lymph node metastases were documented in 70 patients (40%). The median number of positive LNs per patient was 2 (range, 1-10). The rate of LN involvement increased significantly according to pT stage, with 1 of 9 pT1 patients (11.1%), 8 of 34 pT2 patients (23.5%), and 59 of 129 pT3-4 patients (45.7%) having LN metastasis (P = .01) (eFigure 1 in the Supplement).
After a mean follow-up of 39.4 months (median, 30 months), 5-year actual OS was 32.1%. Seventeen percent (30 of 175) of patients were alive more than 5 years after resection, and 9 of these patients were alive after more than 10 years. Among the 30 patients, LN metastasis occurred in 10% (3 patients).
On univariate analysis, 4 factors were associated with significantly lower OS. These include LN metastasis, perineural invasion, T stage of 3 or higher, and R1 resection (Table 2). On multivariable analysis, R1 resection (odds ratio, 0.529; 95% CI, 0.330-0.849; P = .008) and LN metastasis (odds ratio, 3.085; 95% CI, 2.004-4.750; P < .001) were independent predictors of poor OS.
Association of the LN Status With Survival
Five-year OS of N1 patients was 9.0%, significantly lower than the 46.6% of N0 patients (P < .001). Association of the LNR with survival was evaluated in the 70 patients with LN metastasis. The median LNR was 0.41 (range, 0.04-1.00). An LNR exceeding 0.20 was associated with significantly lower 5-year OS than an LNR of 0.20 or less (10.6% vs 24.4%, P = .04) (Figure 1). An LNR exceeding 0.20 was the only independent predictor of poor OS on both univariate and multivariate analysis (Table 3). Of the 70 patients, 27.1% (19 patients) had an LNR of 0.20 or less, and 72.9% (51 patients) had an LNR exceeding 0.20. When the TLNC was 1 to 4, all 30 N1 patients had an LNR exceeding 0.20. When the TLNC was 5 or higher, 52.5% (21 of 40) of patients had an LNR exceeding 0.20, and the difference was statistically significant (100% vs 52.5%, P < .001) (eFigure 2 in the Supplement). The number of positive LNs (1 vs >1) did not show any association with OS (P = .27) (Table 3). The TLNC did not demonstrate any association with OS in patients with LN metastasis: 5-year OS in patients with 1 to 5 retrieved LNs was not significantly different from that in patients with 6 to 7 retrieved LNs and in patients with 8 or more retrieved LNs (10.4%, 0.0%, and 12.6%, respectively; P = .74).
Finally, association of the TLNC with OS was evaluated in the 105 patients without LN metastasis. Five-year OS in patients with 1 to 5 retrieved LNs was significantly lower than that in patients with 6 to 7 retrieved LNs and in patients with at least 8 retrieved LNs (34.2%, 64.5%, and 62.7%, respectively; P = .047) (Figure 2). Five-year OS of patients with 6 to 7 retrieved LNs was not significantly different from that of patients with 8 or more LNs retrieved (P = .24). This survival analysis showed that the optimal cutoff point in the number of LNs required to be removed for adequate staging was more than 5. This value was confirmed in the ROC curve analysis in which association of the TLNC among N0R0 patients with 5-year actual OS was tested. In this analysis, 5 retrieved LNs in N0R0 patients was the most accurate cutoff to predict 5-year actual OS (area under the curve, 0.624; P = .004).
This Italian multicenter study in 175 patients after liver resection for HC represents the largest Western series focusing on the association of LN involvement with OS. Our study confirmed that LN metastasis and ductal margin status were the strongest prognostic factors for OS after liver resection for HC. In the literature, the incidence of LN involvement in resected specimens of HC ranges from 19%9,10,21,26-29 to greater than 50%.30 In our series, 40.0% (70 of 175) of patients who underwent resection had LN metastasis, and their 5-year OS was significantly lower than that in patients without LN metastasis (9% [70 of 175] vs 46.6% [105 of 175], P < .001). These results are similar to those reported in the literature, whereby 5-year OS in N1 patients resected for HC is reported to range from 0% to 20%.10,13,14,21 It should be emphasized that the OS data in our study were actual data, not actuarial data, because all patients included in the analysis completed a 5-year follow-up. Seventeen percent (30 of 175) of patients were alive more than 5 years after resection. In these patients, the rate of LN metastasis was 10% (3 of 30). Traditional histologic examination by single sectioning of each LN was performed in our study. Lymph nodes were stained with hematoxylin-eosin. This technique may underestimate the rate of LN micrometastases that are identified by immunohistochemical analyses. However, association of LN micrometastasis with survival in patients resected for HC without evidence of LN metastasis by traditional histologic examination is controversial. In a study by Tojima et al,31 the rate of LN micrometastasis in N0 patients was 24.4%, but it had no survival effect.
Some prognostic factors have been shown to better stratify the prognosis in N1 patients resected for HC, including the LNR12,14,16,19 and the number of positive LNs.16,21 The LNR may predict the effect of multiple LN metastases in the context of the number of dissected LNs, some of which may have no tumor involvement.32 Several research groups have evaluated the association of the LNR with OS after resection for extrahepatic cholangiocarcinoma, but most studies12,15,20 included patients with various tumor types (hilar together with distal cholangiocarcinoma) that required different surgical procedures (liver resection for HC and Whipple procedure for distal cholangiocarcinoma) associated with variable prognosis. Our multicenter study focused on a unique and specific tumor entity. Patients with intrahepatic cholangiocarcinoma involving the hepatic hilum (peri-HC) were excluded to evaluate the prognostic association of the LNR in patients with similar long-term outcome. To date, few articles14,16,19,21 have focused on the prognostic effect of the LNR in patients with HC as a unique and specific tumor entity. Results of these studies are controversial, and different LNR cutoff values have been shown to significantly influence survival, ranging from 0.20 in the study by Nari et al16 to 0.25 in the study by Guglielmi et al19 to 0.37 in the study by Hakeem et al.14 Our multicenter study confirmed that the LNR is an accurate prognostic factor that allowed us to better stratify the prognosis in resected N1 patients. Indeed, patients with an LNR exceeding 0.20 had significantly lower 5-year OS than patients with an LNR of 0.20 or less (10.6% vs 24.4%, respectively; P = .04). On multivariable analysis, the LNR was the strongest prognostic factor for OS in patients with LN metastasis and was more accurate than the number of positive LNs.
The accuracy of the LNR has been evaluated in several gastrointestinal tumors and has been increasingly considered an important additional prognostic factor.4-7 It has been demonstrated that the LNR is less influenced by the number of dissected nodes.4 For this reason, patients with identical LNRs but different TLNCs will have a similar outcome. Therefore, the LNR can be considered a simple staging system with strong ability to predict outcome at different institutions with variable LN dissection procedures. However, because the accuracy of the LNR has been largely validated in several tumor types (eg, gastric, colorectal, or pancreatic tumors) but not in HC, the reason may be that the TLNC in other malignant neoplasms in the gastrointestinal tractare is often larger than those reported in HC.4-7,33 In a 2012 study by Robinson et al5 of 134 patients who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma, the median number of examined LNs was 19 (range, 7-36). With regard to gastric cancer, in a 2008 study by Persiani et al4 of 247 patients who underwent resection, the reported median number of examined LNs was 30 (range, 3-93). As shown by Aoba et al,21 the median number of harvested nodes in patients resected for HC reported in the Western literature is often small at less than 10 LNs.10,13,14,16,20 The small TLNC in HC may result in lower clinical value of the LNR. Indeed, the LNR in our study was influenced by the TLNC, with 100% (30 of 30) of patients with 1 to 4 retrieved LNs having an LNR exceeding 0.20, demonstrating that in such patients the LNR cannot be used to stratify the prognosis. When the TLNC was 5 or higher, approximately 52.5% (21 of 40) of patients had an LNR exceeding 0.20, and this difference was statistically significant (100% vs 52.5%, P < .001).
These results are similar to those reported by Aoba et al,21 whereby the LNR in patients with a TLNC of 16 or higher was significantly smaller than that in patients with a TLNC ranging between 3 and 5 or between 6 and 10. The small TLNC in patients resected for HC results in inaccurate staging of these patients, with differences in OS, and may explain why the accuracy of the LNR has not been largely validated in this type of tumor. For this reason, the required “magic number” of adequate LN dissection for conclusive LN staging in HC has been analyzed by different study groups.19 Lymphadenectomy is of course necessary in the surgical therapy for HC but only for accurate detection of N1 patients because a therapeutic effect of lymphadenectomy remains controversial.11,34 In our study, an increased number of harvested LNs in patients with LN metastasis did not show any improvement in OS, confirming that the extent of lymphadenectomy in such patients had no therapeutic value. In the seventh edition of the TNM classification,35 the minimum number of harvested nodes required for histologic examination was increased from 3 to 15, but this number does not represent normal clinical practice. Except for some Eastern series,15 the median TLNC is always less than 15 for HC.10,13,14,16,20,21 In a recent systematic review11 of the literature in almost 4000 patients resected for peri-HC, the cumulative median TLNC was 7, and a median TLNC of 15 or higher was reported in only 9% of patients. Furthermore, an increase in LN retrieval exceeding 5 showed no additional improvement in predicting survival.11 In our study, the median TLNC was 6.5 (range, 1-25). The association of the TLNC with OS was evaluated in the 105 patients without LN metastasis. Five-year OS in patients with 1 to 5 retrieved LNs was significantly lower than that in patients with 6 to 7 retrieved LNs and in patients with 8 or more retrieved LNs (34.2%, 64.5%, and 62.7%, respectively; P = .047). Five-year OS did not significantly improve when the number of retrieved LNs was greater than 6. These results were confirmed in the ROC curve analysis performed among N0R0 patients, in whom more than 5 LNs retrieved was the most accurate cutoff to predict 5-year OS.
Our Italian multicenter analysis confirmed the prognostic association of the LN status with OS after liver resection for HC. The LNR could help to better stratify OS in N1 patients. However, in patients resected for HC, the LNR was influenced by the total number of retrieved LNs, and removal of more than 5 LNs was the minimum number required to be harvested for adequate staging.
Accepted for Publication: April 25, 2016.
Corresponding Author: Francesco Ardito, MD, Hepatobiliary Surgery Unit, A. Gemelli Hospital, Catholic University of the Sacred Heart, Rome, Italy 00168 (francesco.ardito@unicatt.it).
Published Online: August 24, 2016. doi:10.1001/jamasurg.2016.1769.
Author Contributions: Dr Ardito had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Giuliante, Ardito, Giulini, Jovine, De Rose, Pinna, Nuzzo.
Acquisition of data: Ardito, Guglielmi, Aldrighetti, Ferrero, Calise, Giulini, Breccia, De Rose, Pinna.
Analysis and interpretation of data: Ardito, De Rose.
Drafting of the manuscript: Ardito, De Rose.
Critical revision of the manuscript for important intellectual content: Giuliante, Guglielmi, Aldrighetti, Ferrero, Calise, Giulini, Jovine, Breccia, De Rose, Pinna, Nuzzo.
Statistical analysis: Ardito, Breccia.
Administrative, technical, or material support: Guglielmi, Giulini, Breccia.
Study supervision: Giuliante, Ardito, Aldrighetti, Ferrero, Calise, Giulini, Jovine, De Rose, Pinna, Nuzzo.
Conflict of Interest Disclosures: None reported.
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