Abstract
Background/Aim: The prognostic effect of lymph node dissection (LND) in intrahepatic cholangiocarcinoma (ICC) remains unclear. The aim of this study was to reveal the clinical benefits of LND in patients with ICC after curative hepatic resections. Patients and Methods: We retrospectively analyzed 64 patients with ICC who underwent primary curative resections between June 2002 and February 2016 and evaluated the survival benefits of LND. Results: We performed LND on patients suspected to have LN metastasis before operation (23/64 cases; 35.9%). There was no significant difference in prognosis between the LND(+) group (n=22) and the LND(−) group (n=41); relapse-free survival (RFS): p=0.635 and overall survival (OS): p=0.347. Among the groups, pN0 (n=17), pN1 (n=7) and pNX (without LND or LN sampling; n=39), the survival curves of pN0 and pNX groups were similar (p=0.568). Conclusion: Special attention should be given to the indication of LND and the practice of secure operation.
Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with a typically poor prognosis (1). According to the Japanese registry compiled by the Liver Cancer Study Group of Japan, which has 18,213 newly-registered patients, approximately 94% of patients had hepatocellular carcinoma (HCC) and only 4.1 % had ICC (2), while a subsequent report revealed an increase in the incidence of ICC (3). ICC is, thus, considered a highly malignant neoplasm because it is frequently associated with lymph node (LN) involvement, intrahepatic metastasis and peritoneal dissemination (4). Although surgery has been considered a potentially curative treatment for ICC, high recurrence rates and poor adjuvant therapies have resulted in a 5-year survival for resectable ICC of 48%, with median survival ranging from 30 to 43 months (5, 6).
Although many local and regional treatment modalities are available for patients with ICC, most modalities, including local ablation and hepatic intra-arterial therapies, have marginal therapeutic roles as a result of inherent limitations and/or lack of a durable tumor response (7). Surgical resection has only been shown to improve long-term survival for patients with ICC at present (8).
In clinicopathological factors, LN metastasis is a very strong poor prognostic factor (9, 10); however, the indications and roles of lymph node dissection (LND) in patients with ICC are still subject to discussion. Although some consider that the standard surgical procedure for ICC is a hepatectomy combined with extensive LND, not all centers support routine LND (11). In addition, there are not clear guidelines on LND, including the standard route and extent of LND. Some reports have shown LND for ICC is not effective in patients' prognosis with ICC (4, 12). However, other reports have shown that regional LND should be considered a standard part of surgical therapy for patients undergoing resection of ICC (13). Therefore, the aim of the current study was to evaluate the clinical benefits of LND in patients with ICC after curative resections.
Patients and Methods
Patients. We performed a retrospective analysis of consecutive patients to examine the surgical outcomes of patients with ICC who underwent curative resections. Between June 2002 and February 2016, 78 patients underwent laparotomy for ICC at Kumamoto University Hospital, Kumamoto, Japan. Of these 78 patients, 64 underwent primary curative resections, which resulted in pathological curative resection (pR0). Among 14 excluded patients, 10 patients were surgeries for recurrence and 4 were non-curative resections. Therefore, we included the 64 patients with primary curative resections and analyzed the clinical benefits of LND. Mortality case was excluded when we analyzed survival rate. The median follow-up time for censored patients was 37 months. We performed 5-fluorouracil-based adjuvant chemotherapy to the patients with lymph node metastasis or vascular invasion if patients' performance status was 0 or 1. Written informed consent was obtained from each patient. The Institutional Review Board approved this study.
Clinicopathological features in 64 patients with ICC.
Indications for lymph node dissection. We performed LND in patients who were suspected to have LN metastasis in preoperative computed tomography (CT) scan or positron emission tomography (PET) or macroscopic findings during the operations (14). We suspected LN metastasis if LN enlargement was detected in CT scan or fluorodeoxyglucose accumulated at LN in PET. In such cases, we mainly resected LN along the common hepatic artery (#8 LN) and LN in the hepatoduodenal ligament (#12 LN) and, occasionally, added on some LN, such as LN on the right cardiac (#1 LN), LN along the lesser curvature (#3 LN), LN along the left gastric artery (#7 LN) and LN on the posterior surface of the pancreatic head (#13 LN). Sampling of LN was not included in LND.
Overall survival of all 63 patients with intrahepatic cholangiocarcinoma (ICC) who underwent curative resections. The 5-year-survival rate was 63.9%.
Statistical analysis. Comparison between the two groups was examined by the Student's t-tests for continuous variables and χ2 tests or Fisher's exact tests for nominal variables. The continuous variables in Table I show mean±standard deviation (SD). The overall survival rate (OS) and relapse-free survival rate (RFS) were calculated using the Kaplan-Meier method from the date of surgery to date of last follow-up. The comparisons of survival curves were performed using the log-rank test. Significance levels were set at p<0.05. All tests were two-sided. All statistical analyses were performed using JMP software (Version 12; SAS Institute, Cary, NC, USA).
Results
Clinicopathological characteristics and perioperative outcomes. Table I shows the clinicopathological characteristics and perioperative outcomes of 64 patients with pathologically-confirmed ICC who were included in the study. Twenty-three patients (35.9%) underwent LND. In pathological nodal (pN) status, 39 (60.9%) patients who did not have LND or who had LN sampling were described as pNX (n=39, 60.9%). There were no differences in background characteristics between the two groups, such as gender, age and tumor marker. In tumor-related and pathological factors, pN status was significantly different (p<0.0001). In the LND (+) group, the positive rate of LN metastasis was 26.1%. On the other hand, in the LND (−) group, two patients (3.1%) were positive for LN metastasis. These two patients underwent LN sampling without frozen pathology and diagnosed as positive for LN metastasis in hematoxylin & eosin staining after the operations. In perioperative data, operating time was significantly longer in the LND(+) group (p<0.0001). Five patients were subjected to bile duct resections in the LND(+) group. The complication rate, which was defined as Clavien-Dindo classification III or more, was significantly higher in the LND (+) group (p=0.022) (15).
(A) Relapse-free survival (RFS) and (B) overall survival (OS) in patients with intrahepatic cholangiocarcinoma (ICC) who underwent curative resections with or without lymph node dissection (LND). There is no significant difference between the two groups in RFS (p=0.635) and OS (p=0.347), respectively.
The survival benefits of LND. Figure 1 shows the overall survival curve of all patients in current study, with 1-, 3- and 5-year-survival rates being 89.5%, 79.2% and 63.9%, respectively. Figure 2 demonstrates no significant differences on OS and RFS between the LND(+) and the LND(−) groups (RFS: p=0.635, OS: p=0.347). RFS at 5 years was 28.1% in the LND(+) group and 30.9% in the LND(−) group. OS at 5 years was 62.6% in the LND(+) group and 63.4% in the LND(−) group. Although pN1 group had significantly poor prognosis than pN0 and pNX group (p=0.035), pN0 and pNX groups had similar prognoses (p=0.568) (Figure 3). The clinical courses of 8 patients in the pN1 group are summarized in Table II. Two patients (25%) had a long-term survival without recurrence after hepatectomies with LND.
Discussion
In the present study, we report our experience with ICC as single-institution study and demonstrate that LND may not improve RFS and OS in 63 patients with ICC after curative hepatic resections. We also report that the patients who were diagnosed as pNX or pN0 had similar prognosis.
Overall survival in each of pN stage (pN0, pN1 and pNX) after curative resections. Patients with pN1 had significantly poor prognosis than pN0 and pNX patients (p=0.035).
LN metastases have been reported as a poor prognostic factor for patients with ICC (10). Weber et al. discussed the role of LND concluding that LND should be considered a standard part of surgical therapy for patients undergoing resection of ICC (13). On the other hand, Shimada et al. concluded that LND in ICC was not suitable to improve patients' survival (4). Moreover, Morine et al. showed that prophylactic systematic LND did not affect surgical outcomes in ICC without LN metastasis (16). In the present study, LND did not tend to prolong RFS and OS. We also showed that patients, who did not undergo LND and those without LN metastasis who did, had similar survival outcomes (p=0.568) (Figure 3), thus suggesting that LND may not improve the survival in patients without LN metastasis. In addition, recurrence rate was statistically similar between the three groups (pN0; 58.8%, pN1; 71.4%, pNX; 43.6%, p=0.288). On the other hand, two patients who underwent LND and had LN metastasis had a good prognosis after hepatectomies. Therefore, hepatectomies with LND may be effective and approved for patients who were suspected to have LN metastasis.
Patients' characteristics, perioperative and prognosis data with LN metastasis.
However, we have some concerns about avoiding LND. First, the difficulty of diagnosis of LN metastasis has to be taken into account. Adachi et al. mentioned the difficulties of diagnosis by CT or PET and reported that inflammation, such as cholangitis or necrosis of the original tumor, causes LN enlargement (14). Second, the diagnosis of LN metastasis is affected by the location of LN sampling. It is important to note which LNs are being resected. In the present study, positive LN status was seen in five patients (62.5%) with #12 LN metastasis, a patient (12.5%) with #13 LN metastasis, a patient with #8 LN and #12 LN metastasis, as well as a patient (12.5%) with #1 LN metastasis (Table II). In these eight patients, two patients (25%) did not undergo LND. Six of eight patients had #12 LN metastasis. Li et al. showed that the LN in hepatoduodenal ligament was the most common LN metastasis site in 104 patients with ICC (17). Therefore, these results suggested that the routine LN sampling of #12 LN was useful to detect whether LN metastasis was present or not.
We also demonstrated that patients with LND had longer operating time, more blood loss and more postoperative complications. Basically, postoperative complications are one of poor prognostic factors in cancer therapy (18, 19). Some reports show that postoperative complications can lead to an immune modulation, a decrease in tumor surveillance and, possibly, an increased risk of disease recurrence and disease-specific death (20, 21). Therefore, we should pay attention as to perform hepatectomies without postoperative complications in order to improve patients' prognosis by avoidance of routine LND.
This study has several limitations. First, this study was performed as a retrospective single-institution study with small number of patients. Second, the policy of LN sampling and LND was not consistent; for example, #1 and #3 LN in left-sided ICC and #8 LN in right-sided ICC (22, 4, 12). Therefore, some larger and prospective study with a consistent policy for LND is necessary to reveal the influence of LND in ICC on clinical benefits.
In conclusion, we should pay attention to the indication of LND in patients with ICC and perform safe operation without postoperative complications to improve patient's prognosis.
Footnotes
Conflicts of Interest
The Authors declare that they have no conflict of interest and this study was not funded.
- Received March 10, 2017.
- Revision received March 19, 2017.
- Accepted March 20, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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