Clinical implications and optimal extent of lymphadenectomy for intrahepatic cholangiocarcinoma: A multicenter analysis of the therapeutic index

Abstract Aims Lymph node metastases (LNM) are associated with lethal prognosis in intrahepatic cholangiocarcinoma (ICC). Lymphadenectomy is crucial for accurate staging and hopes of possible oncological treatment. However, the therapeutic implications and optimal extent of lymphadenectomy remain contentious. Methods To clarify the prognostic value and optimal extent of lymphadenectomy, the therapeutic index (TI) for each lymph node was analyzed for 279 cases that had undergone lymphadenectomy in a multi‐institutional database. Tumor localization was divided into hilar lesions (n = 130), right peripheral lesions (n = 60), and left peripheral lesions (n = 89). In addition, the lymph node station was classified as Level 1 (LV1: hepatoduodenal ligament node), Level 2 (LV2: postpancreatic or common hepatic artery nodes), or Level 3 (LV3: gastrocardiac, left gastric artery, or celiac artery nodes). Results Lymph node metastases were confirmed in 109 patients (39%). Five‐y survival rates were 45.3% for N0 disease, 27.1% for LV1‐LNM, 22.9% for LV2‐LNM, and 7.3% for LV3‐LNM (P < 0.001). LV3‐LNM were the most frequent and earliest recurrence outcome, including multisite recurrence, followed by LV2, LV1, and N0 disease. The 5‐year TI (5year‐TI) for lymphadenectomy was 7.2 for LV1, 5.5 for LV2, and 1.9 for LV3. Regarding tumor location, hilar lesions showed 5‐year TI >5.0 in LV1 and LV2, whereas bilateral peripheral lesions showed 5‐year TI > 5.0 in LV1. Conclusion The implications and extent of lymphadenectomy for ICC appear to rely on tumor location. In the peripheral type, the benefit of lymphadenectomy would be limited and dissection beyond LV1 should be avoided, while in the hilar type, lymphadenectomy up to LV2 could be recommended.


| INTRODUC TI ON
Intrahepatic cholangiocarcinoma (ICC) is one of the primary hepatocellular carcinomas, second only to hepatocellular carcinoma in its incidence. ICC arises from the epithelial cells of either small intrahepatic ducts or large intrahepatic ducts near the bifurcation of intrahepatic ducts. 1 In both clinical situations, the pathological findings are usually classified as adenocarcinoma, although mixed hepatocellular cholangiocarcinoma also occurs, particularly in chronic liver disease. Despite its rarity, ICC is difficult to detect and treat and tends to be advanced at diagnosis.
Surgical resection is the only established option for treating ICCs, offering the best chance of cure. 2 However, because many patients with ICC have large, locally advanced tumors that require technically complex and challenging surgery, only about 20%-40% of patients with operable disease undergo surgical resection. In addition, the incidence of lymph node metastases (LNM) reportedly ranges from 17% to 62% and reflects a poor prognosis. [3][4][5][6] Despite LNM being a significant predictor of poor prognosis, the evidence of therapeutic benefit from lymph node dissection is insufficient and no consensus has been reached regarding whether lymphadenectomy should be routinely performed.
In terms of clinical implications, routine lymphadenectomy has been considered paramount for accurate staging and determination of prognosis and for guiding the postoperative treatment strategy. 2,7 Moreover, recent clinical studies have consistently shown the oncological efficacy of lymphadenectomy for ICC and have thus tended to support this approach. 8,9 However, clear evidence is lacking regarding the extent of lymphadenectomy required for accurate staging and the prognostic value of lymphadenectomy for each lymph node station. Moreover, ICCs invading the hilar structures tend to be associated with a higher incidence of LNM than peripherally located tumors. [10][11][12] Basing the extent of routine lymphadenectomy for accurate staging and treatment on tumor localization may thus be preferable.
The present study therefore aimed to investigate the survival benefit of lymphadenectomy among patients undergoing resection for ICC using a therapeutic index. We also evaluated the optimal extent of lymph node dissection for accurate staging and treatment by assessing tumor activity based on tumor localization.

Assessment of lymph node metastasis and therapeutic index of lymphadenectomy
Lymph node metastases were assessed according to "Classification of Biliary Tract Cancers established by the Japanese Society of Hepato-Biliary-Pancreatic Surgery: Third Edition." 15 Furthermore, lymph nodes were then classified into three levels from the hepatic hilum to the distal side of the liver: Level 1, hepatoduodenal ligament node; Level 2, postpancreatic head or common hepatic artery nodes; and Level 3, gastrocardiac, left gastric artery, or celiac artery nodes.
Moreover, the extent of LNM was judged from the most distal node from the hepatic hilum, with the distribution of LNM classified into a more significant number of levels. To evaluate the therapeutic value of lymphadenectomy at any nodal station, we determined the frequency of metastasis at that nodal station and calculated the cumu- Finally, the frequency of LNM was multiplied by the 2-and 5-year survival rates of patients with LNM to calculate a therapeutic index (TI) of benefit from lymphadenectomy at each station. 16 Based on these results, we recommended lymphadenectomy when the 5-year TI was significant for indices exceeding 5.0.

| RE SULTS
Overall patient background characteristics and differences between tumor locations are summarized in Table 1 In risk analysis for LNM by using patient background and tumor factor, logistic regression analysis identified "component of PI" (odds ratio [OR] 2.90, P = 0.002), "preoperative CA19-9 level ≥ 118 U/ml" (OR 6.77, P < 0.001), "serosa invasion" (OR 1.81, P = 0.043), and "moderate or poor differentiation" (OR 4.51, P = 0.001) as independent risk factors for LNM (Table S1). An overview of LNM rates for each lymph node station and the therapeutic value of lymphadenectomy is provided in Table 2. Concerning TI for the overall cohort, 2-/5-y TI by lymphadenectomy were 12.8/7.2 for Level 1, 10.7/5.5 for Level 2, and 4.8/1.9 for Level 3. Subgroup analysis revealed that 5-y TI varied between tumor locations; the 5-y TI of lymphadenectomy in the hilar lesion was 4 for Level 1, 6.6 for Level 2, and 1.7 for Level 3. Moreover, the left peripheral lesion showed TIs of 7.5 for Level 1, 4.5 for Level 2, and 2.7 for Level 3. Particularly in the left peripheral lesion, incidences of metastasis in left gastric artery nodes and gastrocardiac nodes were 27.8% and 21.7%, respectively. Although the 2-y TI for these nodes was approximately 10, the 5-y TI was only 2.7.
On the other hand, the right peripheral lesion contributed to 5-y TI  Table 3). Furthermore, the highest early recurrence rate was seen for Level 3-LNM, followed by Level 2-LNM, Level 1-LNM, and N0 disease (P < 0.001, Figure 3). The proportion of extrahepatic spread as recurrence increased with the extent of LNM (P = 0.083, Table 3     factors (Table 4). In particular, the prognostic impacts of the extent of Level 1-, Level 2-, and Level 3-LNM were well categorized.

| DISCUSS ION
Routine lymphadenectomy for ICC has been controversial because of the lack of clinical evidence. Nevertheless, recent clinical studies have supported lymphadenectomy for oncological treatment and staging. 8,9 Thus, in current trends, the proportion of patients undergoing lymph node dissection for ICC has increased year by year, particularly in Western countries. 17 However, specifics of the scope and methods of lymphadenectomy have yet to be defined. The American Joint Committee on Cancer (AJCC) recommends harvesting at least six lymph nodes to ensure accurate staging. 18 International collaborative studies were concordant with this recommendation. 19,20 The National Comprehensive Cancer Network guidelines also recommend regional lymphadenectomy in the hilar region of the liver, while AJCC guidelines recommend a broader level, depending on tumor location. 18  Concerning therapeutic value, the 5-year TI of lymphadenectomy was 7.2 for Level 1, 5.5 for Level 2, and 1.9 for Level 3.  Expanding the range of lymphadenectomy could thus lead to more accurate staging.

TA B L E 3 Recurrence outcome by extent of lymph node metastasis
Nonetheless, it must be noted that lymphadenectomy is also associated with a specific risk of postoperative morbidity. These results may be difficult to accept because of previous reports referring to dismal results from lymphadenectomy. However, our results suggest that a certain number of patients will gain therapeutic value from lymphadenectomy significant enough to determine the exact extent of ICC. Moreover, the classification of lymph node level could contribute to determination of the extent of lymphadenectomy. We report the therapeutic value and clinical implications of lymphadenectomy for ICC differently from previous reports.
Further, tumor location could offer a significant determinant for the priority of lymphadenectomy.

| CON CLUS IONS
Lymphadenectomy achieved by liver resection with curative intent should be a minimal requirement for the multimodal treatment of ICC. Furthermore, the implications and extent of lymphadenectomy for ICC should be determined according to the tumor location and preoperative risk of LNM. In peripheral type ICC, the prognostic benefit of lymphadenectomy would be limited and dissection beyond level 1 should be eliminated, while in hilar-type, lymphadenectomy up to level 2 would be necessary.

FU N D I N G I N FO R M ATI O N
Financial support was received from the Japan Society for the Promotion of Science (grant number 22 K08775 to Yuzo UMEDA).

CO N FLI C T O F I NTE R E S T
The authors declare no conflicts of interest for this article.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets generated and/or analyzed during the present study are not publicly available due to the data privacy policy at our facility, but are available from the corresponding author on reasonable request. Toshiyoshi Fujiwara https://orcid.org/0000-0002-5377-6051