Prognostic Significance and Predictive Factors of Lymph Node Metastasis in Resectable Intrahepatic Cholangiocarcinoma

Research Article

Austin J Surg. 2019; 6(4): 1168.

Prognostic Significance and Predictive Factors of Lymph Node Metastasis in Resectable Intrahepatic Cholangiocarcinoma

Navarro JG, Rho SY, Lee JH, Choi GH*, Han DH, Kim SK and Choi JS

Department of Surgery, Yonsei University College of Medicine, Korea

*Corresponding author: Choi GH, Department of Surgery, Yonsei University College of Medicine, Yonseiro, Seodaemun-gu, Korea

Received: December 20, 2018; Accepted: February 08, 2019; Published: February 15, 2019


Background: Lymph node metastasis portend a worse prognosis following resection of Intrahepatic Cholangiocarcinoma (ICC); however, the role of lymphadenectomy is still controversial and not routinely performed. In this study, we investigated the oncologic significance and predictive factors of lymph node metastasis in patients with ICC, which can potentially influence decision making for the patient’s oncologic benefit with lymphadenectomy.

Materials and Methods: We retrospectively reviewed patients who underwent curative-intent surgery for intrahepatic cholangiocarcinoma between 2001 and 2014. The data was collected from the electronic medical record database of the hospital.

Results: A total of 168 patients were included in the study. Multivariable analysis revealed that: age >65 years, lymph node metastasis, tumor size >5 cm and periductal infiltrating tumor morphology, were independently associated with poor OS (P<0.05); moreover, tumor size >5 cm, periductal infiltrating tumor morphology, multiple tumor, vascular invasion, and lymph node metastasis, were independently associated with increased risk of tumor recurrence (P<0.05). The CT finding of enlarged lymph nodes and CA 19-9 >120 IU/ml were preoperative predictors for lymph node metastasis; however, the sensitivity and specificity were only 62.5% and 88.0%, respectively, to identify lymph node metastasis.

Conclusion: Lymph node metastasis is associated with poor overall survival and disease-free survival following curative-intent resection in patients with ICC. Routine lymph node dissection for preoperatively diagnosed ICC should be recommended to properly assess the lymph node status of patients with ICC.

Keywords: Intrahepatic cholangiocarcinoma; Lymph node; Survival


ICC: Intrahepatic Cholangiocarcinoma; CA19-9: Carbohydrate Antigen 19-9; CEA: Carcinoembryonic Antigen; CT: Computed Tomography; MRCP: Magnetic Resonance Imaging with Cholangiography; PET: Positron Emission Tomography; AJCC: American Joint Committee on Cancer; OS: Overall Survival; DFS: Disease-Free Survival


Intrahepatic Cholangiocarcinoma (ICC) is the second most common primary liver malignancy [1]. In Korea, it represents approximately 10% of liver cancers (8.8% for males and 10.6% for females) and this proportion increases by year with an estimated annual percentage change of 7.9% and 10.6% for males and females, respectively, from 1999 to 2005 [2]. Up to date, there is limited data regarding the effectiveness of adjuvant chemotherapy for ICC; therefore, surgical resection remains the only definitive treatment available [3]. Although survival has improved in the last decade, [4] the 5-year survival still ranges from 20-40%, [5-7] and the recurrence rates remain as high as 50-60% [8,9] even after complete surgical resection.

As a result, it is important to recognize prognostic factors associated with long-term survival for patients with ICC for risk stratification after surgery. Most prominently, the lymph node status which can be influenced by the surgeon through an adequate lymphadenectomy. Several reports have documented the incidence of lymph node metastasis in patients with ICC as high a 45-62% [10,11]. Moreover, although its oncologic significance is well-documented in different studies, [12] the role of lymphadenectomy is still controversial and not even routinely performed [13]. Therefore, we sought to investigate the prognostic factors of patients with ICC who underwent curative intent surgery. In addition, we sought to identify the preoperative determinants of lymph node metastasis in patients with ICCs as it might potentially influence the decision making and the patient’s oncologic benefit on lymphadenectomy.

Materials and Methods

Study design

A retrospective review of all patients with a histologically confirmed intrahepatic cholagiocarcinoma who underwent curative intent resection in Severance hospital, Yonsei University College of Medicine, Seoul, Korea, between 2000 and 2014. Patients with incomplete clinical and histologic data were excluded from this study. Also excluded were patients with other underlying malignancies. The study protocol was approved by the Yonsei Institutional Review Board.

Clinicopathologic data

The data was collected from the electronic medical record database of the hospital. Patients’ demographic characteristics, clinical presentations, preoperative comorbidities, perioperative outcomes, imaging studies, and laboratory results were reviewed and analyzed. Preoperative evaluation including: carbohydrate antigen 19-9 (CA19- 9), Computed Tomography (CT), Magnetic Resonance Imaging with Cholangiography (MRCP) and Positron Emission Tomography (PET), were reviewed. Tumor characteristics such as tumor size, type, number, and the presence or absence of enlarged lymph nodes were obtained from the report of preoperative imaging studies. An enlarged lymph nodes on preoperative imaging was determined as exceeding the short axis diameter of 8 mm in the gastrohepatic ligament, 7 mm in the porta hepatis, 10 mm in the portocaval space, and 9 mm in the paraaortic region [14]. Enlarged lymph nodes on preoperative imaging were defined as clinical N1 whereas clinical N0 if no enlarged lymph nodes. The standard lymph node dissection in this cohort was defined as removal of the hilar and hepatoduodenal ligament (station 12) or more such as the retropancreatic, the common hepatic artery, the celiac axis, the left gastric artery, or the caval lymph nodes.

Pathology review was performed by an experienced hepatobiliary pathologist. Tumor growth type, grade, vascular invasion, multicentricity, and lymph node status were obtained. The tumor growth pattern was classified as being of mass-forming type, periductal infiltrating type, intraductal, and mixed type (massforming/ periductal infiltrating type) according to the Liver Cancer Study Group of Japan [15]. The pathological stage was defined according to the 8th edition of the American Joint Committee on Cancer 8th edition (AJCC) [16].

Study outcomes

The primary endpoints of this study were the long-term survival outcomes of patients with intrahepatic cholangiocarcinoma after curative-intent resection. Overall survival was calculated from the date of surgery to the date of death or last follow-up. Disease-free survival was calculated from the date of surgery to the date of recurrence or last follow-up. Patients were also followed up regularly for serum CA 19-9, Carcinoembryonic Antigen (CEA) level determination, and computed tomography scan to detect tumor recurrence.

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics, version 22 (SPSS Inc., Chicago, IL, USA). Categorical variables were expressed as frequencies (%), whereas continuous variables were presented as means with their range or ±standard deviation. The means of continuous variables were compared using an independent sample t-test. Categorical variables were compared using the Pearson P2 test. The Receiver Operating Characteristic (ROC) curve analysis was used to determine the optimal cutoff value of CA 19-9 in determining lymph node metastasis. Overall survival and diseasefree survival were estimated using the Kaplan-Meier method and compared using a log-rank test. A multivariable Cox proportional hazards model was applied to identify the statistically significant independent prognostic factors for overall survival and disease-free survival. Association between the preoperative variables and lymph nodes metastases was tested, as continues and categorical, using logistic regression analysis. A P-value of <.05 was used to define statistical significance.


Clinicopathologic characteristics

A total of 179 patients who underwent curative liver resection for ICC were initially identified. Among them, only 168 patients met the inclusion criteria. The median age was 64 years (range, 360-84 years). The characteristics of patients are summarized in (Table 1). With a median follow-up period of 21 months (range, 1-156 months), 88 patients (52%) had a recurrence and 53 patients (32%) died in this cohort. Moreover, among 88 patients with tumor recurrence, 77 (86.5%) recurred within 2 years of follow-up.