Patients and clinicopathological data collection
The medical records of 78 consecutive patients who underwent major hepatectomy with EBDR for perihilar cholangiocarcinoma between May 2006 and June 2017 at our institution were reviewed. Perihilar cholangiocarcinoma was defined as a tumor located in the extrahepatic biliary tree proximal to the origin of the cystic duct, consistent with the Union for International Cancer Control (UICC) Classification 8th Edition [15]. In all patients, perihilar cholangiocarcinoma was diagnosed by radiological imaging and pathological confirmation of surgical specimens. The following patients were excluded from analysis: 2 patients who died secondary to postoperative complications, 10 patients lost to follow-up within 12 months postoperatively, and 11 patients who received adjuvant chemotherapy as part of a clinical trial (there was 1 patient who both lost to follow-up and received adjuvant chemotherapy). Therefore, 56 patients were investigated.
Clinicopathological data, which could be affected survival or change of skeletal muscle mass, were retrieved from medical records. Those data included age, sex, body mass index (BMI), American Society of Anesthesiologists classification score, Charlson comorbidity index, preoperative biliary drainage, and portal vein embolization. Preoperative laboratory data included serum concentrations of total bilirubin, albumin, and carbohydrate antigen 19–9 (CA 19–9). Intraoperative factors included type of surgical procedure, operation time, blood loss, and blood transfusion. Postoperative complications included major complications consistent with Clavien-Dindo grade ≥ IIIa [16], surgical site infection, bile leakage, liver failure, and length of hospitalization. Pathological findings included tumor size, T factor, lymph node metastasis, and resection curability. Serum CA 19–9 level was measured 3–6 months (early postoperative period) and 12 months (late postoperative period) postoperatively (Fig. 1). Elevated serum CA 19–9 level was defined as > 37 U/mL.
This study was approved by the ethics committee of the National Cancer Center (#2018–053).
Preoperative management, surgical technique, and postoperative follow-up
Computed tomography (CT), ultrasonography, magnetic resonance imaging, and endoscopic retrograde cholangiopancreatography were routinely performed for the diagnosis of perihilar cholangiocarcinoma. Preoperative biliary drainage was performed in patients with obstructive jaundice. When the serum total bilirubin concentration decreased to < 2 mg/dL after biliary drainage, liver function was evaluated by testing indocyanine green retention at 15 min. Indocyanine green retention at 15 min and CT volumetry were routinely examined to evaluate the functional reserve of the future liver remnant. Preoperative portal vein embolization was performed in patients who were judged to have insufficient future liver remnant volume relative to liver function [17, 18].
All patients underwent major hepatectomy with EBDR. In particular, regional lymph node dissection of the common hepatic artery and hepatoduodenal ligament were performed. Common bile duct was divided at the level of the pancreas and submitted for frozen section analysis to evaluate tumor negativity of the cut-end. Hemilateral hepatic artery and portal vein were divided. Hepatic parenchymal dissection was performed and caudate lobectomy was routinely performed. The proximal hemilateral bile duct was divided and a specimen was extracted. After confirmation of the tumor negativity of the proximal bile duct cut-end, hepaticojejunostomy with Roux-en-Y anastomosis were performed.
Postoperative follow-up included medical examination, blood tests with serum CA 19–9 level, and CT examination every 3 months for the first 3 years, then every 6 months for the next 2 years, and then annually thereafter.
SMV measurement
As shown in Fig. 2, SMV was measured at the third lumbar vertebra using a Hounsfield unit range of − 29 to 150 on CT axial images. A single investigator (S.Y.), who was blinded to the patients’ clinical histories and outcomes, assessed the images and manually traced the skeletal muscle area. The skeletal muscle index (SMI, cm2·m− 2) for each patient was calculated as follows: SMI = (skeletal muscle area) / (height).2 Sarcopenia was defined as SMI < 43 cm2·m− 2 in men with a body mass index < 25 kg·m− 2, SMI < 53 cm2·m− 2 in men with a body mass index ≥25 kg·m− 2, or SMI < 41 cm2·m− 2 in women [19]. All studied patients underwent CT examination within 30 days prior to surgery (preoperative period), 3–6 months after surgery (early postoperative period), and 12 months after surgery (late postoperative period). The percent change of the SMI in each patient between the preoperative period and the early or late postoperative period was calculated. CT images were analyzed by Volume Analyzer SYNAPSE VINCENT (Fujifilm Medical, Tokyo, Japan).
Statistical analysis
Categorical variables are presented as n (%) and were analyzed using Fisher’s exact test. Continuous variables are presented as median [range] and were analyzed using the Mann-Whitney U-test. Cutoffs were determined as the upper limit of the normal range for laboratory data and as the median for other continuous variables. Correlations between the variables were evaluated using Spearman’s rank correlation coefficient. Overall survival (OS) was defined as the time from surgery to death or the date at last follow-up. Recurrence-free survival (RFS) was calculated as the time from surgery to recurrence, death, or the date at last follow-up. Recurrence was defined as the detection of a tumor on imaging or by pathological confirmation.
The study observation period was until December 2019. OS and RFS were determined by Kaplan-Meier survival analysis and the log-rank test. Clinicopathological findings and SMI were evaluated for the associations with a shorter OS or RFS by calculating hazard ratios (HRs) and 95% confidence intervals (95% CIs) using Cox regression analysis. Variables that were shown to be significant in univariable analysis were included in multivariable analysis, excluding the confounder with a lower hazard ratio if a correlation was shown between variables with Spearman’s rank analysis. The significant correlation coefficient was set at r s > 0.3. Variables in the early and late postoperative periods were evaluated separately because risk analysis for a shorter OS or RFS should be performed using the variables of each early and late postoperative period. The associations of decreased SMI and elevated serum CA 19–9 level in the early and late postoperative period with recurrence and poor survival was compared. All P-values were based on two-sided statistical tests, and the significance level was set at P < 0.05. All statistical analyses were performed using JMP version 13 (SAS Institute, Cary, NC, USA).
