Classification of Intrahepatic Cholangiocarcinoma into Perihilar Versus Peripheral Subtype.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well as propose modifications of the current classification system. METHODS: Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed. RESULTS: Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p = 0.581) and DFS (12.8 vs. 16.8 months; p = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p < 0.001). CONCLUSIONS: ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy.

Lymph Node Examination and Patterns of Nodal Metastasis Among Patients with Left- Versus Right-Sided Intrahepatic Cholangiocarcinoma After Major Curative-Intent Resection.

BACKGROUND: We sought to investigate whether the unique lateral patterns of lymphatic drainage impacted lymphadenectomy (LND), lymph node metastasis (LNM), and long-term survival of patients after curative hemi-hepatectomy for left- versus right-sided intrahepatic cholangiocarcinoma (ICC). METHODS: Data on patients who underwent curative hemi-hepatectomy for left- or right-sided ICC were collected from 15 high-volume centers worldwide, as well as from the Surveillance, Epidemiology, and End Results (SEER) registry. Primary outcomes included overall survival (OS) and disease-free survival (DFS). RESULTS: Among 697 patients identified from the multi-institutional database, patients who underwent hemi-hepatectomy for left-sided ICC (n = 363, 52.1%) were more likely to have an increased number of LND versus patients with right-sided ICC (n = 334, 47.9%) (median, left 5 versus right 3, p = 0.012), although the frequency (left 66.4% versus right 63.8%, p = 0.469) and station (beyond station no. 12, left 25.3% versus right 21.1%, p = 0.293) were similar. Consequently, left-sided ICC was associated with higher incidence of LNM (left 33.3% versus right 25.7%, p = 0.036), whereas the station and number of LNM were not different (both p > 0.1). There was no difference in OS (median, left 34.9 versus right 29.6 months, p = 0.130) or DFS (median, left 14.5 versus right 15.2 months, p = 0.771) among patients who underwent hemi-hepatectomy for left- versus right-sided ICC, which were also verified in the SEER dataset. LNM beyond station no. 12 was associated with even worse long-term survival versus LNM within station no. 12 among patients with either left- or right-sided ICC after curative-intent resection (all p < 0.05). CONCLUSIONS: The unique lateral patterns of lymphatic drainage were closely related to utilization of LND, as well as LNM of left- versus right-sided ICC.

Dynamic Prediction of Survival After Curative Resection of Intrahepatic Cholangiocarcinoma: A Landmarking-Based Analysis.

BACKGROUND: The current study aimed to develop a dynamic prognostic model for patients undergoing curative-intent resection for intrahepatic cholangiocarcinoma (ICC) using landmark analysis. METHODS: Patients who underwent curative-intent surgery for ICC from 1999 to 2017 were selected from a multi-institutional international database. A landmark analysis to undertake dynamic overall survival (OS) prediction was performed. A multivariate Cox proportional hazard model was applied to measure the interaction of selected variables with time. The performance of the model was internally cross-validated via bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index. Accuracy was evaluated with calibration plots. RESULTS: Variables retained in the multivariable Cox regression OS model included age, tumor size, margin status, morphologic type, histologic grade, T and N category, and tumor recurrence. The effect of several variables on OS changed over time. Results were provided as a survival plot and the predicted probability of OS at the desired time in the future. For example, a 65-year-old patient with an intraductal, T1, grade 3 or 4 ICC measuring 3 cm who underwent an R0 resection had a calculated estimated 3-year OS of 76%. The OS estimate increased if the patient had already survived 1 year (79%). The discrimination ability of the final model was very good (C-index: 0.80). CONCLUSION: The long-term outcome for patients undergoing curative-intent surgery for ICC should be adjusted based on follow-up time and intervening events. The model in this study showed excellent discriminative ability and performed well in the validation process.

Prognostic impact of perineural invasion in intrahepatic cholangiocarcinoma: multicentre study.

BACKGROUND: The aim of this study was to investigate the prognostic impact of perineural invasion (PNI) on tumour recurrence and survival among patients with resected intrahepatic cholangiocarcinoma (ICC). METHODS: This was a multicentre, retrospective study of patients who underwent resection with curative intent for ICC between 2000 and 2017. The relationship between PNI, clinicopathological characteristics, and long-term survival was analysed in the overall cohort and the subset of patients with early-stage ICC. RESULTS: Among 1095 patients who underwent resection of ICC, PNI was present in 239 (21.8 per cent). In univariable analysis, PNI was associated with worse disease-free survival (DFS) (median 13.2 versus 16.1 months for patients with and without PNI respectively; P = 0.038) and overall survival (OS) (26.4 versus 41.5 months; P < 0.001). In multivariable analysis, PNI was an independent risk factor associated with reduced DFS (hazard ratio (HR) 1.56, 95 per cent c.i. 1.06 to 2.13; P = 0.019) and OS (HR 1.74, 1.16 to 2.60; P = 0.007). In subgroup analysis of patients with early-stage disease (AJCC T1-2, 981 patients; or N0, 249 patients), PNI remained associated with worse DFS (T1-2: median 13.7 versus 16.6 months in patients with and without PNI respectively, P = 0.019; N0: 11.7 versus 17.5 months, P = 0.022) and OS (T1-2: 28.5 versus 45.7 months, P < 0.001; N0: 34.9 versus 47.5 months, P = 0.036). CONCLUSION: PNI is a strong independent predictor of tumour recurrence and long-term survival following resection of ICC with curative intent, even among patients with early-stage disease. The presence of PNI should be assessed routinely.

Proposed modification of the eighth edition of the AJCC staging system for intrahepatic cholangiocarcinoma.

BACKGROUND: To improve the prognostic accuracy of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for intrahepatic cholangiocarcinoma (ICC) with establishment and validation of a modified TNM (mTNM) staging system. METHODS: Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide (n = 643). An external validation dataset was obtained from the SEER registry (n = 797). The mTNM staging system was proposed by redefining T categories, and incorporating the recently proposed N status as N0 (no lymph node metastasis [LNM]), N1 (1-2 LNM) and N2 (≥3 LNM). RESULTS: The 8th AJCC TNM staging system failed to stratify overall survival (OS) of stage II versus IIIA, stage IIIB versus IV, as well as overall stage III versus IV among all patients from the two databases, as well as stage I versus II, and stage III versus III among patients who had ≥6 LNs examined. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the multi-institutional (Median OS, stage I 69.8 vs. II 37.1 vs. III 18.9 vs. IV 16.4 months, all p < 0.05), and SEER (Median OS, stage I 87.0 vs. II 29.3 vs. III 17.7 vs. IV 14.2 months, all p < 0.05) datasets, which was also verified among patients who had ≥6 lymph node harvested from both databases. CONCLUSION: The modified TNM staging system for ICC using the new T and N definitions provided an improved means to stratify patients relative to long-term OS versus the 8th AJCC staging.

Number and Station of Lymph Node Metastasis After Curative-intent Resection of Intrahepatic Cholangiocarcinoma Impact Prognosis.

OBJECTIVES: To determine the prognostic implication of the number and station of LNM, and the minimal number of LNs needed for evaluation to accurately stage patients with intrahepatic cholangiocarcinoma (ICC). BACKGROUND: Impact of the number and station of LNM on long-term survival, and the minimal number of LNs needed for accurate staging of ICC patients remain poorly defined. METHODS: Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide. External validation was performed using the SEER registry. Primary outcomes included overall (OS), disease-specific, and recurrence-free survival. RESULTS: Among 603 patients who underwent curative-intent resection, median and 5-year OS were 30.6 months and 30.4%. Patients with 1 or 2 LNM had comparable worse OS versus patients with no nodal disease (median OS, 1 LNM 18.0, 2 LNM 20.0 vs no LNM 45.0 months, both P < 0.001), yet better OS versus patients with 3 or more LNM (median OS, 1-2 LNM 19.8 vs ≥3 LNM 16.0 months, P < 0.01). On multivariable analysis, a proposed new nodal staging with N1 (1-2 LNM) (Ref. N0, HR 2.40, P < 0.001) and N2 (≥3 LNM) [Ref. N0, hazard ratio (HR) 3.85, P < 0.001] categories were independently associated with incrementally worse OS. Patients with no nodal metastasis, 1-2 LNM and ≥3 LNM also had an increasingly worse disease-specific survival, and recurrence-free survival (both P < 0.05). Total number of LNs examined ≥6 had the greatest discriminatory power relative to OS among patients with 1-2 LNM, and patients with ≥3 LNM in both the multi-institutional (area under the curve 0.780) and SEER database (area under the curve 0.820) (n = 1036). Among patients who underwent an adequate regional lymphadenectomy (total number of LNs examined ≥6), LNM beyond the HDL was associated with worse OS versus LNM within the HDL only (median OS, 14.0 vs 24.0 months, HR 2.41, P = 0.003). CONCLUSION: Standard lymphadenectomy of at least 6 LNs is strongly recommended and should include examination beyond station 12 to have the greatest chance of accurate staging. The proposed new nodal staging of N0, N1, and N2 should be considered to stratify outcomes among patients after curative-intent resection of ICC.

Clinical practice guidelines for the management of biliary tract cancers 2019: the 3rd English edition / 中华消化外科杂志

The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary cancer) in 2007, then published the 2nd version in 2014. In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence-based approach. Recommendations were graded as grade 1 (strong) or grade 2 (weak) according to the concepts of the grading of recommendations assessment, development, and evaluation system. The 31 CQs covered the six topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, and (6) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded. This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.

Redefining Conditional Overall and Disease-Free Survival After Curative Resection for Intrahepatic Cholangiocarcinoma: a Multi-institutional, International Study of 1221 patients.

OBJECTIVES: To assess conditional survival (CS) according to recurrence status, as well as conditional disease-free survival (cDFS) among patients with intrahepatic cholangiocarcinoma (ICC). METHODS: CS and cDFS were evaluated among ICC patients who underwent curative-intent resection for ICC by using a multi-institutional database. Five-year CS (CS5) at "x" years was calculated separately for patients who did and did not experience recurrence. The cDFS3 at "x" years was defined as the chance to be disease-free for an additional 3 years after not having experienced a recurrence for "x" years postoperatively. RESULTS: Among 1221 patients, median OS was 36.8 months. While estimated actuarial OS decreased over time, CS5 increased as patients survived over longer periods of time and reached 93.9% at 4 years among 139 patients who did not experience a recurrence. Among the 725 (59.4%) patients who did experience a tumor recurrence, CS5 decreased to 17.7% the first postoperative year; however, CS5 subsequently increased to 79.7% for 81 patients who had survived 4 years after surgery. While actuarial DFS decreased from 54.6% at 1 year to 28.2% at 5 years, estimated cDFS3 following liver resection increased over time. Of note, patients with known risk factors for recurrence had even more marked improvements in cDFS3 over subsequent years versus patients without risk factors for recurrence. CONCLUSION: CS and cDFS changed over time according to the presence of disease-specific risk factors, as well as the presence of recurrence.

Recurrence Patterns and Timing Courses Following Curative-Intent Resection for Intrahepatic Cholangiocarcinoma.

BACKGROUND: Recurrence of intrahepatic cholangiocarcinoma (ICC) after curative resection is common. OBJECTIVE: The aim of this study was to investigate the patterns, timing and risk factors of disease recurrence after curative-intent resection for ICC. METHODS: Patients undergoing curative resection for ICC were identified from a multi-institutional database. Data on clinicopathological and initial operation information, timing and first sites of recurrence, recurrence management, and long-term outcomes were analyzed. RESULTS: A total of 920 patients were included. With a median follow-up of 38 months, 607 patients (66.0%) experienced ICC recurrence. In the cohort, 145 patients (23.9%) recurred at the surgical margin, 178 (29.3%) recurred within the liver away from the surgical margin, 90 (14.8%) recurred at extraheptatic sites, and 194 (32.0%) developed both intrahepatic and extrahepatic recurrence. Intrahepatic margin recurrence (median 6.0 m) and extrahepatic-only recurrence (median 8.0 m) tended to occur early, while intrahepatic recurrence at non-margin sites occurred later (median 14.0 m; p < 0.05). On multivariate analysis, surgical margin < 10 mm was associated with increased margin recurrence (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.11-2.60; p = 0.014), whereas female sex (HR 2.12, 95% CI 1.40-3.22; p < 0.001) and liver cirrhosis (HR 2.36, 95% CI 1.31-4.25; p = 0.004) were both associated with an increased risk of intrahepatic recurrence at other sites. Median survival after recurrence was better among patients who underwent repeat curative-intent surgery (48.7 months) versus other treatments (9.7 months) [p < 0.001]. CONCLUSIONS: Different recurrence patterns and timing of recurrence suggest biological heterogeneity of ICC tumor recurrence. Understanding timing and risk factors associated with different types of recurrence can hopefully inform discussions around adjuvant therapy, surveillance, and treatment of recurrent disease.

A Multi-institutional International Analysis of Textbook Outcomes Among Patients Undergoing Curative-Intent Resection of Intrahepatic Cholangiocarcinoma.

Importance: Composite measures may be superior to individual measures for the analysis of hospital performance and quality of surgical care. Objective: To determine the incidence of a so-called textbook outcome, a composite measure of the quality of surgical care, among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma. Design, Setting, and Participants: This cohort study involved an analysis of a multinational, multi-institutional cohort of patient from 15 major hepatobiliary centers in North America, Europe, Australia, and Asia who underwent curative-intent resection of intrahepatic cholangiocarcinoma between 1993 and 2015. Data analysis was conducted from April 2018 to May 2018. Main Outcomes and Measures: Hospital variation in the composite end point of textbook outcome, defined as negative margins, no perioperative transfusion, no postoperative surgical complications, no prolonged length of stay, no 30-day readmissions, and no 30-day mortality. Secondary end points were factors associated with achieving textbook outcomes. Results: Among 687 patients (of whom 370 [53.9%] were men; median patient age, 61 [range, 18-86] years) undergoing curative-intent resection of intrahepatic cholangiocarcinoma, a textbook outcome was achieved in 175 patients (25.5%). Being 60 years or younger (odds ratio [OR], 1.61 [95% CI, 1.04-2.49]; P = .03), absence of preoperative jaundice (OR, 4.40 [95% CI, 1.28-15.15]; P = .02), no neoadjuvant chemotherapy (OR, 2.57 [95% CI, 1.05-6.29]; P = .04), T1a/T1b-stage disease (OR, 1.58 [95% CI, 1.01-2.49]; P = .049), N0 status (OR, 3.89 [95% CI, 1.77-8.54]; P = .001), and no bile duct resection (OR, 2.46 [95% CI, 1.25-4.84]; P = .009) were independently associated with achieving a textbook outcome after resection. A prolonged length of stay had the greatest negative association with a textbook outcome. A nomogram to assess the probability of textbook outcome was developed and had good accuracy in both the training data set (area under the curve, 0.755) and validation data set (area under the curve, 0.763). Conclusions and Relevance: In this study, while hepatic resection for intrahepatic cholangiocarcinoma was performed with less than 5% mortality in specialized centers, a textbook outcome was achieved in only approximately 26% of patients. A textbook outcome may be useful for the reporting of patient-level hospital performance and hospital variation, leading to quality improvement efforts after resection of intrahepatic cholangiocarcinoma.

Impact of body mass index on tumor recurrence among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma- a multi-institutional international analysis.

BACKGROUND: The association between body mass index (BMI) and long-term outcomes of patients with ICC has not been well defined. We sought to define the presentation and oncologic outcomes of patients with ICC undergoing curative-intent resection, according to their BMI category. METHODS: Patients who underwent resection of ICC were identified in a multi-institutional database. Patients were categorized as normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2) and obese (BMI≥30 kg/m2) according to the World Health Organization (WHO) definition. Impact of clinico-pathological factors on recurrence-free survival (RFS) was assessed using Cox proportional hazards model among patients in the three BMI categories. RESULTS: Among a total of 790 patients undergoing curative-intent resection of ICC in the analytic cohort, 399 (50.5%) had normal weight, 274 (34.7%) were overweight and 117 (14.8%) were obese. Caucasian patients were more likely to be obese (66.7%, n = 78) and overweight (47.1%, n = 129) compared with Asian (obese: 18.8%, n = 22; overweight: 46%, n = 126) and other races (obese: 14.5%, n = 17; overweight: 6.9%, n = 19)(p < 0.001). There were no differences in the presence of cirrhosis (10.9%, vs. 12.8%, vs. 12.9%), preoperative jaundice (8.6% vs. 9.5% vs. 12.0%), or levels of CA 19-9 (75, IQR 24.6-280 vs. 50.9, IQR 17.9-232 vs. 43, IQR 16.9-192.7) among the BMI groups (all p > 0.05). On multivariable analysis, increased BMI was an independent risk factor for tumor recurrence (OR 1.16, 95% CI 1.02-1.32, for every 5 unit increase). CONCLUSION: Increasing BMI was associated with incremental increases in the risk of recurrence following curative-intent resection of ICC. Future studies should aim to achieve a better understanding of BMI-related factors relative to prognosis of patients with ICC.

Should Utilization of Lymphadenectomy Vary According to Morphologic Subtype of Intrahepatic Cholangiocarcinoma?

OBJECTIVE: We sought to evaluate the utilization of lymphadenectomy (LND) and the incidence of lymph node metastasis (LNM) among different morphologic types of intrahepatic cholangiocarcinoma (ICC). METHODS: Clinical data of patients undergoing curative-intent resection for ICC between 1990 and 2017 were collected and analyzed. The preoperative nodal status was evaluated by imaging studies, and the morphologic and lymph node (LN) status was collected on final pathology report. RESULTS: Overall, 1032 patients had a mass-forming (MF) or intraductal growth (IG) ICC subtype, whereas 150 patients had a periductal infiltrating (PI) or MF + PI subtype. Among the 924 patients with MF/IG ICC subtype who had nodal assessment on preoperative imaging, 747 (80.8%) were node-negative, whereas 177 (19.2%) patients were suspicious for metastatic nodal disease. On final pathological analysis, 71 of 282 (25.2%) patients who had preoperative node-negative disease ultimately had LNM. In contrast, 79 of 135 (58.5%) patients with preoperative suspicious/metastatic LNs had pathologically confirmed LNM (odds ratio [OR] 4.2, p < 0.001). Among the 129 patients with PI/MF + PI ICC subtype and preoperative nodal information, 72 (55.8%) were node-negative on preoperative imaging. In contrast, 57 (44.2%) patients had suspicious/metastatic LNs. On final pathologic examination, 45.3% (n = 24) of patients believed to be node-negative on preoperative imaging had LNM; 68.0% (n = 34) of patients who had suspicious/positive nodal disease on imaging ultimately had LNM (OR 2.6, p = 0.009). CONCLUSION: Given the low accuracy of preoperative imaging evaluation of nodal status, routine LND should be performed at the time of resection for both MF/IG and PI/MF + PI ICC subtypes.

Impact of microvascular invasion on clinical outcomes after curative-intent resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Microvascular invasion (MiVI) is a histological feature of intrahepatic cholangiocarcinoma (ICC) that may be associated with biological behavior. We sought to investigate the impact of MiVI on long-term survival of patients undergoing curative-intent resection for ICC. METHODS: A total of 1089 patients undergoing curative-intent resection for ICC were identified. Data on clinicopathological characteristics, disease-free survival (DFS), and overall survival (OS) were compared among patients with no vascular invasion (NoVI), MiVI, and macrovascular invasion (MaVI). RESULTS: A total of 249 (22.9%) patients had MiVI, while 149 (13.7%) patients had MaVI (±MiVI). MiVI was associated with higher incidence of perineural, biliary and adjacent organ invasion, and satellite lesions (all P < 0.01). On multivariable analysis, MiVI was an independent risk factor of DFS (hazard ratios [HR] 1.5; 95%confidence intervals [CI], 1.3-1.9; P < 0.001), but not OS (HR 1.1; 95%CI, 0.9-1.3; P = 0.379). While MiVI and MaVI patients had similar DFS (median, MiVI 14.0 vs MaVI 12.0 months, HR 0.9; 95%CI, 0.7-1.2; P = 0.377), OS was better among MiVI patients (median, MiVI 39.0 vs MaVI 21.0 months, HR 0.7; 95%CI, 0.5-0.8; P = 0.002). Whereas nodal metastasis, R1 margin, and postoperative morbidity were associated with early death (≤18 months) among patients with MiVI, only nodal metastasis was associated with late (>18 months) prognosis. CONCLUSIONS: Roughly 1 out of 5 patients with resected ICC had MiVI. MiVI was associated with advanced tumor characteristics and a higher risk of tumor recurrence.

Preoperative prognostic nutritional index predicts survival of patients with intrahepatic cholangiocarcinoma after curative resection.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy. We sought to examine the association between preoperative prognostic nutritional index (PNI) and long-term overall survival among patients with ICC who underwent curative-intent resection. METHODS: Patients who underwent hepatectomy for ICC between 1990 and 2015 were identified using an international multi-institutional database. Clinic-pathological characteristics and long-term outcomes of patients with PNI ≥ 40 and <40 were compared using univariable and multivariable analyses. RESULTS: Among 637 patients, 53 patients had PNI < 40 (8.3%) and 584 patients had PNI ≥ 40 (91.7%). While there was no difference between PNI groups with regard to tumor size (P = .87), patients with PNI < 40 were more likely to have multifocal disease (PNI < 40, n = 16, 30.2% vs PNI ≥ 40, n = 65, 11.1%; P < 0.001), poorly differentiated or undifferentiated ICC (PNI < 40, n = 13, 25.5% vs PNI ≥ 40, n = 75, 13.1%; P = 0.020) and T2/T3/T4 disease vs patients with PNI ≥ 40 (PNI < 40, n = 38, 71.7% vs PNI ≥ 40, n = 265, 45.4%; P < 0.001). Patients with PNI ≥ 40 had better OS vs patients with PNI < 40 (5-year OS: PNI ≥ 40: 47.5%, 95% CI, 42.2 to 52.6% vs PNI < 40: 24.6%, 95% CI, 12.1 to 39.6%; P < 0.001). On multivariable analysis, PNI < 40 remained associated with increase risk of death (HR, 1.71; 95% CI, 1.15 to 2.53; P = 0.008). CONCLUSION: A low preoperative PNI was associated with a more aggressive ICC phenotype. After controlling for these factors, PNI remained independently associated with a markedly worse prognosis.

Long-term outcomes of patients with intraductal growth sub-type of intrahepatic cholangiocarcinoma.

BACKGROUND: Intraductal-growth (IG) type of intrahepatic cholangiocarcinoma (ICC) may be associated with a favorable prognosis compared with mass-forming (MF) and periductal-infiltrating (PI) ICC. METHODS: The clinico-pathological characteristics and long-term outcomes of 1206 patients undergoing liver resection for ICC were compared based on the ICC morphological classification. RESULTS: Compared with MF patients, IG patients had a higher incidence of poor/un-differentiated tumor, lympho-vascular, and perineural invasion (poor/un-differentiated: MF, 18% vs. IG, 24%; lympho-vascular invasion: MF, 30% vs. IG, 35%; perineural invasion: MF, 17% vs. IG, 33%; all p > 0.05). The pattern of recurrence was different among MF patients (intrahepatic only: 63%; extrahepatic only: 22%; both intra- and extrahepatic: 16%) versus IG patients (intrahepatic only: 46%; extrahepatic: 25%; both intra- and extrahepatic: 29%) (p < 0.001). Moreover, while 78% of patients with MF had an early recurrence (<18 months from surgery), 59% of IG patients had and early recurrence (p = 0.039). On multivariable analysis, after controlling for competing risk factors, IG patients had a similar prognosis as MF patients (HR 0.90, p = 0.69). CONCLUSION: While IG patients more frequently presented with more adverse pathological characteristics, the prognosis of IG patients was comparable with MF patients after controlling for all these adverse factors.

Perioperative and long-term outcome of intrahepatic cholangiocarcinoma involving the hepatic hilus after curative-intent resection: comparison with peripheral intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma with hepatic hilus involvement has been either classified as intrahepatic cholangiocarcinoma or hilar cholangiocarcinoma. The present study aimed to investigate the clinicopathologic characteristics and short- and long-term outcomes after curative resection for hilar type intrahepatic cholangiocarcinoma in comparison with peripheral intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. METHODS: A total of 912 patients with mass-forming peripheral intrahepatic cholangiocarcinoma, 101 patients with hilar type intrahepatic cholangiocarcinoma, and 159 patients with hilar cholangiocarcinoma undergoing curative resection from 2000 to 2015 were included from two multi-institutional databases. Clinicopathologic characteristics and short- and long-term outcomes were compared among the 3 groups. RESULTS: Patients with hilar type intrahepatic cholangiocarcinoma had more aggressive tumor characteristics (eg, higher frequency of vascular invasion and lymph nodes metastasis) and experienced more extensive resections in comparison with either peripheral intrahepatic cholangiocarcinoma or hilar cholangiocarcinoma patients. The odds of lymphadenectomy and R0 resection rate among patients with hilar type intrahepatic cholangiocarcinoma were comparable with hilar cholangiocarcinoma patients, but higher than peripheral intrahepatic cholangiocarcinoma patients (lymphadenectomy incidence, 85.1% vs 42.5%, P < .001; R0 rate, 75.2% vs 88.8%, P < .001). After curative surgery, patients with hilar type intrahepatic cholangiocarcinoma experienced a higher rate of technical-related complications compared with peripheral intrahepatic cholangiocarcinoma patients. Of note, hilar type intrahepatic cholangiocarcinoma was associated with worse disease-specific survival and recurrence-free survival after curative resection versus peripheral intrahepatic cholangiocarcinoma (median disease-specific survival, 26.0 vs 54.0 months, P < .001; median recurrence-free survival, 13.0 vs 18.0 months, P = .021) and hilar cholangiocarcinoma (median disease-specific survival, 26.0 vs 49.0 months, P = .003; median recurrence-free survival, 13.0 vs 33.4 months, P < .001). CONCLUSION: Mass-forming intrahepatic cholangiocarcinoma with hepatic hilus involvement is a more aggressive type of cholangiocarcinoma, which showed distinct clinicopathologic characteristics, worse long-term outcomes after curative resection, in comparison with peripheral intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma.

The Limitations of Standard Clinicopathologic Features to Accurately Risk-Stratify Prognosis after Resection of Intrahepatic Cholangiocarcinoma.

BACKGROUND: The ability to provide accurate prognostic data after hepatectomy for intrahepatic cholangiocarcinoma (ICC) remains poor. We sought to develop and validate a nomogram to predict survival, as well as investigate the clinical implications of underestimating patients' risk of recurrence. METHODS: Patients undergoing curative-intent resection of ICC between 1990 and 2015 at 14 major hepatobiliary centers were included. Variables significant on multivariable analysis were used to construct a nomogram to predict disease-free survival (DFS). The nomogram assigned a score to each variable included in the model and calculated the risk of recurrence. RESULTS: Eight hundred ninety-seven patients are included in the analytic cohort. On multivariable Cox regression analysis, tumor size > 5 cm (HR 1.98, 95% CI 1.44-2.13; p < 0.001), multifocal ICC (HR 1.64, 95% CI 1.32-2.03; p < 0.001), lymph node metastasis (HR 1.63, 95% CI 1.25-2.11; p < 0.001), poorly differentiated tumor grade (HR 1.50, 95% CI 1.21-1.89; p < 0.001), and periductal infiltrating type (PI) morphology (HR 1.42, 95% CI 1.09-1.83; p = 0.008) were independent adverse risk factors associated with decreased DFS. The Harrell's c-index for the nomogram was 0.633 (with n = 5000 bootstrapping resamples) and the plot comparing predicted and actuarial DFS demonstrated a good calibration of the model. A subset of patients (n = 282) had a DFS worse than predicted (ΔPredicted DFS - Actuarial DFS > 6 months). Moreover, underestimation of a recurrence risk was more common among patients with clinicopathologic features traditionally considered "favorable." CONCLUSION: A nomogram based on standard clinicopathologic characteristics was suboptimal in its ability to predict accurately risk of recurrence among patients with ICC after curative-intent liver resection. Particularly, the risk of underestimating patient risk of recurrence was highest among patients with historically favorable characteristics. Over one third of patients recurred > 6 months earlier than the DFS predicted by the nomogram.

Surgical Management of Intrahepatic Cholangiocarcinoma in Patients with Cirrhosis: Impact of Lymphadenectomy on Peri-Operative Outcomes.

BACKGROUND: The consequences of lymphadenectomy (LND) on cirrhotic patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC) have not been investigated. We sought to analyze the impact of LND on morbidity among patients undergoing resection for ICC. METHODS: A total of 1005 patients who underwent hepatectomy for ICC at one of the 14 participating institutions between 1990 and 2015 were identified. A propensity score match analysis was performed to reduce confounding biases between cirrhosis and non-cirrhosis groups. RESULTS: Cirrhosis was diagnosed in 118 (11.7%) patients. Among non-cirrhotic patients, 63% underwent major liver resection versus only 20% among patients with cirrhosis (p < 0.001). LND was also less common among cirrhotic versus non-cirrhotic patients (19 vs. 50%, p < 0.001). The incidence of complications was 41 and 30% among patients who did not and did have cirrhosis, respectively (p = 0.022). The propensity-matched cohort included 150 patients. The incidence of complications was 71% among patients who underwent lymphadenectomy versus 23% among patients who did not undergo lymphadenectomy (OR 8.39) (p < 0.001). In the propensity-matched analysis, the median HLN was comparable among patients independent of cirrhosis status (median HLN: non-cirrhosis, 2.5 vs. cirrhosis, 2) (p = 0.95). While lymphadenectomy was associated with a higher risk of infections (non-cirrhosis, 0% vs. cirrhosis, 21%, p < 0.001) among patients with cirrhosis, infections were not associated with lymphadenectomy among non-cirrhotic patients (p = 0.19). CONCLUSION: Lymphadenectomy was associated with an increased risk of complications among patients with cirrhosis undergoing surgery for ICC. The benefit of lymphadenectomy in cirrhotic patients should be considered in light of the higher risk of postoperative complications compared with non-cirrhotic patients.