Resection For Intrahepatic Cholangiocarcinoma Research Articles

The Expression of Yes-Associated Protein (YAP) Maintains Putative Cancer Stemness and Is Associated with Poor Prognosis in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is resistant to most chemotherapeutic agents. Yes-associated protein (YAP) is related to tumor progression; however, its role in ICC remains unknown. We investigated the mechanism underlying YAP-mediated cancer progression by focusing on the property of cancer stem cells (CSCs) in ICC. Immunohistochemistry results revealed the positive YAP expression in 37 of 52 resected ICC cases. Those with positive YAP expression showed poor prognosis in Kaplan-Meier analysis (P=0.023). YAP expression was associated with vimentin and the putative CSC marker, hepatic oval cell marker 6 (OV-6). The knockdown of YAP expression using specific siRNAs in ICC cells decreased octamer-binding transcription factor 4 (OCT4) expression in Western blot analyses and OV-6 and CD133 expression in flow cytometry analysis. Verteporfin, a YAP inhibitor, decreased N-cadherin and OCT4 expression in Western blot analyses. Invitro sphere formation and anoikis resistance assays revealed the impairment in CSC property and anoikis resistance in response to the decrease in YAP expression. Verteporfin treatment activated the protein kinase B/mechanistic target of rapamycin signaling pathway and dramatically impaired IL-6-stimulated STAT3 phosphorylation in ICC cells. The combination of verteporfin and rapamycin, an inhibitor of mechanistic target of rapamycin phosphorylation, inhibited cell proliferation and tumor growth. In conclusion, verteporfin regulates multiple signaling pathways and, in combination with rapamycin, might be a promising therapeutic strategy for ICC treatment.

Prognostic utility of albumin-bilirubin grade for short- and long-term outcomes following hepatic resection for intrahepatic cholangiocarcinoma: A multi-institutional analysis of 706 patients.

The objective of the current study was to define the impact of albumin-bilirubin (ALBI) grade on short- as well as long-term outcomes among patients with intrahepatic cholangiocarcinoma (ICC). Patients who underwent hepatectomy for ICC between 1990 and 2016 were identified using an international multi-institutional database. Clinicopathologic factors including ALBI score were assessed using bivariate and multivariable analyses, as well as standard survival analyses. Among 706 patients, 453 (64.2%) patients had ALBI grade 1, 231 (32.7%) ALBI grade 2, and 22 (3.1%) had ALBI grade 3. After adjusting for all competing factors, patients with ALBI grade 2/3 had higher odds of a prolonged length-of-stay (>10 days, odds ratio [OR] = 2.37, 95% confidence interval [CI]:1.47-3.80), perioperative transfusion (OR = 2.15, 95% CI:1.45-3.18) and 90-day mortality (OR = 2.50, 95% CI:1.16-5.38). Median and 5-year overall survival (OS) for the entire cohort was 41.5 months (IQR:15.7-107.8) and 39.8%, respectively. Of note, median OS incrementally worsened with increased ALBI grade: grade 1, 49.6 months (IQR:18.3-NR) vs grade 2, 29.6 months (IQR:12.6-98.4) vs grade 3, 16.9 months (IQR:6.5-32.4; P < 0.001). On multivariable analysis, higher ALBI grade remained associated with higher hazards of death (grade 2/3: hazard ratio = 1.36, 95% CI:1.04-1.78). The ALBI score was associated with both short- and long-term outcomes following resection for ICC and could prove a useful surrogate marker to identify patients at risk for adverse outcomes.

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

Recurrence of intrahepatic cholangiocarcinoma (ICC) after curative resection is common. The aim of this study was to investigate the patterns, timing and risk factors of disease recurrence after curative-intent resection for ICC. 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. A total of 920 patients were included. With a median follow-up of 38months, 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 6.0m) and extrahepatic-only recurrence (median 8.0m) tended to occur early, while intrahepatic recurrence at non-margin sites occurred later (median 14.0m; p < 0.05). On multivariate analysis, surgical margin < 10mm 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 (48.7months) versus other treatments (9.7months) [p < 0.001]. 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 novel online prognostic tool to predict long-term survival after liver resection for intrahepatic cholangiocarcinoma: The "metro-ticket" paradigm.

The aim of the current study was to develop an online calculator to predict survival after liver resection for intrahepatic cholangiocarcinoma (ICC) based on the "metro-ticket" paradigm. Between 1990 and 2016, patients who underwent liver resection for ICC were identified in an international multi-institutional database. The final multivariable model of survival was used to develop an online prognostic calculator of survival. Among 643 patients, actual 5-year overall survival (OS) after resection for ICC was 42.7%. On multivariable analysis, CA19-9 > 200 (hazard ratio (HR), 2.62; 95% CI, 2.01-3.42), sum of the number and largest tumor size >7 (HR, 1.88; 95% CI, 1.46-2.42), N1 disease (HR, 2.87; 95% CI, 1.98-4.16), R1 resection (HR, 1.72; 95% CI, 1.21-2.46), poor/undifferentiated tumor grade (HR, 1.74; 95% CI, 1.25-2.44), major vascular invasion (HR, 1.47; 95% CI, 1.03-2.10), and adjuvant chemotherapy (HR, 0.64; 95% CI, 0.45-0.89) were significantly associated with survival and were included in the online calculator. The predictive accuracy of the model was good to very good as the C-statistics to predict 5-year OS was 0.696 in the training dataset and 0.672 with bootstrapping resamples (n = 5000) in the test dataset. A novel, online calculator was developed to estimate the 5-year survival probability for patients undergoing resection for ICC. This tool could help provide useful information to guide treatment decision-making and inform conversations about prognosis.

Short- and Long-Term Outcomes of Liver Resection for Intrahepatic Cholangiocarcinoma Associated with the Metabolic Syndrome.

While the metabolic syndrome (MS) is being recognized as an important risk factor for intrahepatic cholangiocarcinoma (ICC), the outcomes of liver resection in this context remain poorly described. This study aims to report the short- and long-term results of hepatectomy for patients with MS as risk factor for the development of ICC (MS+). All patients undergoing hepatectomy for ICC between 2000 and 2016 at a single center were retrospectively analyzed. The perioperative outcomes of MS+ and ICCpatients without MS (MS-) were compared. Among 115 resected ICC patients, 40 (34.8%) were MS+ and 75 (65.2%) were MS-. MS+ exhibited an increased Charlson comorbidity index (5 ± 2 vs. 2 ± 2, p < 0.001) than MS- patients. While operative characteristics did not differ significantly between the 2 groups, MS+ experienced higher rate of major complications (62.5 vs. 29.3%, p = 0.001). On multivariate analysis, MS+ was an independent risk factor of major complication (HR 2.86, 95% CI 1.07-7.60, p = 0.036) and major cardiorespiratory complication (HR 4.35, 95% CI 1.50-12.62, p = 0.007). Pathological analysis revealed that MS+ displayed higher rates of non-alcoholic fatty liver disease (60.0 vs. 31.1%, p = 0.003) and non-alcoholic steatohepatitis (25 vs. 5.4%, p = 0.005). MS+ was independently associated with decreased risk of recurrence (HR 0.47, 95% CI 0.26-0.85, p = 0.001). MS+ accounts for 35% of resected ICC patients. The existence of significant cardiovascular comorbidities increases postoperative morbidity and requires specific management.

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

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). 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. 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). 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.

Laparoscopic Approach to Intrahepatic Cholangiocarcinoma is Associated with an Exacerbation of Inadequate Nodal Staging

Laparoscopic approach to liver resection is feasible and safe, though its utilization with intrahepatic cholangiocarcinoma (ICC) remains poorly documented. We sought to evaluate the use laparoscopy for ICC, and to examine adherence to oncologic standards. The National Cancer Database was queried for patients who underwent resection for ICC. Patients were stratified by laparoscopic (LLR) versus open liver resection (OLR). Clinicopathologic parameters and hospital volumes were recorded. In total, 2309 patients with ICC underwent hepatic resection (1997 OLR, 312 LLR) between 2010 and 2015. LLR increased from 12 to 16% during the study period and was utilized more commonly than OLR for wedge and segmental resections (56% vs. 33%, p < 0.001). Nodal evaluation was performed in 58% of all patients with ICC and was significantly more common in patients undergoing OLR (61%, n = 1210) versus LLR (39%, n = 120), p < 0.001. Of the 120 patients undergoing LLR with any nodal evaluation, 31% (n = 37) had a single node evaluated. Patients who underwent LLR were less likely to have ≥ 6 lymph nodes evaluated compared with those who underwent OLR (9% vs. 15%, respectively, p < 0.001). The use of laparoscopy for ICC is associated with an exacerbation of inadequate nodal evaluation compared with open resections.

Survival after Resection of Multiple Tumor Foci of Intrahepatic Cholangiocarcinoma

BackgroundMultiple tumor foci of intrahepatic cholangiocarcinoma (ICC) are often considered a contra-indication for resection. We sought to define long-term outcomes after resection of ICC in patients with multiple foci. MethodsPatients who underwent resection for ICC between 1990 and 2017 were identified from 12 major HPB centers. Outcomes of patients with solitary lesions, multiple lesions (ML), and oligometastases (OM) were compared. OM were defined as extrahepatic metastases spread to a single organ. ResultsOne thousand thirteen patients underwent resection of ICC. On final pathology, 185 patients (18.4%) had ML and 27 (2.7%) had OM. Median survival of patients with a solitary tumor was 43.2 months, while the median survival of patients with 2 tumors was 21.2 months; the median survival of patients with 3 or more tumors was 15.3 months (p < 0.001). Five-year survival was 43.3%, 28.0%, and 8.6%, respectively. The median survival of patients without OM was 37.8 months versus 14.9 months among patients with OM (p < 0.001); estimated 5-year survival was 39.3% and 10.6%, respectively. In multivariable analysis, the presence of two lesions was not an independent poor prognostic factor for OS (HR 1.19; 95%CI 0.90–1.57; p = 0.229). However, the presence of three or more tumors was an independent poor prognostic factor for OS (HR 1.97; 95%CI 1.48–2.64; p < 0.001). ConclusionResection of multiple liver tumors for patients with ICC did not preclude 5-year survival: in particular, estimated 5-year OS for resection of two tumors was 28.0%.

Predictors of adjuvant treatment and survival in patients with intrahepatic cholangiocarcinoma who undergo resection

BackgroundAdministration of adjuvant therapy (AT) in patients with intrahepatic cholangiocarcinoma (ICC) remains inconsistent despite recent trial data. This study investigates predictors of receipt of AT and survival. MethodsPatients with ICC who underwent resection were identified using the NCDB (2004–2014). Logistic regression and Cox analysis were used to determine predictors of AT and survival, respectively. “High-risk” was defined as positive margins/nodes or stage III/IVa disease. Results2813 patients were identified, of whom 42.3% received AT. Patients with positive margins, positive nodes, and higher stage tended to receive AT (p < 0.001). Black patients and patients with Medicare/Medicaid were less likely to receive AT. In “high-risk” patients, AT was associated with lower mortality (HR 0.66, 95% CI 0.56–0.78, p < 0.001). ConclusionsAT after ICC resection is associated with improved survival in patients with positive margins, positive nodes, and stage III/IVa disease. There are disparities and regional variations in the receipt of AT.

An Integrated Nomogram Combining Clinical Factors and Microtubule-Associated Protein 1 Light Chain 3B Expression to Predict Postoperative Outcomes in Patients with Intrahepatic Cholangiocarcinoma

Background: Microtubule-associated protein 1 light chain 3 B (LC3B) serves as a key component of autophagy, which is associated with the progression of carcinoma. Yet, it is still unclear whether LC3B is also an independent risk factor for predicting the progression of resectable intrahepatic cholangiocarcinoma (ICC). We aim to explore the values of LC3B on risk and prognosis of ICC, and to establish a novel and available nomogram incorporating clinical factors and LC3B expression to predict recurrence-free survival (RFS) and overall survival (OS) for these patients after radical hepatectomy. Methods: From August 2004 to March 2017, 105 ICC patients were eligibly enrolled in the Third Affiliated Hospital of Sun Yat-sen University. Preoperative clinical information of enrolled patients was collected. Expression LC3B in the ICC specimen was detected by immunohistochemistry. Cox regression analysis was used to screen the independent risk factors, which were integrated to establish prognostic nomograms to predict OS and RFS. Findings: The 5-year RFS and OS in this cohort were 15.7% and 29.6%, respectively. On multivariate analysis, independent factors for 5-year OS were CA-125, microvascular invasion (MVI), LC3B expression and lymph node metastasis (LNM). Except for the above 4 factors, NLR and tumor differentiation were independent factors for 5-year RFS. The AUC of nomograms for OS and RFS were 0.820 and 0.747, respectively. Interpretation: The nomograms based on LC3B can be considered as effective models to predict postoperative survival for ICC patients. Funding Statement: Natural Science Foundation of China (81570593, 81770648), Guangdong Natural Science Foundation (2015A030312013), Sci-tech Research Development Program of Guangdong Province (2017A020215023), Sci-tech Research Development Program of Guangzhou City (158100076), Sun Yat-Sen University Clinical Research 5010 Program (2014006), Science and Technology Program of Guangzhou City (201508020262, 201400000001-3). Declaration of Interests: All authors in the present study declare that the research was conducted without any potential conflict of interest. Ethics Approval Statement: The study was approved by the Clinical Research Ethic Committee of the Third Affiliated Hospital of Sun Yat-sen University, and all patients signed the informed consent to participate in this study.

Adjuvant chemotherapy improves oncological outcomes of resectable intrahepatic cholangiocarcinoma: A meta-analysis.

Objective:To define the role of adjuvant chemotherapy in the management of resectable intrahepatic cholangiocarcinoma (ICC) by performing a meta-analysis.Summary background data:Oncological benefit of adjuvant chemotherapy in resectable ICC remains controversial, high-level evidence in such context is lacking.Method:A comprehensive search using Pubmed, EMbase, and Web of Science was performed from inception to October 2018. Studies compared the survival of patients receiving adjuvant chemotherapy versus surgery alone were included. Data were analyzed using random effect model. Quality of each study and presence of publication bias were assessed by Newcastle–Ottawa score (NOS) and funnel plot with Egger test respectively.Results:The present meta-analysis included 15 studies (all were retrospective series) and 5060 patients. Adjuvant chemotherapy was administered either intravenously or intra-arterially in the form of trans-arterial chemo-embolization (TACE). The average NOS for the included studies was 6.5. Pooled analysis of the included studies demonstrated significant advantage in the adjuvant chemotherapy group (HR 0.66, 0.55–079, P <.001, I-square [I2] = 20.8%). After 2 studies were removed for heterogeneity, advantage of adjuvant chemotherapy remained (HR 0.72, 0.62–0.84, P <.001, I2 = 0%). Funnel plot suggested no significant publication bias (Egger test, 2-tailed P = .203). Subgroup analyses suggested that intravenous route of chemotherapy injection (P <.001) and use of gemcitabine base regimen (P = .004) are associated with improved overall survival. Adjuvant chemotherapy did not improve disease-free survival in subgroup analysis (P = .94).Conclusion:Adjuvant chemotherapy is associated with improved overall survival and should be considered in patients with ICC following curative resection and in particular to patients with advance disease.

Role of nonalcoholic steatohepatitis as a risk factor for intrahepatic cholangiocarcinoma and its role in patients’ prognosis: A case-control study.

224 Background: The prevalence of intrahepatic cholangiocarcinoma (ICC) is rising worldwide. The current epidemics of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) might be partly responsible for this trend. Methods: Case control study investigating the prevalence of histology-confirmed NASH in peritumoral liver of resected ICC patients and controls (pre-explant biopsies of liver donors). Controls were matched for age and sex in a 2:1 fashion. Correlates between NASH, tumor characteristics and overall survival (OS) were also explored in the ICC cohort. Results: Between 2006 and 2017, 84 ICCs were resected in our Institution. Sixty-two (74%) had no apparent risk factors for ICC. Amongst this group, the prevalence of NAFLD and NASH was 45.2% and 24.2%,respectively, compared to 44.3 and 8.9% in the 124 matched liver donors (p = 1.000 and p = 0.007, respectively). The 5-year OS rate was 20.0% in NASH and 57.4% in ICC without either NASH and other risk factors (p = 0.017). Main tumor size, sex and NASH (hazard ratio 2.618 , 95% confidence interval 1.140-6.013, p = 0.023) were independent predictors of the OS at the multivariate Cox regression. Conclusions: NASH (but not NAFLD) acts as a risk factor for ICC and may affect its long-term outcome. A collaborative multicenter approach could confirm and strengthen these data.

Intrahepatic Mass-forming Cholangiocarcinoma: Arterial Enhancement Patterns at MRI and Prognosis.

Purpose To identify whether arterial enhancement pattern at MRI could predict the prognosis after surgical resection of intrahepatic mass-forming cholangiocarcinoma (IMCC). Materials and Methods Patients who underwent curative hepatic resection and preoperative MRI for IMCC from November 2007 to September 2016 were retrospectively evaluated. MRI enhancement pattern was classified by two radiologists. Recurrence and death data were retrieved until September 31, 2017. Prognostic factor analysis was performed by using preoperative and postoperative clinical-pathologic factors, as well as imaging findings. Results Data in 134 patients (median age, 63.0 years; 87 men and 47 women) were evaluated; median tumor size was 4.5 cm. Arterial phase MRI showed diffuse hypoenhancement in 33 patients, peripheral rim enhancement in 81 patients, and diffuse hyperenhancement in 20 patients. The 5-year risk of death in patients with IMCC with diffuse hyperenhancement was lower than that of patients with diffuse hypoenhancement or peripheral rim enhancement (5-year risk of death: 5.9% vs 87.9% vs 59.2%). Diffuse hypoenhancement (hazard ratio [HR], 41; 95% confidence interval [CI]: 5, 312; P < .01) and peripheral rim enhancement (HR, 11; 95% CI: 2, 85; P = .02) were associated with an increased risk of death compared with diffuse hyperenhancement. Patients with diffuse hyperenhancement of IMCCs had more frequent chronic liver disease (13 of 20; 65%), less frequent vascular invasion (six of 20; 30%), and less frequent tumor necrosis (three of 20; 15%) than other enhancement group (P < .05 for all). Conclusion The MRI arterial enhancement pattern was a prognostic marker in the preoperative evaluation of patients with resectable intrahepatic mass-forming cholangiocarcinoma. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Yoon and Lee .

Recurrence of intrahepatic cholangiocarcinoma – Patterns and therapy

Background: After resection of intrahepatic cholangiocarcinoma (ICC) recurrence is common, but data regarding therapy and prognosis of tumor recurrence are lacking. Methods: Patients with ICC (n = 153) were recorded prospectively (2008 – 2015). Site of recurrence, disease-free interval as well as treatment were further analysed using Kaplan Meier model for overall and recurrence free survival. Results: Out of 115 resections recurrence occurred in 70 cases (60.9 %). Location was intrahepatic (n = 30 patients; 42.9%), intra- and extrahepatic (n = 21; 30%) and extrahepatic (n = 19; 27.1%). The median recurrence free survival (RFS) was 9.2 months (range 0.4 – 68.3) with a 1-, 3- and 5-year RFS of 35%, 16% and 16%, respectively. In total, 16 re-explorations with 13 resections (81.25%) were performed (8 external primary resections) and 10 R0 resections achieved. Patients not considered for surgical therapy underwent chemotherapy (n = 40), TACE (n = 2), RFA (n = 3), SIRT (n = 1) or best supportive care (n = 16). Survival of repeated resection was significantly superior to alternative therapies (p = 0.017). The repeated resection group had a median overall survival (OS) of 61.6 months (range 11.7 – 183.8, data starting with first liver resection) with a 1-, 3- and 5-year OS rate of 90%, 68% and 54%, respectively. Conclusion: In solely intrahepatic recurrence repeated resection should be attempted to offer a chance for cure. Recurrent ICC amenable to repeated resection seem to be a positive selection associated with better survival.

Prognostic Value and Predication Model of Microvascular Invasion in Patients with Intrahepatic Cholangiocarcinoma.

Background: Whether microvascular invasion (MVI) adversely influences oncological outcomes for intrahepatic cholangiocarcinoma (ICC) patients remains unclear. The purpose of this study was to determine the impact of MVI on postoperative survival and establish a new predictive model for MVI before surgical intervention in patients with ICC.Methods: In this two-center retrospective study, 556 and 31 consecutive patients who underwent curative liver resection for ICC at ZSH and XJFH were analyzed, respectively. Propensity score matching (PSM) and Cox regression analyses were used to explore the prognostic role of MVI on the OS and DFS. Multivariate logistic regression was used to identify the relative risk factors of MVI, which were incorporated into the nomogram.Results: After PSM, 50 MVI cases matched with 172 non-MVI cases, and no bias was observed between the two groups (propensity score, 0.118 (0.099, 0.203) vs. 0.115 (0.059, 0.174), p=0.251). The multivariate Cox analysis showed that MVI was negatively associated with OS (HR 1.635, 95% CI 1.405-1.993, p=0.04) and DFS (HR 1.596, 95% CI 1.077-2.366, p=0.02). The independent factors associated with MVI were ALT, AFP, tumor maximal diameter, and tumor capsule. The nomogram that incorporated these variables achieved good concordance indexes for predicting MVI. Patients with a cutoff score of 168 were considered to have different risks of the presence of MVI preoperatively.Conclusions: The presence of MVI was an adverse prognostic factor for ICC patients. Using the nomogram model, the risk of an individual patient harboring MVI was determined, which led to a rational therapeutic choice.

The value of lymph node dissection for intrahepatic cholangiocarcinoma: a systemic review and meta-analysis

Introduction: Although lymph node metastasis was an adverse prognostic factor in patients who underwent hepatic resection for intrahepatic cholangiocarcinoma (ICC), the benefit of performing an lymph node dissection (LND) remains controversial. Our aim is to investigate whether LND could confer any survival benefit in patients with ICC. Method: A comprehensive search of several databases was performed to identify comparative studies evaluating survival outcomes between patients with and without LND. Overall survival (OS) and disease-free survival (DFS) were pooled by using the hazard ratio (HR) and the corresponding 95% confidence interval (CI). Result: Nine case-control studies were identified, including 1292 patients who underwent LND and 902 who did not undergo LND. Patients in the LND(+) group had a better OS than the LND(-) group, but the difference was not statistically significant (HR=0.76, 95%CI 0.58-1.00, Z = 1.93, P = 0.05). Pooled analysis revealed a significantly poorer DFS for patients without LND compared to patients with LND (HR, 0.70; 95% CI, 0.55-0.88, P=0.003). Subgroup analyses revealed that the OS of patients without lymph node metastasis is significantly better than those with lymph node metastasis (P<0.00001). There was no significant difference in the OS between patients without lymph node metastasis and patients who did not undergo LND (P=0.47). Conclusion: Routine LND can improve DFS rather than OS in the patient who underwent hepatic resection for ICC. LND might be useful to confirm tumor staging, to predict prognostic outcomes and to decide whether to apply adjuvant treatments.

Membrane human equilibrative nucleoside transporter 1 is associated with a high proliferation rate and worse survival in resected intrahepatic cholangiocarcinoma patients not receiving adjuvant treatments

Human equilibrative nucleoside transporter 1 (hENT-1) is a membrane nucleoside transporter mediating the intracellular uptake of nucleosides and their analogues. hENT-1 was recently reported to have a predictive role in intrahepatic cholangiocarcinoma (iCC) patients receiving adjuvant gemcitabine-based chemotherapy, but its biological and clinical significance in iCC remains unsettled. This study investigated the role of hENT-1 in regulating tumour growth and predicting the survival of 40 resected iCC patients not receiving adjuvant treatments. hENT-1 expression was found to be significantly higher in iCC than in the matched non-tumoural liver. Patients harbouring hENT-1 localised on the tumour cell membrane had a worse overall survival than membrane hENT-1–negative patients (median 21.2 months vs 30.3 months, p = 0.031), with an adjusted hazard ratio of 2.8 (95% confidence interval 1.01–7.76). Moreover, membrane hENT-1–positive patients had a higher percentage of Ki67-positive cells in tumour tissue than membrane hENT-1-negative patients (median 23% vs 5%, p < 0.0001). Functional analyses in iCC cell lines revealed that hENT-1 silencing inhibited cell proliferation and induced apoptosis in HUH-28 cells expressing hENT-1 on the cell membrane, but not in SNU-1079 cells expressing the transporter only in the cytoplasm. Overall, these findings suggest that membrane hENT-1 is involved in iCC proliferation and associated with worse survival in resected iCC patients. Further prospective studies on larger cohorts are required to confirm these results and better define the potential prognostic role of membrane hENT-1 in this setting of patients.

Prognostic Impact of Tumor Multinodularity in Intrahepatic Cholangiocarcinoma

BackgroundThe prognostic value of tumor multinodularity in intrahepatic cholangiocarcinoma (ICC) remains debated. We aimed to evaluate the impact of tumor multinodularity according to the presence and distribution of multiples ICC’s nodules. MethodsA retrospective review of a prospectively maintained database of patients undergoing resection for ICC from January 1995 to September 2017 was performed. Prognostic factors for survival were assessed by multivariate Cox analysis. Tumoral nodules were defined according to their number (single and multiple) and localization (satellites and contralateral). ResultsOut of 120 selected patients, 64 (53%) had single and 56 (47%) had multiple lesions. Multiple lesions included tumors with satellites (n = 40; 71.5%) and tumors with contralateral lesions (n = 16; 28.5%). Patients with multiple tumors had significantly larger mean main lesion size (p = 0.02), required a higher rate of perioperative transfusion (p = 0.04), had a greater rate of lymph node involvement (p < 0.0001), vascular invasion (p = 0.04), and poor differentiation (p = 0.04) than single tumors. Patients with single tumors experienced a 5-year survival significantly longer (40%) than patients with multiple tumors (14%; p = 0.004). Patients having tumors with satellites had inferior median overall survival and 5-year survival rates (20 months, 7%) compared with patients with contralateral tumors (33.6 months, 29%) (p = 0.09). Multivariable analysis identified tumor multinodularity, morbidity, tumor size < 5 cm, poor differentiation, and lymph node involvement as independent prognostic factors for overall survival. ConclusionsTumor multinodularity represents an independent risk factor for survival in ICCs and identifies a category of patients in need of more effective perioperative treatment.

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

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. 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). 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. 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.

Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) has universally poor outcome, mainly due to its late clinical presentation. Identification of specific biomarkers and development of effective treatment are still urgently required. Mutations in PBRM-1 and BAP-1 genes, and the expression of S100P have been related to survival in ICC. miR-31 seems also to play important regulatory functions in ICC and it directly regulates BAP-1 expression in lung cancer. In this study, tissue expression of BAP-1, PBRM-1, S100P, and miR-31 was investigated in ICC and correlated with clinical-pathological features. Sixty-one consecutive patients who underwent curative hepatic resection for ICC were enrolled. None received any therapy prior to surgery. Immunostaining for BAP-1, PBRM-1, and S100P, and in situ hybridization for miR-31 were performed, using tissue microarray slides. A strong retained expression of BAP-1 and PBRM-1 was associated with a reduced overall (p = 0.04 and p = 0.002, respectively) and disease-free survival (p = 0.05 and p = 0.02, respectively). An overexpression of S100P was related to a reduced overall survival (p = 0.005). The multivariate analyses identified the presence of perineural invasion and the retained PBRM-1 expression as independent predictors of worse overall [p = 0.02, hazard ratio (HR) = 2.25 (1.16-4.39) and p = 0.001, HR = 3.13 (1.56-6.28), respectively] and disease-free survivals [p = 0.03, HR = 2.43 (1.09-5.4) and p = 0.03, HR = 2.51 (1.11-5.67), respectively]. An overexpression of S100P was predictive of a worse overall survival [p = 0.02, HR = 1.66 (1.08-2.55)]. High levels of miR-31 were significantly associated to a low expression of BAP-1 protein (p = 0.03). In ICC, a retained expression of BAP-1 and PBRM-1, and an overexpression of S100P are related to a poor prognosis.