Advertisement

Prognostic influence of multiple hepatic lesions in resectable intrahepatic cholangiocarcinoma: A systematic review and meta-analysis

Open AccessPublished:January 15, 2023DOI:https://doi.org/10.1016/j.ejso.2023.01.006

      Highlights

      • Both satellite lesions and other multiple lesions found to be prognostic factors
      • Tumor distribution and number should be reported in intrahepatic cholangiocarcinoma
      • Evaluation of both tumor distribution and number could improve risk stratification

      Abstract

      Background

      Presence of multiple hepatic lesions in intrahepatic cholangiocarcinoma (iCCA) is included in staging as a negative prognostic factor, but both prognostic value and therapeutic implications remain debated. The aim of this study was to systematically review the prognostic influence of multiple lesions on survival after resection for iCCA, with stratification for distribution and number of lesions.

      Methods

      Medline and Embase were systematically searched to identify records (2010–2021) reporting survival for patients undergoing primary resection for iCCA. Included were original articles reporting overall survival, with data on multiple lesions including tumour distribution (satellites/other multiple lesions) and/or number. For meta-analysis, the random effects model and inverse variance method were used. PRISMA 2020 guidelines were followed.

      Results

      Thirty-one studies were included for review. For meta-analysis, nine studies reporting data on the prognostic influence of satellite lesions (2737 patients) and six studies reporting data on multiple lesions other than satellites (1589 patients) were included. Satellite lesions (hazard ratio 1.89, 95% confidence interval 1.67–2.13) and multiple lesions other than satellites (hazard ratio 2.41, 95% confidence interval 1.72–3.37) were significant negative prognostic factors. Data stratified for tumour number, while limited, indicated increased risk per additional lesion.

      Conclusion

      Satellite lesions, as well as multiple lesions other than satellites, was a negative prognostic factor in resectable iCCA. Considering the prognostic impact, both tumour distribution and number of lesions should be evaluated together with other risk factors to allow risk stratification for iCCA patients with multiple lesions, rather than precluding resection for the entire patient group.

      Keywords

      Abbreviations

      AJCC
      American Joint Committee on Cancer
      AT
      adjuvant therapy
      AUS
      Australia
      BR
      Brazil
      CHI
      China
      CI
      confidence interval
      CIR
      cirrhosis
      CT
      computerized tomography
      df
      degrees of freedom
      ENSCCA
      European Network for the Study of Cholangiocarcinoma
      EUR
      Europe
      FR
      France
      FU
      follow-up;
      GER
      Germany
      G3
      grade 3 (low differentiation)
      HBV
      hepatitis B virus
      HCV
      hepatitis C virus
      hep,
      hepatectomy
      HR
      hazard ratio
      iCCA
      intrahepatic cholangiocarcinoma
      IV
      inverse variance
      IT
      Italy
      KOR
      Korea
      LND
      lymph node dissection
      md
      median
      MeSH
      medical subject headings
      MF
      mass-forming
      mm
      millimeter
      MRI
      magnetic resonance imaging
      mult
      multiple
      N1
      lymph node metastasis
      N.AM
      North America
      NAT
      neoadjuvant therapy
      No
      number
      NS
      reported not significant
      PAT
      histopathology
      Pts
      patients
      RAD
      radiology
      R1
      microscopically tumour positive resection margin
      R2
      macroscopically tumour positive resection margin
      Ref
      reference
      SE
      standard error
      SEER
      Surveillance, Epidemiology, and End Results Program
      TNM
      TNM Classification of Malignant Tumours
      TWN
      Taiwan
      US
      United States
      vs
      versus

      1. Introduction

      The presence of multiple tumours in intrahepatic cholangiocarcinoma (iCCA) is included in the AJCC/TNM staging system as a negative prognostic factor [
      • Amin M.B.
      • Edge S.B.
      • Greene F.L.
      • Byrd D.R.
      • Brookland R.K.
      • Washington M.K.
      • et al.
      AJCC cancer staging manual.
      ,
      • Brierley J.
      • Gospodarowicz M.K.
      • Wittekind C.
      TNM classification of malignant tumours.
      ]. However, the precise prognostic value of multiple hepatic lesions, and the implications for therapy decisions, remain debated [
      • Lamarca A.
      • Santos-Laso A.
      • Utpatel K.
      • La Casta A.
      • Stock S.
      • Forner A.
      • et al.
      Liver metastases of intrahepatic cholangiocarcinoma: implications for an updated staging system.
      ,
      • Zhang X.F.
      • Lv Y.
      • Pawlik T.M.
      Letter to the editor: does multiple intrahepatic cholangiocarcinoma worsen prognosis as "M1" stage?.
      ,
      • Jansson H.
      • Sparrelid E.
      Letter to the editor: the role of surgery in multiple intrahepatic cholangiocarcinoma should not Be dismissed without further analysis.
      ].
      While multiple iCCA has been considered a relative contraindication to surgery [
      • Bridgewater J.
      • Galle P.R.
      • Khan S.A.
      • Llovet J.M.
      • Park J.W.
      • Patel T.
      • et al.
      Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
      ], long-term survival after resection of two or three lesions has been presented in large multicenter series [
      • Spolverato G.
      • Kim Y.
      • Alexandrescu S.
      • Popescu I.
      • Marques H.P.
      • Aldrighetti L.
      • et al.
      Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
      ,
      • Kudo M.
      • Izumi N.
      • Kokudo N.
      • Sakamoto M.
      • Shiina S.
      • Takayama T.
      • et al.
      Report of the 21st nationwide follow-up survey of primary liver cancer in Japan (2010-2011).
      ]. In trials of locoregional oncological therapy, multiple hepatic lesions has been considered as an unresectability criteria [
      • Cercek A.
      • Boerner T.
      • Tan B.R.
      • Chou J.F.
      • Gonen M.
      • Boucher T.M.
      • et al.
      Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial.
      ,
      • Massani M.
      • Bonariol L.
      • Stecca T.
      Hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma, a comprehensive review.
      ,
      • Edeline J.
      • Lamarca A.
      • McNamara M.G.
      • Jacobs T.
      • Hubner R.A.
      • Palmer D.
      • et al.
      Locoregional therapies in patients with intrahepatic cholangiocarcinoma: a systematic review and pooled analysis.
      ]. With regard to oncological therapy in iCCA, advances have been made in immunotherapy as well as systemic and regional oncological therapy, but with a majority of studies in patients with advanced disease and with evidence from randomized controlled-trials for neoadjuvant therapy still lacking [
      • Ohaegbulam K.C.
      • Koethe Y.
      • Fung A.
      • Mayo S.C.
      • Grossberg A.J.
      • Chen E.Y.
      • et al.
      The multidisciplinary management of cholangiocarcinoma.
      ,
      • Normanno N.
      • Martinelli E.
      • Melisi D.
      • Pinto C.
      • Rimassa L.
      • Santini D.
      • et al.
      Role of molecular genetics in the clinical management of cholangiocarcinoma.
      ].
      Recently, multiple lesions was proposed to represent a metastatic “M1a stage” of iCCA [
      • Lamarca A.
      • Santos-Laso A.
      • Utpatel K.
      • La Casta A.
      • Stock S.
      • Forner A.
      • et al.
      Liver metastases of intrahepatic cholangiocarcinoma: implications for an updated staging system.
      ], this analysis however did not take into account number or distribution of lesions, nor did it stratify for other factors including nodal and resection status [
      • Zhang X.F.
      • Lv Y.
      • Pawlik T.M.
      Letter to the editor: does multiple intrahepatic cholangiocarcinoma worsen prognosis as "M1" stage?.
      ,
      • Jansson H.
      • Sparrelid E.
      Letter to the editor: the role of surgery in multiple intrahepatic cholangiocarcinoma should not Be dismissed without further analysis.
      ,
      • Lamarca A.
      • Santos-Laso A.
      • Utpatel K.
      • La Casta A.
      • Stock S.
      • Forner A.
      • et al.
      Reply to Letter by Zhang et al.
      ,
      • Lamarca A.
      • Santos-Laso A.
      • Utpatel K.
      • La Casta A.
      • Stock S.
      • Forner A.
      • et al.
      Reply to letter by Jansson and Sparrelid.
      ]. Other authors have proposed multiple lesions to represent a T4 tumour extension [
      • Zhang X.F.
      • Xue F.
      • He J.
      • Alexandrescu S.
      • Marques H.P.
      • Aldrighetti L.
      • et al.
      Proposed modification of the eighth edition of the AJCC staging system for intrahepatic cholangiocarcinoma.
      ].
      According to the College of American Pathologists and the 8th edition of the AJCC/TNM staging system, the term multiple lesions comprises tumours with satellite nodules as well as multiple separate lesions (intrahepatic metastases and/or multifocal primary cholangiocarcinomas) [
      • Amin M.B.
      • Edge S.B.
      • Greene F.L.
      • Byrd D.R.
      • Brookland R.K.
      • Washington M.K.
      • et al.
      AJCC cancer staging manual.
      ,
      • Burgart L.
      • Chopp W.
      • Jain D.
      Protocol for the examination of specimens from patients with carcinoma of the intrahepatic bile ducts.
      ]. Discordant results have been reported regarding the prognostic impact of satellite lesions [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ,
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ].
      The aim of this study was therefore to systematically review survival outcomes after resection of multiple iCCA, stratified according to distribution and number of multiple lesions.

      2. Materials and methods

      The PRISMA 2020 guidelines were followed in reporting this review [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ]. The PRISMA 2020 Checklist for the study is presented in Supplemental Table 1. The study was preregistered in the International prospective register of systematic reviews (PROSPERO, study ID: CRD42021244952) [
      • Jansson H.
      • Sparrelid E.
      ].

      2.1 Literature search

      A broad systematic search of MEDLINE (Ovid) (28 April 2021) and Embase (4 May 2021) was undertaken in consultancy with specialized librarians at the Karolinska Institutet university library. The database searches were repeated on 15 December 2021 before finalisation of study screening. Medical subject headings (MeSH) and synonyms for ‘surgical resection’, ‘intrahepatic cholangiocarcinoma’ and ‘prognosis’ were combined. The search was limited to reports in English, published 2010 and later. The search was not limited to records mentioning tumour multiplicity/multifocality or synonyms thereof in title or abstract. Duplicate records were removed before screening. The search strategy documentation is presented in Supplemental Tables 2 and 3
      Two authors (HJ and CV) independently screened and assessed the identified records. Discrepancies were solved by discussion and input from a third reviewer (ES). The PRISMA 2020 flow diagram is presented in Fig. 1. Non-automated screening on title and abstract was performed in a reference manager for systematic reviews (Rayyan, Rayyan Systems Inc. Cambridge, MA, USA) [
      • Ouzzani M.
      • Hammady H.
      • Fedorowicz Z.
      • Elmagarmid A.
      Rayyan - a web and mobile app for systematic reviews.
      ]. Original research articles reporting prognosis after primary resection of iCCA were assessed for inclusion. Review articles reporting prognosis after primary resection of iCCA were also assessed for any additional records. Studies not reporting overall survival after primary resection of iCCA, or lacking comparative univariable survival data for patients with and without multiple tumours, were excluded, as were case reports/series of <10 patients. The outcome of interest was postoperative long-term survival and outcome data collected was limited to overall survival. Studies further stratifying survival outcomes depending on multiple tumour distribution (satellites i.e. nodules surrounding a primary lesion; or multiple lesions other than satellites) or for subgroups according to number of lesions were included for review, and assessed for inclusion in meta-analysis. For studies found to report overlapping cohorts, the largest or if similar cohort size the most recent, was chosen for comparison. When studies with overlapping cohorts reported additional data, they were included for comparison. For meta-analyses, no overlapping cohorts were included.

      2.2 Data extraction

      For included studies, the following demographic/clinicopathological characteristics were recorded: country/region, number of patients, time period and setting, staging modalities employed, any study specific limits to inclusion (e.g. only certain iCCA patient subgroups/iCCA subtypes), median follow-up time, median overall survival, median age, median tumour size, neoadjuvant/adjuvant therapy and proportion of patients with: lymph node metastasis (N1), microscopic tumour positive resection margin (R1), high tumour grade (poor tumour differentiation), mass-forming iCCA, underlying cirrhosis and viral hepatitis. The overall proportion of patients with multiple lesions as well as proportions with satellite lesions, multiple lesions other than satellites and in subgroups according to number of lesions were recorded. Overall survival for patients with a single tumour and for patients with multiple tumours (multiple all distributions, satellites, multiple other than satellites, subgroup according to number of lesions) was recorded. Non-automated data collection was performed by one reviewer (HJ), and recorded data assessed by a second reviewer (ES). Study quality and risk of bias was assessed independently with the Newcastle-Ottawa scale [
      • Margulis A.V.
      • Pladevall M.
      • Riera-Guardia N.
      • Varas-Lorenzo C.
      • Hazell L.
      • Berkman N.D.
      • et al.
      Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank.
      ,
      • Zeng X.
      • Zhang Y.
      • Kwong J.S.
      • Zhang C.
      • Li S.
      • Sun F.
      • et al.
      The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review.
      ,

      Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 10 January 2022.

      ] by two reviewers (HJ and ES). For meta-analysis the hazard ratios with confidence intervals or the comparison group sizes, number of events and log rank p-values were recorded. For studies reporting event data only as Kaplan-Meier curves with numbers at risk, survival proportion data was extracted using Engauge Digitizer v12.1 [
      • Mitchell M.
      • Muftakhidinov B.
      • Winchen T.
      Engauge digitizer software.
      ]. Confidence of pooled estimates was further assessed for downrating according to the GRADE framework for prognostic studies [
      • Iorio A.
      • Spencer F.A.
      • Falavigna M.
      • Alba C.
      • Lang E.
      • Burnand B.
      • et al.
      Use of GRADE for assessment of evidence about prognosis: rating confidence in estimates of event rates in broad categories of patients.
      ].

      2.3 Statistical analysis

      Meta-analysis was performed in Review Manager v5.4 (The Cochrane Collaboration) [
      ], using the inverse variance method and the random effects model. To compute pooled hazard ratios, the standard error of the log hazard ratio was calculated from summary statistics according to Parmar et al. [
      • Parmar M.K.
      • Torri V.
      • Stewart L.
      Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.
      ,
      • Tierney J.F.
      • Stewart L.A.
      • Ghersi D.
      • Burdett S.
      • Sydes M.R.
      Practical methods for incorporating summary time-to-event data into meta-analysis.
      ]. For studies reporting survival curve data, the log hazard ratio and its standard error were estimated according to Williamson et al. [
      • Tierney J.F.
      • Stewart L.A.
      • Ghersi D.
      • Burdett S.
      • Sydes M.R.
      Practical methods for incorporating summary time-to-event data into meta-analysis.
      ,
      • Williamson P.R.
      • Smith C.T.
      • Hutton J.L.
      • Marson A.G.
      Aggregate data meta-analysis with time-to-event outcomes.
      ]. Heterogeneity was assessed by the I2 statistic and Chi-square test, and publication bias assessed graphically with funnel plots. Categorical variables were reported with numbers and percentages, continuous variables with medians. Relative risks were presented as hazard ratios with 95% confidence intervals, when reported, or as estimated when sufficient data was available from published survival and follow-up. Sensitivity analyses were performed excluding studies with the highest risk of bias according to study quality assessment.

      3. Results

      3.1 Identification of studies

      A total of 4184 unique records were identified after database searches of Medline (Ovid) and Embase, with deduplication. After first screening on title and abstract, 855 reports were assessed for eligibility. Reasons for exclusion are given in the PRISMA diagram in Fig. 1. Out of 248 reports with univariable overall survival data for patients with multiple lesions, 204 reports lacked data stratified for distribution or number of lesions. Thirteen reports of overlapping cohorts were excluded [
      • Kudo M.
      • Izumi N.
      • Kokudo N.
      • Sakamoto M.
      • Shiina S.
      • Takayama T.
      • et al.
      Report of the 21st nationwide follow-up survey of primary liver cancer in Japan (2010-2011).
      ,
      • Zhang X.F.
      • Xue F.
      • Dong D.H.
      • Weiss M.
      • Popescu I.
      • Marques H.P.
      • et al.
      Number and station of lymph node metastasis after curative-intent resection of intrahepatic cholangiocarcinoma impact prognosis.
      ,
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • Alex
      • rescu S.
      • Marques H.P.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      ,
      • Conci S.
      • Vigano L.
      • Ercolani G.
      • Gonzalez E.
      • Ruzzenente A.
      • Isa G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      ,
      • Ikai I.
      • Kudo M.
      • Arii S.
      • Omata M.
      • Kojiro M.
      • Sakamoto M.
      • et al.
      Report of the 18th follow-up survey of primary liver cancer in Japan.
      ,
      • Kudo M.
      • Izumi N.
      • Ichida T.
      • Ku Y.
      • Kokudo N.
      • Sakamoto M.
      • et al.
      Report of the 19th follow-up survey of primary liver cancer in Japan.
      ,
      • Kudo M.
      • Izumi N.
      • Kubo S.
      • Kokudo N.
      • Sakamoto M.
      • Shiina S.
      • et al.
      Report of the 20th Nationwide follow-up survey of primary liver cancer in Japan.
      ,
      • Liu H.
      • Lin L.
      • Lin Z.
      • Chen Y.
      • Huang Q.
      • Ding L.
      • et al.
      Impact of surgical margin width on long-term outcomes for intrahepatic cholangiocarcinoma: a multicenter study.
      ,
      • Tian M.X.
      • Zhou Y.F.
      • Qu W.F.
      • Liu W.R.
      • Jin L.
      • Jiang X.F.
      • et al.
      Histopathology-based immunoscore predicts recurrence for intrahepatic cholangiocarcinoma after hepatectomy.
      ,
      • Wang L.
      • Deng M.
      • Ke Q.
      • Lou J.
      • Zheng S.
      • Bi X.
      • et al.
      Postoperative adjuvant therapy following radical resection for intrahepatic cholangiocarcinoma: a multicenter retrospective study.
      ,
      • Wang L.
      • Lin Z.G.
      • Ke Q.
      • Lou J.Y.
      • Zheng S.G.
      • Bi X.Y.
      • et al.
      Adjuvant transarterial chemoembolization following radical resection for intrahepatic cholangiocarcinoma: a multi-center retrospective study.
      ,
      • Wang T.
      • Zhang J.
      • Wang W.
      • Yang X.
      • Kong J.
      • Shen S.
      • et al.
      Development and validation of nomograms for predicting cancer-specific survival in elderly patients with intrahepatic cholangiocarcinoma after liver resection: a competing risk analysis.
      ,

      Ke Q, Wang L, Lin Z, Lou J, Zheng S, Bi X, Wang J, Guo W, Li F, Wang J, Zheng Y, Li J, Cheng S, Zhou W, Zeng Y. Prognostic Value of Lymph Node Dissection for Intrahepatic Cholangiocarcinoma Patients With Clinically Negative Lymph Node Metastasis: A Multi-Center Study From China. Front Oncol. 2021 Mar 11;11:585808.

      ], and are presented in Supplemental Table 4. A total of 31 studies, all retrospective cohort studies, were included in this review and are presented in Table 1. The included studies comprised 21 single center studies [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ,
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ,
      • Aherne E.A.
      • Pak L.M.
      • Goldman D.A.
      • Gonen M.
      • Jarnagin W.R.
      • Simpson A.L.
      • et al.
      Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics?.
      ,
      • Chen Q.
      • Li F.
      • Gao Y.
      • Xue H.
      • Li Z.
      • Zou Q.
      • et al.
      Developing a selection-aided model to screen cirrhotic intrahepatic cholangiocarcinoma for hepatectomy.
      ,
      • Fu K.
      • Yang X.
      • Wu H.
      • Gong J.
      • Li X.
      Diabetes and PKM2 affect prognosis in patients with intrahepatic cholangiocarcinoma.
      ,
      • Kim S.H.
      • Park Y.N.
      • Lim J.H.
      • Choi G.H.
      • Choi J.S.
      • Kim K.S.
      Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
      ,
      • King M.J.
      • Hectors S.
      • Lee K.M.
      • Omidele O.
      • Babb J.S.
      • Schwartz M.
      • et al.
      Outcomes assessment in intrahepatic cholangiocarcinoma using qualitative and quantitative imaging features.
      ,
      • Lee C.T.
      • Wu T.T.
      • Lohse C.M.
      • Zhang L.
      High-mobility group AT-hook 2: an independent marker of poor prognosis in intrahepatic cholangiocarcinoma.
      ,
      • Liu L.Z.
      • Yang L.X.
      • Zheng B.H.
      • Dong P.P.
      • Liu X.Y.
      • Wang Z.C.
      • et al.
      CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
      ,
      • Lu C.D.
      • Wang K.
      • Zhang C.Z.
      • Zhou F.G.
      • Guo W.X.
      • Wu M.C.
      • et al.
      Outcomes of intrahepatic cholangiocarcinoma with portal vein tumor thrombus following hepatic resection.
      ,
      • Nuzzo G.
      • Giuliante F.
      • Ardito F.
      • De Rose A.M.
      • Vellone M.
      • Clemente G.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after liver resection.
      ,
      • Scheuermann U.
      • Kaths J.M.
      • Heise M.
      • Pitton M.B.
      • Weinmann A.
      • Hoppe-Lotichius M.
      • et al.
      Comparison of resection and transarterial chemoembolisation in the treatment of advanced intrahepatic cholangiocarcinoma--a single-center experience.
      ,
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ,
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ,
      • Tian M.
      • Liu W.
      • Tao C.
      • Tang Z.
      • Zhou Y.
      • Song S.
      • et al.
      Prediction of overall survival in resectable intrahepatic cholangiocarcinoma: ISICC-applied prediction model.
      ,
      • Wang T.
      • Kong J.
      • Yang X.
      • Shen S.
      • Zhang M.
      • Wang W.
      Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
      ,
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ,
      • Yeh C.N.
      • Hsieh F.J.
      • Chiang K.C.
      • Chen J.S.
      • Yeh T.S.
      • Jan Y.Y.
      • et al.
      Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma.
      ,
      • Zhou H.B.
      • Wang H.
      • Li Y.Q.
      • Li S.X.
      • Wang H.
      • Zhou D.X.
      • et al.
      Hepatitis B virus infection: a favorable prognostic factor for intrahepatic cholangiocarcinoma after resection.
      ,
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ,
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ], nine multicenter studies [
      • Brustia R.
      • Langella S.
      • Kawai T.
      • Fonseca G.M.
      • Schielke A.
      • Colli F.
      • et al.
      Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
      ,
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ,
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ,
      • De Rose A.M.
      • Cucchetti A.
      • Clemente G.
      • Ardito F.
      • Giovannini I.
      • Ercolani G.
      • et al.
      Prognostic significance of tumor doubling time in mass-forming type cholangiocarcinoma.
      ,
      • Moro A.
      • Paredes A.Z.
      • Farooq A.
      • Sahara K.
      • Tsilimigras D.I.
      • Mehta R.
      • et al.
      Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: a preoperative vs postoperative perspective.
      ,
      • Spolverato G.
      • Kim Y.
      • Alex
      • rescu S.
      • Popescu I.
      • Marques H.P.
      • et al.
      Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
      ,
      • Tsilimigras D.I.
      • Mehta R.
      • Moris D.
      • Sahara K.
      • Bagante F.
      • Paredes A.Z.
      • et al.
      A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • Moris D.
      • Beal E.W.
      • Weiss M.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Chen Y.
      • Liu H.
      • Zhang J.
      • Wu Y.
      • Zhou W.
      • Cheng Z.
      • et al.
      Prognostic value and predication model of microvascular invasion in patients with intrahepatic cholangiocarcinoma: a multicenter study from China.
      ], and one study reporting a nationwide survey [
      • Kudo M.
      • Izumi N.
      • Kokudo N.
      • Sakamoto M.
      • Shiina S.
      • Takayama T.
      • et al.
      Report of the 22nd nationwide follow-up survey of primary liver cancer in Japan (2012-2013).
      ]. Seventeen studies showed overlap between cohorts as evaluated according to reported center and study period (Table 1). Qualitative assessment according to the Newcastle-Ottawa scale is presented in Supplemental Table 5. The median score on the scale was seven stars. Three studies had a total score of four [
      • Chen Q.
      • Li F.
      • Gao Y.
      • Xue H.
      • Li Z.
      • Zou Q.
      • et al.
      Developing a selection-aided model to screen cirrhotic intrahepatic cholangiocarcinoma for hepatectomy.
      ,
      • Lee C.T.
      • Wu T.T.
      • Lohse C.M.
      • Zhang L.
      High-mobility group AT-hook 2: an independent marker of poor prognosis in intrahepatic cholangiocarcinoma.
      ,
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ], and four studies had a total score of five [
      • Lu C.D.
      • Wang K.
      • Zhang C.Z.
      • Zhou F.G.
      • Guo W.X.
      • Wu M.C.
      • et al.
      Outcomes of intrahepatic cholangiocarcinoma with portal vein tumor thrombus following hepatic resection.
      ,
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ,
      • De Rose A.M.
      • Cucchetti A.
      • Clemente G.
      • Ardito F.
      • Giovannini I.
      • Ercolani G.
      • et al.
      Prognostic significance of tumor doubling time in mass-forming type cholangiocarcinoma.
      ,
      • Chen Y.
      • Liu H.
      • Zhang J.
      • Wu Y.
      • Zhou W.
      • Cheng Z.
      • et al.
      Prognostic value and predication model of microvascular invasion in patients with intrahepatic cholangiocarcinoma: a multicenter study from China.
      ], out of a maximal possible score of nine.
      Table 1Studies included for review: background characteristics of reported cohorts.
      Study (year)Time period/Country or regionNo. of pts.&/single- or multi-centreiCCA sub-group% Mass-form.% WomenMd age (Y)/Md max size (mm)Diagn.mod.% Mult./Satell.% Other group% Sub-group no. (no. of lesions)% Cirrhosis/% HBV or HBV + HCV
      Addeo (2019) [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ]
      1995–2017119644713c
      FRsingle78#33a
      Aherne (2018) [
      • Aherne E.A.
      • Pak L.M.
      • Goldman D.A.
      • Gonen M.
      • Jarnagin W.R.
      • Simpson A.L.
      • et al.
      Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics?.
      ]
      1993–201466MF!1006265CT6d
      USsingle5918
      Bartsch (2021) [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ]
      2000–20181254964CT/MRI258c
      GERsingle10
      Bednarsch (2021) [
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ]
      2010–20201395665#CT/M29.512 (2–3)
      GERsingleRI7 (4–5)
      10 (>5)
      Brustia (2020) [
      • Brustia R.
      • Langella S.
      • Kawai T.
      • Fonseca G.M.
      • Schielke A.
      • Colli F.
      • et al.
      Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
      ]
      2001–201824648e68ePAT9$9e
      EUR, BR, JPNmulti50e2018e
      Buettner (2017) [
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ]
      1990–201610549246597d
      N. AM, EUR, ASIA, AUSmultif6123
      Chen Q (2020) [
      • Chen Q.
      • Li F.
      • Gao Y.
      • Xue H.
      • Li Z.
      • Zou Q.
      • et al.
      Developing a selection-aided model to screen cirrhotic intrahepatic cholangiocarcinoma for hepatectomy.
      ]
      2006–2011305CIR135241100
      CHIsinglef502087
      Chen Y (2021) [
      • Chen Y.
      • Liu H.
      • Zhang J.
      • Wu Y.
      • Zhou W.
      • Cheng Z.
      • et al.
      Prognostic value and predication model of microvascular invasion in patients with intrahepatic cholangiocarcinoma: a multicenter study from China.
      ]
      2009–2017704R042PAT28
      CHImulti2736
      Conci (2018) [
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ]
      1995–20152435068PAT3514$
      ITmultik5722
      De Rose (2013) [
      • De Rose A.M.
      • Cucchetti A.
      • Clemente G.
      • Ardito F.
      • Giovannini I.
      • Ercolani G.
      • et al.
      Prognostic significance of tumor doubling time in mass-forming type cholangiocarcinoma.
      ]
      2000–200979MF1004267CT/MRI
      ITmultij6544b34
      Fu (2020) [
      • Fu K.
      • Yang X.
      • Wu H.
      • Gong J.
      • Li X.
      Diabetes and PKM2 affect prognosis in patients with intrahepatic cholangiocarcinoma.
      ]
      2006–20111104453#4021d
      CHIsingle
      Kim (2014) [
      • Kim S.H.
      • Park Y.N.
      • Lim J.H.
      • Choi G.H.
      • Choi J.S.
      • Kim K.S.
      Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
      ]
      2000–20097735613$
      KORsingle5017d @21
      King (2020) [
      • King M.J.
      • Hectors S.
      • Lee K.M.
      • Omidele O.
      • Babb J.S.
      • Schwartz M.
      • et al.
      Outcomes assessment in intrahepatic cholangiocarcinoma using qualitative and quantitative imaging features.
      ]
      2003–201752sMF10064e63eCT5$e4e
      USsinglek68e27o15e
      Kudo (2021) [
      • Kudo M.
      • Izumi N.
      • Kokudo N.
      • Sakamoto M.
      • Shiina S.
      • Takayama T.
      • et al.
      Report of the 22nd nationwide follow-up survey of primary liver cancer in Japan (2012-2013).
      ]
      2002–2013302271&39& ^PAT156 (2)8&
      JPNmulti9 (>2)
      Lee (2014) [
      • Lee C.T.
      • Wu T.T.
      • Lohse C.M.
      • Zhang L.
      High-mobility group AT-hook 2: an independent marker of poor prognosis in intrahepatic cholangiocarcinoma.
      ]
      1995–20035362e61#e
      USsingle79#e32
      Liu (2018) [
      • Liu L.Z.
      • Yang L.X.
      • Zheng B.H.
      • Dong P.P.
      • Liu X.Y.
      • Wang Z.C.
      • et al.
      CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
      ]
      2005–201121443582628
      CHIsinglei5540
      Lu (2016) [
      • Lu C.D.
      • Wang K.
      • Zhang C.Z.
      • Zhou F.G.
      • Guo W.X.
      • Wu M.C.
      • et al.
      Outcomes of intrahepatic cholangiocarcinoma with portal vein tumor thrombus following hepatic resection.
      ]
      2000–2005303MF1003252#32
      CHIsingleg68#53
      Moro (2019) [
      • Moro A.
      • Paredes A.Z.
      • Farooq A.
      • Sahara K.
      • Tsilimigras D.I.
      • Mehta R.
      • et al.
      Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: a preoperative vs postoperative perspective.
      ]
      1990–2016114584§456010
      N. AM, EUR, ASIA, AUSmultif602017
      Nuzzo (2010) [
      • Nuzzo G.
      • Giuliante F.
      • Ardito F.
      • De Rose A.M.
      • Vellone M.
      • Clemente G.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after liver resection.
      ]
      1997–2008558645643615 (2)
      ITsingle60#22 (>2)38
      Scheuermann (2013) [
      • Scheuermann U.
      • Kaths J.M.
      • Heise M.
      • Pitton M.B.
      • Weinmann A.
      • Hoppe-Lotichius M.
      • et al.
      Comparison of resection and transarterial chemoembolisation in the treatment of advanced intrahepatic cholangiocarcinoma--a single-center experience.
      ]
      1997–20121305065PAT75 (1–3)
      GERsingle7025 (>3)3
      Shen (2018) [
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ]
      2009–20139149578$15
      CHIsingleh64#2086
      Spolverato (2015) [
      • Spolverato G.
      • Kim Y.
      • Alex
      • rescu S.
      • Popescu I.
      • Marques H.P.
      • et al.
      Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
      ]
      1990–2013342≥70 mm or mult.49609
      N. AM, EUR, ASIA, AUSmultif85
      Tabrizian (2015) [
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ]
      1995–20118151PAT11$9
      USsinglek24
      Tian (2020) [
      • Tian M.
      • Liu W.
      • Tao C.
      • Tang Z.
      • Zhou Y.
      • Song S.
      • et al.
      Prediction of overall survival in resectable intrahepatic cholangiocarcinoma: ISICC-applied prediction model.
      ]
      2005–2011168R0412012 (2)
      CHIsinglei608 (>2)43
      Tsilimigras (2020) [
      • Tsilimigras D.I.
      • Mehta R.
      • Moris D.
      • Sahara K.
      • Bagante F.
      • Paredes A.Z.
      • et al.
      A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
      ]
      1990–2017114687§44601813 (2–3)11
      N. AM, EUR, ASIA, AUSmultif605 (>3)
      Wang T (2020) [
      • Wang T.
      • Kong J.
      • Yang X.
      • Shen S.
      • Zhang M.
      • Wang W.
      Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
      ]
      2008–2018398R047RAD PAT3213
      CHIsingleh1632
      Wang Y (2013) [
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ]
      2002–20073673353PAT89 (1–2)21
      CHIsinglef11 (>2)51
      Yeh (2015) [
      • Yeh C.N.
      • Hsieh F.J.
      • Chiang K.C.
      • Chen J.S.
      • Yeh T.S.
      • Jan Y.Y.
      • et al.
      Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma.
      ]
      1977–200784R1+R22610$
      TWNsingle8
      Zhang (2017) [
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • Moris D.
      • Beal E.W.
      • Weiss M.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ]
      1990–20161023804459PAT17$11
      N. AM, EUR, ASIA, AUSmultif22
      Zhou (2011) [
      • Zhou H.B.
      • Wang H.
      • Li Y.Q.
      • Li S.X.
      • Wang H.
      • Zhou D.X.
      • et al.
      Hepatitis B virus infection: a favorable prognostic factor for intrahepatic cholangiocarcinoma after resection.
      ]
      2005–200715555#12$29
      CHIsinglef25q56
      Zhu (2021) [
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ]
      2015–2018126R09459#10$
      CHIsingle64#29
      AUS: Australia; BR: Brazil; EUR: Europe; HBV: hepatitis B virus; HCV: hepatitis C virus; CHI: China; CIR: cirrhosis; CT: computerized tomography; FR: France; GER: Germany; IT: Italy; JPN: Japan; KOR: Korea; Md: median; MF: Mass-forming; mm: millimeter; MRI: magnetic resonance imaging; mass-form: mass-forming; mult: multiple; N.AM: North America; No: number; PAT: histopathology; pts: patients; R0: microscopically tumour negative resection margin; R1: microscopically tumour positive resection margin; R2: macroscopically tumour positive resection margin; RAD: radiology; sat: satellites; TWN: Taiwan; US: United States.
      & with multiple lesion data
      ^ of all patients resectable and unresectable.
      § including intraductal growing.
      ! patients with genetic mutational profiling.
      # mean.
      satellites.
      multiple.
      a all lesions within ipsilateral hemiliver.
      b category reported: “satellitosis”.
      c contralateral.
      including diffuse infiltration.
      d intrahepatic metastasis.
      $ multiple not including satellites.
      @ including satellites and microscopic noduli.
      o including multiple lesions other than satellites in statistical analysis.
      q category reported: "microscopic satellite lesions".
      r data for years 2012-2013 only
      s subset with computerized tomography
      e of all patients assessed/wider cohort.
      f overlap of cohorts (Buettner, Chen Q, Moro, Spolverato, Tsilimigras, Wang Y, Zhang, Zhou).
      g overlap with same cohorts as f except Chen Q.
      h overlap of cohorts (Shen, Wang T, Wang L).
      i overlap of cohorts (Tian, Liu).
      j overlap of cohorts (Conci, De Rose).
      k overlap of cohorts (King, Tabrizian).

      3.2 Demographic and clinicopathological data

      Characteristics of the included studies and cohorts are presented in Table 1. The proportion of resected iCCA patients with satellite lesions ranged from 8 to 44%, while the proportion of patients resected with multiple lesions ranged from 15 to 47%. The proportion of patients with multiple lesions not including satellites was reported in 10 studies, ranging from three to 17%. Among patients with multiple lesions, the proportion with two or two-three lesions was reported in five studies, ranging from 40 to 71%. Twenty studies reported data for iCCA patients in general, while 11 studies reported data only for patients with a disease subtype (i.e. mass-forming iCCA), or within a certain prognostic group (e.g. patients with radical/non-radical resection margin or underlying cirrhosis).

      3.3 Overall survival and surgical data

      Overall survival outcomes, median follow-up times and surgical data for the included studies are presented in Table 2. Median follow-up ranged from 18 to 55 months. Median overall survival for all resected patients ranged from 17 to 53 months. The proportion of patients undergoing major resections ranged from 40 to 86% and the proportion of patients operated with hepatic resection and associated lymphadenectomy ranged from 33 to 93%. In the five studies in which a majority of patients underwent lymphadenectomy, the proportion of patients with lymph node metastases ranged from 21 to 38%. While five studies limited inclusion to only patients with radical or non-radical resection, the proportion of patients with positive resection margin among the remaining studies ranged from six to 42%. Sixteen studies reported the overall proportions of patients treated with neoadjuvant or adjuvant oncological therapy. The proportion of patients with neoadjuvant therapy ranged from zero to nine percent, while the proportion of patients treated with adjuvant therapy ranged from 20 to 53%.
      Table 2Overall survival and surgical data for included studies.
      Study (year)Overall md FU/md OS (months)Md OS (months) Single/Multiple/SatellitesHR (95% CI) Multiple Yes vs No/Satellites Yes vs No/OtherHR (95% CI) Subgroup number of lesions [Subgroup vs Ref. group]% Major hep./LND% NAT/AT% N1/R1/G3
      Addeo (2019) [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ]
      36.51.8 (1.2–2.8)78038
      28212.2 (1.4–3.7)a [est]932014
      201.1 (0.5–2.3)c [est]22
      Aherne (2018) [
      • Aherne E.A.
      • Pak L.M.
      • Goldman D.A.
      • Gonen M.
      • Jarnagin W.R.
      • Simpson A.L.
      • et al.
      Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics?.
      ]
      418
      533.3 (1.4–8.0)
      NS (no data)d
      Bartsch (2021) [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ]
      277528
      221.4 (0.7–3.1) [est]10
      21.55.0 (1.8–13.8) [est]28
      Bednarsch (2021) [
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ]
      54321.7 (0.9–3.1) [2–3 vs 1]76937
      251.7 (0.8–3.8) [4–5 vs 1]3312
      2.8 (1.5–5.4) [>5 vs 1]30
      Brustia (2020) [
      • Brustia R.
      • Langella S.
      • Kawai T.
      • Fonseca G.M.
      • Schielke A.
      • Colli F.
      • et al.
      Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
      ]
      48722
      261.7 (1.1–2.5)2118
      27
      Buettner (2017) [
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ]
      1.9 (1.5–2.3)1.8 (1.4–2.2) [2–3 vs 1]5918
      382.5 (1.7–3.6) [>3 vs 1]4513
      Chen Q (2020) [
      • Chen Q.
      • Li F.
      • Gao Y.
      • Xue H.
      • Li Z.
      • Zou Q.
      • et al.
      Developing a selection-aided model to screen cirrhotic intrahepatic cholangiocarcinoma for hepatectomy.
      ]
      1.4 (1.3-1-6)y
      1.7 (1.3–2.4)
      Chen Y (2021) [
      • Chen Y.
      • Liu H.
      • Zhang J.
      • Wu Y.
      • Zhou W.
      • Cheng Z.
      • et al.
      Prognostic value and predication model of microvascular invasion in patients with intrahepatic cholangiocarcinoma: a multicenter study from China.
      ]
      1.6 (1.3–2.0)57016
      1.7 (1.4–2.1)330
      20
      Conci (2018) [
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ]
      60826
      462.0 (1.2–3.3) [est]4127
      5.1 (2.7–9.9)$ [est]36
      De Rose (2013) [
      • De Rose A.M.
      • Cucchetti A.
      • Clemente G.
      • Ardito F.
      • Giovannini I.
      • Ercolani G.
      • et al.
      Prognostic significance of tumor doubling time in mass-forming type cholangiocarcinoma.
      ]
      2670024
      40P = 0.272†b775319
      32
      Fu (2020) [
      • Fu K.
      • Yang X.
      • Wu H.
      • Gong J.
      • Li X.
      Diabetes and PKM2 affect prognosis in patients with intrahepatic cholangiocarcinoma.
      ]
      556.1 (3.5–10.8)32
      42
      9.3 (4.9–17.7)d12
      Kim (2014) [
      • Kim S.H.
      • Park Y.N.
      • Lim J.H.
      • Choi G.H.
      • Choi J.S.
      • Kim K.S.
      Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
      ]
      86
      16
      1.9 (0.3–14.3)$
      2.1 (1.6–6.7)d @
      King (2020) [
      • King M.J.
      • Hectors S.
      • Lee K.M.
      • Omidele O.
      • Babb J.S.
      • Schwartz M.
      • et al.
      Outcomes assessment in intrahepatic cholangiocarcinoma using qualitative and quantitative imaging features.
      ]
      025
      1.9 (0.9-4.1)o
      49
      Kudo (2021) [
      • Kudo M.
      • Izumi N.
      • Kokudo N.
      • Sakamoto M.
      • Shiina S.
      • Takayama T.
      • et al.
      Report of the 22nd nationwide follow-up survey of primary liver cancer in Japan (2012-2013).
      ]
      6464&22&
      35++ 17f49&6&
      Lee (2014) [
      • Lee C.T.
      • Wu T.T.
      • Lohse C.M.
      • Zhang L.
      High-mobility group AT-hook 2: an independent marker of poor prognosis in intrahepatic cholangiocarcinoma.
      ]
      23
      341.8 (0.9–3.4)8
      85
      Liu (2018) [
      • Liu L.Z.
      • Yang L.X.
      • Zheng B.H.
      • Dong P.P.
      • Liu X.Y.
      • Wang Z.C.
      • et al.
      CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
      ]
      290.8 (0.5–1.3) [2–3 vs 1]17
      2.7 (1.7-4.2) [>3 vs 1]
      38
      Lu (2016) [
      • Lu C.D.
      • Wang K.
      • Zhang C.Z.
      • Zhou F.G.
      • Guo W.X.
      • Wu M.C.
      • et al.
      Outcomes of intrahepatic cholangiocarcinoma with portal vein tumor thrombus following hepatic resection.
      ]
      P = 0.006
      Moro (2019) [
      • Moro A.
      • Paredes A.Z.
      • Farooq A.
      • Sahara K.
      • Tsilimigras D.I.
      • Mehta R.
      • et al.
      Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: a preoperative vs postoperative perspective.
      ]
      1.2 (1.2–1.3)?62616
      212.1 (1.8–2.6)2814
      19
      Nuzzo (2010) [
      • Nuzzo G.
      • Giuliante F.
      • Ardito F.
      • De Rose A.M.
      • Vellone M.
      • Clemente G.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after liver resection.
      ]
      29P = 0.285P = 0.089 [>3 vs ≤ 2]7826
      30217320
      32
      Scheuermann (2013) [
      • Scheuermann U.
      • Kaths J.M.
      • Heise M.
      • Pitton M.B.
      • Weinmann A.
      • Hoppe-Lotichius M.
      • et al.
      Comparison of resection and transarterial chemoembolisation in the treatment of advanced intrahepatic cholangiocarcinoma--a single-center experience.
      ]
      P = 0.030 [>3 vs ≤ 3]8129
      283727
      31
      Shen (2018) [
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ]
      20
      182.4 (1.3–4.5) [est]8
      2.4 (1.0–6.1)$ [est]73
      Spolverato (2015) [
      • Spolverato G.
      • Kim Y.
      • Alex
      • rescu S.
      • Popescu I.
      • Marques H.P.
      • et al.
      Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
      ]
      22e1.7 (1.2–2.4) [>3 vs ≤ 3]76p21
      21565119
      29
      Tabrizian (2015) [
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ]
      27417326
      272.1 (1.1–4.1) [est]2824
      241.9 (0.8–4.7)$ [est]40
      Tian (2020) [
      • Tian M.
      • Liu W.
      • Tao C.
      • Tang Z.
      • Zhou Y.
      • Song S.
      • et al.
      Prediction of overall survival in resectable intrahepatic cholangiocarcinoma: ISICC-applied prediction model.
      ]
      45e1.2 (0.6–1.3) [2 vs 1]05
      28e0
      30
      Tsilimigras (2020) [
      • Tsilimigras D.I.
      • Mehta R.
      • Moris D.
      • Sahara K.
      • Bagante F.
      • Paredes A.Z.
      • et al.
      A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
      ]
      Md OS months (95% CI): 15 (10–19) vs 21 (16–27) [>3 vs 2–3]61717
      21+++ 15g13
      18
      Wang T (2020) [
      • Wang T.
      • Kong J.
      • Yang X.
      • Shen S.
      • Zhang M.
      • Wang W.
      Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
      ]
      1.8 (1.3–2.3)6125
      1.7 (1.3–2.4)0
      Wang Y (2013) [
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ]
      391.4 (0.9–2.2) [2–3 vs. 1]22
      21
      Yeh (2015) [
      • Yeh C.N.
      • Hsieh F.J.
      • Chiang K.C.
      • Chen J.S.
      • Yeh T.S.
      • Jan Y.Y.
      • et al.
      Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma.
      ]
      9.531
      10.546100μ
      429
      Zhang (2017) [
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • Moris D.
      • Beal E.W.
      • Weiss M.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ]
      5917
      372.1 (1.7–2.6)4713
      2.0 (1.6–2.5)$17
      Zhou (2011) [
      • Zhou H.B.
      • Wang H.
      • Li Y.Q.
      • Li S.X.
      • Wang H.
      • Zhou D.X.
      • et al.
      Hepatitis B virus infection: a favorable prognostic factor for intrahepatic cholangiocarcinoma after resection.
      ]
      21
      17P < 0.001n
      P = 0.007$24
      Zhu (2021) [
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ]
      18126
      291.5 (0.7–2.0)63340
      2.1 (1.0–4.2$41
      AT: adjuvant therapy; CI: confidence interval; FU: follow-up; G3: grade 3 (low differentiation); hep: hepatectomy; HR: hazard ratio; LND: lymph node dissection; md: median; N1: lymph node metastasis; NAT: neoadjuvant therapy; No: number; NS: reported not significant; OS: overall survival; R0: microscopically tumour negative resection margin; R1: microscopically tumour positive resection margin; R2: macroscopically tumour positive resection margin; Ref: reference; vs: versus.
      e of all patients assessed/wider cohort.
      ++ 2 lesions.
      f > 2 lesions.
      +++ 3 lesions.
      g > 3 lesions.
      [est] estimated from summary statistics.
      a all lesions within ipsilateral hemiliver.
      c contralateral.
      including diffuse infiltration.
      d intrahepatic metastasis.
      y per additional lesion.
      $ multiple not including satellites.
      @ including satellites and microscopic noduli.
      n category reported: "microscopic satellite lesions".
      o including multiple lesions other than satellites in statistical analysis.
      satellites.
      b category reported: “satellitosis”.
      ? not specified if per additional lesion.
      & data for years 2010–2011 only.
      p hemihepatectomy/extended hemihepatectomy.
      μ including R2.

      3.4 Systematic review: prognostic influence of number of lesions

      Ten studies reported overall survival data stratified for number of lesions (Table 1, Table 2) [
      • Liu L.Z.
      • Yang L.X.
      • Zheng B.H.
      • Dong P.P.
      • Liu X.Y.
      • Wang Z.C.
      • et al.
      CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
      ,
      • Nuzzo G.
      • Giuliante F.
      • Ardito F.
      • De Rose A.M.
      • Vellone M.
      • Clemente G.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after liver resection.
      ,
      • Scheuermann U.
      • Kaths J.M.
      • Heise M.
      • Pitton M.B.
      • Weinmann A.
      • Hoppe-Lotichius M.
      • et al.
      Comparison of resection and transarterial chemoembolisation in the treatment of advanced intrahepatic cholangiocarcinoma--a single-center experience.
      ,
      • Tian M.
      • Liu W.
      • Tao C.
      • Tang Z.
      • Zhou Y.
      • Song S.
      • et al.
      Prediction of overall survival in resectable intrahepatic cholangiocarcinoma: ISICC-applied prediction model.
      ,
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ,
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ,
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ,
      • Spolverato G.
      • Kim Y.
      • Alex
      • rescu S.
      • Popescu I.
      • Marques H.P.
      • et al.
      Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
      ,
      • Tsilimigras D.I.
      • Mehta R.
      • Moris D.
      • Sahara K.
      • Bagante F.
      • Paredes A.Z.
      • et al.
      A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
      ,
      • Kudo M.
      • Izumi N.
      • Kokudo N.
      • Sakamoto M.
      • Shiina S.
      • Takayama T.
      • et al.
      Report of the 21st nationwide follow-up survey of primary liver cancer in Japan (2010-2011).
      ], nine of which with some statistical comparison between groups [
      • Liu L.Z.
      • Yang L.X.
      • Zheng B.H.
      • Dong P.P.
      • Liu X.Y.
      • Wang Z.C.
      • et al.
      CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
      ,
      • Nuzzo G.
      • Giuliante F.
      • Ardito F.
      • De Rose A.M.
      • Vellone M.
      • Clemente G.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after liver resection.
      ,
      • Scheuermann U.
      • Kaths J.M.
      • Heise M.
      • Pitton M.B.
      • Weinmann A.
      • Hoppe-Lotichius M.
      • et al.
      Comparison of resection and transarterial chemoembolisation in the treatment of advanced intrahepatic cholangiocarcinoma--a single-center experience.
      ,
      • Tian M.
      • Liu W.
      • Tao C.
      • Tang Z.
      • Zhou Y.
      • Song S.
      • et al.
      Prediction of overall survival in resectable intrahepatic cholangiocarcinoma: ISICC-applied prediction model.
      ,
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ,
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ,
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ,
      • Spolverato G.
      • Kim Y.
      • Alex
      • rescu S.
      • Popescu I.
      • Marques H.P.
      • et al.
      Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
      ,
      • Tsilimigras D.I.
      • Mehta R.
      • Moris D.
      • Sahara K.
      • Bagante F.
      • Paredes A.Z.
      • et al.
      A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
      ], and with six studies reporting relative risk with hazard ratios (Table 2) [
      • Liu L.Z.
      • Yang L.X.
      • Zheng B.H.
      • Dong P.P.
      • Liu X.Y.
      • Wang Z.C.
      • et al.
      CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
      ,
      • Tian M.
      • Liu W.
      • Tao C.
      • Tang Z.
      • Zhou Y.
      • Song S.
      • et al.
      Prediction of overall survival in resectable intrahepatic cholangiocarcinoma: ISICC-applied prediction model.
      ,
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ,
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ,
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ,
      • Spolverato G.
      • Kim Y.
      • Alex
      • rescu S.
      • Popescu I.
      • Marques H.P.
      • et al.
      Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
      ]. Both the number of lesions chosen to subgroup patients, and the reference categories used when comparing survival, differed between studies (Table 1, Table 2), precluding any meta-analysis.
      Four studies presented relative risk data for patients with two or three lesions compared to patients with a single lesion (Table 2 and Supplemental Figure 1) [
      • Liu L.Z.
      • Yang L.X.
      • Zheng B.H.
      • Dong P.P.
      • Liu X.Y.
      • Wang Z.C.
      • et al.
      CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
      ,
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ,
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ,
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ]. While Buettner et al. reported a significant risk increase for patients with two or three lesions (HR 1.75, 95% CI 1.39–2.19) [
      • Buettner S.
      • Galjart B.
      • van Vugt J.L.A.
      • Bagante F.
      • Alexandrescu S.
      • Marques H.P.
      • et al.
      Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
      ], Bednarsch et al., Liu et al. and Wang et al. reported non-significant survival differences (HR 1.68, 95% CI 0.93–3.05, HR 0.77, 95% CI 0.47–1.26 and HR 1.39, 95% CI 0.89–2.17 respectively) [
      • Liu L.Z.
      • Yang L.X.
      • Zheng B.H.
      • Dong P.P.
      • Liu X.Y.
      • Wang Z.C.
      • et al.
      CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
      ,
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ,
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ], compared to patients with a solitary tumour. Chen et al. reported the relative risk increase per additional lesion in a cohort of resected iCCA patients with underlying cirrhosis, with hazard ratio 1.44 (95% CI 1.29–1.60) [
      • Chen Q.
      • Li F.
      • Gao Y.
      • Xue H.
      • Li Z.
      • Zou Q.
      • et al.
      Developing a selection-aided model to screen cirrhotic intrahepatic cholangiocarcinoma for hepatectomy.
      ]. Tian et al. found no significant risk increase when comparing overall survival for patients with two lesions to patients with a single lesion [
      • Tian M.
      • Liu W.
      • Tao C.
      • Tang Z.
      • Zhou Y.
      • Song S.
      • et al.
      Prediction of overall survival in resectable intrahepatic cholangiocarcinoma: ISICC-applied prediction model.
      ]. Nuzzo et al. reported similar survival for patients with one or two lesions as for patients with a single lesion (both groups median OS = 29 months) [
      • Nuzzo G.
      • Giuliante F.
      • Ardito F.
      • De Rose A.M.
      • Vellone M.
      • Clemente G.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after liver resection.
      ]. Bednarsch et al. reported a significant survival difference only for patients with more than five lesions compared to patients with a single lesion (median OS = 10 months compared to OS = 32 months) [
      • Bednarsch J.
      • Czigany Z.
      • Heij L.R.
      • Liu D.
      • den Dulk M.
      • Wiltberger G.
      • et al.
      Compelling long-term results for liver resection in early cholangiocarcinoma.
      ].

      3.5 Systematic review: prognostic influence of other categories of tumour distribution

      Six studies reported tumour distribution with specific categories other than satellites or multiple lesions not including satellites, out of which five presented overall survival data for these categories (Table 1, Table 2). Limited data and heterogeneity between studies precluded any meta-analysis. While three studies reported data for patients with ‘intrahepatic metastases’ (Table 2), Kim et al. included patients with satellite lesions to this group and reported a significantly decreased survival [
      • Kim S.H.
      • Park Y.N.
      • Lim J.H.
      • Choi G.H.
      • Choi J.S.
      • Kim K.S.
      Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
      ]. Aherne et al. included all multiple lesions not specified as satellites and found no significant survival difference, without reporting survival or summary data [
      • Aherne E.A.
      • Pak L.M.
      • Goldman D.A.
      • Gonen M.
      • Jarnagin W.R.
      • Simpson A.L.
      • et al.
      Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics?.
      ]. Fu et al. did not specify criteria for the categorisation of lesions as intrahepatic metastases and reported a significant decrease in overall survival [
      • Fu K.
      • Yang X.
      • Wu H.
      • Gong J.
      • Li X.
      Diabetes and PKM2 affect prognosis in patients with intrahepatic cholangiocarcinoma.
      ].
      Two studies analysed survival in multiple iCCA with lesions also in the contralateral liver lobe (Table 2). While Addeo et al. found patients with multiple lesions in the contralateral hemiliver to have similar survival as patients with single lesions [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ], Bartsch et al. reported patients with multiple lesions and a ‘translobar’ dissemination to the contralateral hemiliver to have significantly decreased survival [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ]. Bartsch et al. included patients with diffuse tumour infiltration in the ‘translobar’ subgroup but found similar outcomes (no data reported) for patients with and without diffuse infiltration [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ].

      3.6 Meta-analysis: prognostic influence of satellite lesions

      Seventeen studies presented data on overall survival for patients with and without satellites, 14 reporting hazard ratios or data allowing hazard ratio calculation (Table 2). The study by Addeo et al. was excluded from meta-analysis as it included all patients presenting with multiple lesions confined to one liver lobe in the satellite lesion subgroup [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ], in contrast to definitions of satellites according to histopathology [
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ,
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ,
      • Brustia R.
      • Langella S.
      • Kawai T.
      • Fonseca G.M.
      • Schielke A.
      • Colli F.
      • et al.
      Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
      ,
      • Chen Y.
      • Liu H.
      • Zhang J.
      • Wu Y.
      • Zhou W.
      • Cheng Z.
      • et al.
      Prognostic value and predication model of microvascular invasion in patients with intrahepatic cholangiocarcinoma: a multicenter study from China.
      ] or proximity to the main lesion on radiology (within 10 mm [
      • Aherne E.A.
      • Pak L.M.
      • Goldman D.A.
      • Gonen M.
      • Jarnagin W.R.
      • Simpson A.L.
      • et al.
      Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics?.
      ], 20 mm19 or the same liver segment [
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ]). Five studies with overlapping cohorts were also excluded from meta-analysis [
      • Chen Q.
      • Li F.
      • Gao Y.
      • Xue H.
      • Li Z.
      • Zou Q.
      • et al.
      Developing a selection-aided model to screen cirrhotic intrahepatic cholangiocarcinoma for hepatectomy.
      ,
      • King M.J.
      • Hectors S.
      • Lee K.M.
      • Omidele O.
      • Babb J.S.
      • Schwartz M.
      • et al.
      Outcomes assessment in intrahepatic cholangiocarcinoma using qualitative and quantitative imaging features.
      ,
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ,
      • Wang T.
      • Kong J.
      • Yang X.
      • Shen S.
      • Zhang M.
      • Wang W.
      Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • Moris D.
      • Beal E.W.
      • Weiss M.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ], including the study by King et al. where four patients with other multiple lesions than satellites were included in the satellite lesion group in survival analysis [
      • King M.J.
      • Hectors S.
      • Lee K.M.
      • Omidele O.
      • Babb J.S.
      • Schwartz M.
      • et al.
      Outcomes assessment in intrahepatic cholangiocarcinoma using qualitative and quantitative imaging features.
      ].
      The meta-analysis of nine non-overlapping studies comparing survival for 2737 patients with and without satellite lesions is presented in Fig. 2 A and B. The pooled result indicated a significantly decreased overall survival for patients with satellite lesions (HR 1.89, 95% CI 1.67–2.13), with limited statistical heterogeneity among studies and no apparent bias as evaluated by funnel plot symmetry (Fig. 2B). Pooled data also including the study by Addeo et al. [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ] are presented in Supplemental Fig. 2 A and B, with concurrent results (HR 1.91, 95% CI 1.69–2.14). Pooled data excluding three studies with a score of five or less on the Newcastle-Ottawa scale are presented in Supplemental Fig. 3 A and B, with similar results (HR 2.05, 95% CI 1.75–2.39).
      Fig. 2
      Fig. 2Meta-analysis of satellite lesions as prognostic factor for overall survival after resection for iCCA, A) Forest plot B) Funnel plot.

      3.7 Meta-analysis: prognostic influence of multiple lesions not including satellites

      Six non-overlapping studies reported overall survival data for 1589 patients depending on presence or absence of multiple lesions not including satellites (Table 2), with a meta-analysis presented in Fig. 3 A and B. The overlapping study by Zhou et al. was excluded [
      • Zhou H.B.
      • Wang H.
      • Li Y.Q.
      • Li S.X.
      • Wang H.
      • Zhou D.X.
      • et al.
      Hepatitis B virus infection: a favorable prognostic factor for intrahepatic cholangiocarcinoma after resection.
      ]. For this comparison, a higher degree of statistical heterogeneity was present between studies (I2 = 35% P = 0.18). The pooled result indicated a significant decrease in overall survival for patients with multiple lesions other than satellites (HR 2.41, 95% CI 1.72–3.37). Pooled data excluding one study with a score less than five on the Newcastle-Ottawa scale is presented in Supplemental Fig. 4 A and B, with similar results (HR 2.53, 95% CI 1.64–3.91).
      Fig. 3
      Fig. 3Meta-analysis of multiple lesions (not including satellites) as prognostic factor for overall survival after resection for iCCA, A) Forest plot B) Funnel plot.

      3.8 Assessment of evidence

      Considering GRADE domains for rating of evidence for the pooled hazard ratio for satellite lesions, concerns for risk of bias remained also after sensitivity analyses. Included studies lacked data on diagnostic modalities [
      • Moro A.
      • Paredes A.Z.
      • Farooq A.
      • Sahara K.
      • Tsilimigras D.I.
      • Mehta R.
      • et al.
      Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: a preoperative vs postoperative perspective.
      ], reported exclusion of patients from survival analysis (such as incomplete follow-up or postoperative mortalities) [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ,
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ,
      • Brustia R.
      • Langella S.
      • Kawai T.
      • Fonseca G.M.
      • Schielke A.
      • Colli F.
      • et al.
      Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
      ] or lacked reported data on median length of follow-up [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ,
      • Brustia R.
      • Langella S.
      • Kawai T.
      • Fonseca G.M.
      • Schielke A.
      • Colli F.
      • et al.
      Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
      ,
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ,
      • Moro A.
      • Paredes A.Z.
      • Farooq A.
      • Sahara K.
      • Tsilimigras D.I.
      • Mehta R.
      • et al.
      Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: a preoperative vs postoperative perspective.
      ]. Inconsistency among results was evaluated with limited heterogeneity. Directness, or generalisability for the pooled estimate, was assessed with only one study limiting inclusion to a subgroup of resected patients [
      • Aherne E.A.
      • Pak L.M.
      • Goldman D.A.
      • Gonen M.
      • Jarnagin W.R.
      • Simpson A.L.
      • et al.
      Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics?.
      ]. The imprecision of the pooled estimate for the full meta-analysis implied a risk increase spanning from 69 to 114% for patients with satellites. There was no evidence of publication bias.
      Considering GRADE domains for pooled estimates for multiple lesions other than satellites, concerns for risk of bias were similar to studies reporting outcomes for patients with satellite lesions. Included studies lacked data on diagnostic modalities [
      • Kim S.H.
      • Park Y.N.
      • Lim J.H.
      • Choi G.H.
      • Choi J.S.
      • Kim K.S.
      Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
      ,
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ,
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ], reported exclusion of patients [
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ,
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ,
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • Moris D.
      • Beal E.W.
      • Weiss M.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ] or lacked data for median length of follow-up [
      • Kim S.H.
      • Park Y.N.
      • Lim J.H.
      • Choi G.H.
      • Choi J.S.
      • Kim K.S.
      Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
      ,
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ,
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ,
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ,
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • Moris D.
      • Beal E.W.
      • Weiss M.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ]. Concerns for inconsistency were present, with low to moderate heterogeneity. Funnel plot analysis revealed asymmetry suggesting possible bias. Directness was assessed with only one study limiting inclusion to a subgroup of patients [
      • Zhu H.
      • Wang L.
      • Wang M.
      • He X.
      • Xu W.
      • Zhu W.
      • et al.
      Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
      ]. Imprecision was more pronounced with a pooled estimated risk increase spanning from 72 to 237%. Grade evidence profiles are summarised in Supplemental Table 6.

      3.9 Multivariable comparisons

      Among the nine studies included for meta-analysis of the prognostic influence of satellite lesions, five studies reported multivariable analyses incorporating satellite lesions with other risk factors including lymph node status [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ,
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ,
      • Brustia R.
      • Langella S.
      • Kawai T.
      • Fonseca G.M.
      • Schielke A.
      • Colli F.
      • et al.
      Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
      ,
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ,
      • Moro A.
      • Paredes A.Z.
      • Farooq A.
      • Sahara K.
      • Tsilimigras D.I.
      • Mehta R.
      • et al.
      Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: a preoperative vs postoperative perspective.
      ]. Of these studies, two found satellite lesions to be a significant independent factor (Conci et al.: HR 3.10, 95% CI 1.55–6.2053;Moro et al.: HR 1.65, 95% CI 1.34–2.0455), while the study by Bartsch et al. reported significance for a compound prognostic score including number and distribution of lesions, tumour size, extension and volume [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ]. Brustia et al. and Tabrizian et al. both reported non-significance for satellites on multivariable analysis including lymph node metastasis (Brustia et al.: HR 1.42, 95% CI 0.88–2.3051, Tabrizian et al.: no multivariable HR or P-value reported [
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ]).
      Five out of six studies in the meta-analysis of multiple lesions not including satellites also reported multivariable models with lymph node status [
      • Kim S.H.
      • Park Y.N.
      • Lim J.H.
      • Choi G.H.
      • Choi J.S.
      • Kim K.S.
      Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
      ,
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ,
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ,
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • Moris D.
      • Beal E.W.
      • Weiss M.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ]. Conci et al. found multiple lesions not including satellites to be an independent prognostic factor (HR 4.06, 95% CI 1.83–9.05) [
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ], while four studies reported non-significance (Zhang et al.: HR 1.5, 95% CI 0.9–2.258, Kim et al. [
      • Kim S.H.
      • Park Y.N.
      • Lim J.H.
      • Choi G.H.
      • Choi J.S.
      • Kim K.S.
      Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
      ], Shen et al. [
      • Shen J.
      • Wen T.
      • Li C.
      • Yan L.
      • Li B.
      • Yang J.
      The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
      ] and Tabrizian et al. [
      • Tabrizian P.
      • Jibara G.
      • Hechtman J.F.
      • Franssen B.
      • Labow D.M.
      • Schwartz M.E.
      • et al.
      Outcomes following resection of intrahepatic cholangiocarcinoma.
      ]: no multivariable HR or P-value reported).

      4. Discussion

      As noted in current discussions about prognostic factors in resectable iCCA, the term multiple lesions can incorporate a considerable heterogeneity among patients regarding tumour distribution (satellites and other multiple lesions) and number of lesions. This heterogeneity could extend to prognostic differences within the group of iCCA patients diagnosed with multiple intrahepatic lesions, and impact therapeutic choices when considering resection or locoregional oncological therapies.
      While one previous study found patients with satellite lesions to have outcomes not significantly inferior to those with a single tumour [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ], others have reported satellite lesions, but not separate multiple lesions, to be negatively associated to survival [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ].
      In this systematic review, with a meta-analysis including nine studies reporting univariable survival data for 2737 patients with/without satellites, from a variety of settings and including both radiologically and histopathologically diagnosed lesions, satellite lesions were found to be a significant negative prognostic factor after resection for iCCA. The statistical heterogeneity among studies was low, and with no apparent publication bias.
      When analyzing outcomes for patients with/without multiple lesions other than satellites, in a meta-analysis including six studies and 1589 patients, multiple separate lesions were likewise found to be a significant negative prognostic factor, but with a higher degree of heterogeneity among studies.
      In the broader review, different categories of multiple lesions other than satellites were reported, with conflicting data from the two studies reporting outcomes in multiple iCCA with contralateral lesions [
      • Addeo P.
      • Jedidi I.
      • Locicero A.
      • Faitot F.
      • Oncioiu C.
      • Onea A.
      • et al.
      Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
      ,
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ]. A possible explanation to such opposing outcomes could be underlying differences in other prognostic factors, e.g. tumour size and tumour number between studies and subgroups.
      To what degree multiple lesions other than satellites represent intrahepatic metastases of iCCA or multifocal synchronous lesions, and whether such a differentiation would have a prognostic significance, is not clear from the reviewed literature. In a recent study, performing genomic profiling on multiple tumours from a small group of patients, all multiple lesions (including satellites) were found to represent metastases [
      • Lee S.H.
      • Simoneau E.B.
      • Karpinets T.
      • Futreal P.A.
      • Zhang J.
      • Javle M.
      • et al.
      Genomic profiling of multifocal intrahepatic cholangiocarcinoma reveals intraindividual concordance of genetic alterations.
      ]. Of note, all multiple lesions in this analysis were within 50 mm of the main lesion [
      • Lee S.H.
      • Simoneau E.B.
      • Karpinets T.
      • Futreal P.A.
      • Zhang J.
      • Javle M.
      • et al.
      Genomic profiling of multifocal intrahepatic cholangiocarcinoma reveals intraindividual concordance of genetic alterations.
      ]. It could be hypothesised that multifocal synchronous lesions on a background of chronic liver disease could imply a better oncological prognosis compared to metastasized iCCA, but criteria to differentiate metastases from multifocality remain to be defined, and any possible associated survival difference to be further studied.
      The degree of overlap and of collinearity between prognostic factors also needs to be considered. While negative prognostic factors overlap in some patients, a proportion of patients with satellites but without other multiple lesions, or vice versa, were presented in several studies [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ,
      • Yeh C.N.
      • Hsieh F.J.
      • Chiang K.C.
      • Chen J.S.
      • Yeh T.S.
      • Jan Y.Y.
      • et al.
      Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma.
      ,
      • Conci S.
      • Ruzzenente A.
      • Vigano L.
      • Ercolani G.
      • Fontana A.
      • Bagante F.
      • et al.
      Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
      ]. If, and to what extent, underlying differences in other prognostic factors (such as presence of lymph node metastasis) between patients with and without multiple lesions explain the observed survival differences is not clear. Moro et al., with the largest international multicentric cohort in this review, reported satellite lesions to be an independent negative prognostic factor in a multivariable model adjusted for important variables such as lymph node metastasis, tumour differentiation, resection margin and tumour size [
      • Moro A.
      • Paredes A.Z.
      • Farooq A.
      • Sahara K.
      • Tsilimigras D.I.
      • Mehta R.
      • et al.
      Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: a preoperative vs postoperative perspective.
      ].
      The broader question of clinical benefit of resection, compared to other therapy options for patients with multiple iCCA, which has been addressed in several studies in recent years, was beyond the scope of this review. While single-center regional therapy cohorts (hepatic arterial infusion [
      • Franssen S.
      • Soares K.C.
      • Jolissaint J.S.
      • Tsilimigras D.I.
      • Buettner S.
      • Alexandrescu S.
      • et al.
      Comparison of hepatic arterial infusion pump chemotherapy vs resection for patients with multifocal intrahepatic cholangiocarcinoma.
      ] or transarterial chemoembolization/hepatic arterial infusion [
      • Wright G.P.
      • Perkins S.
      • Jones H.
      • Zureikat A.H.
      • Marsh J.W.
      • Holtzman M.P.
      • et al.
      Surgical resection does not improve survival in multifocal intrahepatic cholangiocarcinoma: a comparison of surgical resection with intra-arterial therapies.
      ]) have reported similar survival as with surgical resection, analysis of data from a United States national registry (SEER) found improved survival in resected patients with multiple lesions, also when adjusting for chemoradiotherapy in a multivariable model [
      • Yin L.
      • Zhao S.
      • Zhu H.
      • Ji G.
      • Zhang X.
      Primary tumor resection improves survival in patients with multifocal intrahepatic cholangiocarcinoma based on a population study.
      ]. In a large European multi-center cohort (ENSCCA), when surgery was analysed as a univariable prognostic factor, resection in patients with multiple iCCA was associated with improved survival [
      • Lamarca A.
      • Santos-Laso A.
      • Utpatel K.
      • La Casta A.
      • Stock S.
      • Forner A.
      • et al.
      Reply to letter by Jansson and Sparrelid.
      ]. Which iCCA patients with multiple lesions would benefit most from resection surgery, and how surgery compares to locoregional therapies in different risk groups within the multiple lesion group, remains to be further studied. The overall proportion of patients receiving neoadjuvant therapy reported from cohorts in this review remained low, and the role for neoadjuvant systemic chemotherapy in iCCA with multiple lesions or other negative prognostic factors is an important focus for clinical trials [
      • Maithel S.K.
      • Javle M.M.
      • Mahipal A.
      • Lin B.S.-L.
      • Akce M.
      • Switchenko J.M.
      • et al.
      NEO-GAP: a phase II single-arm prospective feasibility study of neoadjuvant gemcitabine/cisplatin/nab-paclitaxel for resectable high-risk intrahepatic cholangiocarcinoma.
      ]. The overall proportion of patients receiving adjuvant therapy, when reported, remained below 50% in nine out of eleven studies. How real-world outcomes of surgery will develop with current implementation of adjuvant chemotherapy after recent randomized controlled trials also remains to be studied [
      • Primrose J.N.
      • Fox R.P.
      • Palmer D.H.
      • Malik H.Z.
      • Prasad R.
      • Mirza D.
      • et al.
      Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.
      ,
      • Ikeda M.
      • Nakachi K.
      • Konishi M.
      • Nomura S.
      • Katayama H.
      • Kataoka T.
      • et al.
      Adjuvant S-1 versus observation in curatively resected biliary tract cancer: a phase III trial (JCOG1202: ASCOT).
      ].
      This systematic review was based on a broad search of the current literature, focusing specifically on resected iCCA patients, evaluating overall survival outcomes for patients with multiple lesions according to both tumour distribution and number. Furthermore, it permitted the meta-analysis of relative risks according to distribution of multiple lesions, the first such analysis to date to our knowledge. A previous systematic review of prognostic factors for overall survival in patients undergoing resection for iCCA, published in 2014, included five studies with data on multiple tumours in meta-analysis, without further stratification [
      • Mavros M.N.
      • Economopoulos K.P.
      • Alexiou V.G.
      • Pawlik T.M.
      Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis.
      ]. A recent systematic review on prognostic factors for early recurrence included only three studies in a meta-analysis, also with unstratified data [
      • Choi W.J.
      • Williams P.J.
      • Claasen M.
      • Ivanics T.
      • Englesakis M.
      • Gallinger S.
      • et al.
      Systematic review and meta-analysis of prognostic factors for early recurrence in intrahepatic cholangiocarcinoma after curative-intent resection.
      ]. With a comprehensive search, the current study was able to include nine and six studies respectively in meta-analyses, with granular data on tumor distribution and relative risks, allowing sensitivity analyses and presenting a synthesis of best available current evidence to shape further scientific discussion and research specifically for the sizable group of patients with multiple iCCA.
      However, the study also had several limitations. A considerable heterogeneity was found among studies regarding definitions, diagnostic modalities and patient cohorts. Several criteria to define satellite lesions have been proposed, such as lesions within 10 mm of the main tumour [
      • Aherne E.A.
      • Pak L.M.
      • Goldman D.A.
      • Gonen M.
      • Jarnagin W.R.
      • Simpson A.L.
      • et al.
      Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics?.
      ] or lesions within the same segment [
      • Baheti A.D.
      • Tirumani S.H.
      • Shinagare A.B.
      • Rosenthal M.H.
      • Hornick J.L.
      • Ramaiya N.H.
      • et al.
      Correlation of CT patterns of primary intrahepatic cholangiocarcinoma at the time of presentation with the metastatic spread and clinical outcomes: retrospective study of 92 patients.
      ], and different definitions of proximity to the primary lesion were employed in the reviewed studies. Most studies did not specify which diagnostic modalities were used to determine tumour multiplicity. Among studies reporting survival for patients with satellite lesions compared to patients without satellites, it is possible that the reference category in some reports could include multiple lesions without satellites, and not only patients with single lesions. Regarding terminology for tumour distribution, the terms bilobar or bilateral iCCA were not investigated in this review, as they also describe patients with large or central single lesions engaging both hemilivers [
      • Bartsch F.
      • Hahn F.
      • Muller L.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Kloeckner R.
      • et al.
      Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • Moris D.
      • Beal E.W.
      • Weiss M.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Zhang X.F.
      • Xue F.
      • Dong D.H.
      • Weiss M.
      • Popescu I.
      • Marques H.P.
      • et al.
      Number and station of lymph node metastasis after curative-intent resection of intrahepatic cholangiocarcinoma impact prognosis.
      ]. A majority of studies reported single center data. For studies reporting survival curves with numbers at risk, relative risks were estimated from summary data. Upon review, data was limited for number of lesions and other categories of tumour distribution, only permitting qualitative synthesis. For meta-analyses, assessment of evidence indicated risk of bias both for studies reporting data on satellite lesions and other multiple lesions, with further limitations for the meta-analysis on multiple lesions not including satellites, with a higher degree of imprecision in the pooled estimate and further possible bias.
      In conclusion, this systematic review and meta-analysis of the prognostic influence of multiple lesions in resectable iCCA found patients with satellite lesions, as well as patients with multiple lesions not including satellites, to have significantly decreased overall survival. Data stratified for number of lesions was limited, but suggested increased risk per additional lesion. Number of tumours, presence of satellite lesions and presence of multiple lesions other than satellites should be separately reported, to allow further analysis as possible additive prognostic factors. To evaluate these variables separately, together with other prognostic factors, could permit an improved risk stratification for the considerable proportion of iCCA patients presenting with multiple lesions, rather than contraindicating surgery for an entire patient group.

      Sources of funding and role of the funding source

      Hannes Jansson was supported by grants from Region Stockholm and the Swedish Society of Medicine. Ernesto Sparrelid was supported by grants from the Bengt Ihre Foundation, the Center for Innovative Medicine at Karolinska Institutet, the Swedish Society for Medical Research (SSMF) and Region Stockholm. The funding sources were not involved in the design or conduct of the review, the writing of the report or the decision to submit the article for publication.

      Data availability statement

      The data collected and analysed during the current review are available from the corresponding author on reasonable request.

      CRediT authorship contribution statement

      Hannes Jansson: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. Christina Villard: Conceptualization, Investigation, Writing – review & editing. Lynn E. Nooijen: Investigation, Writing – review & editing. Poya Ghorbani: Writing – review & editing. Joris I. Erdmann: Conceptualization, Writing – review & editing. Ernesto Sparrelid: Conceptualization, Investigation, Writing – original draft, Writing – review & editing, Supervision, All authors contributed to interpretation of data, critical revisions, and approved the final version of the manuscript.

      Conflict of interest disclosure

      Hannes Jansson, Christina Villard, Lynn E. Nooijen, Poya Ghorbani, Joris I. Erdmann and Ernesto Sparrelid have no conflicts of interest do disclose.

      Acknowledgements

      The authors would like to acknowledge Narcisa Hannerz and Emma-Lotta Säätelä (the search consultation service of the Karolinska Institutet University Library); and the EURO-CHOLANGIO-NET European Cholangiocarcinoma Network.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article.

      References

        • Amin M.B.
        • Edge S.B.
        • Greene F.L.
        • Byrd D.R.
        • Brookland R.K.
        • Washington M.K.
        • et al.
        AJCC cancer staging manual.
        Eight ed. Springer, Chicago IL2017
        • Brierley J.
        • Gospodarowicz M.K.
        • Wittekind C.
        TNM classification of malignant tumours.
        eighth ed. John Wiley & Sons, Inc., Chichester, West Sussex, UK ;Hoboken, NJ2017
        • Lamarca A.
        • Santos-Laso A.
        • Utpatel K.
        • La Casta A.
        • Stock S.
        • Forner A.
        • et al.
        Liver metastases of intrahepatic cholangiocarcinoma: implications for an updated staging system.
        Hepatology. 2021; 73: 2311-2325
        • Zhang X.F.
        • Lv Y.
        • Pawlik T.M.
        Letter to the editor: does multiple intrahepatic cholangiocarcinoma worsen prognosis as "M1" stage?.
        Hepatology. 2021; 74: 1128
        • Jansson H.
        • Sparrelid E.
        Letter to the editor: the role of surgery in multiple intrahepatic cholangiocarcinoma should not Be dismissed without further analysis.
        Hepatology. 2021; 74: 2318-2319
        • Bridgewater J.
        • Galle P.R.
        • Khan S.A.
        • Llovet J.M.
        • Park J.W.
        • Patel T.
        • et al.
        Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
        J Hepatol. 2014; 60: 1268-1289
        • Spolverato G.
        • Kim Y.
        • Alexandrescu S.
        • Popescu I.
        • Marques H.P.
        • Aldrighetti L.
        • et al.
        Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
        Ann Surg Oncol. 2015; 22: 2218-2225
        • Kudo M.
        • Izumi N.
        • Kokudo N.
        • Sakamoto M.
        • Shiina S.
        • Takayama T.
        • et al.
        Report of the 21st nationwide follow-up survey of primary liver cancer in Japan (2010-2011).
        Hepatol Res. 2021;51(4):355-405;
        • Cercek A.
        • Boerner T.
        • Tan B.R.
        • Chou J.F.
        • Gonen M.
        • Boucher T.M.
        • et al.
        Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial.
        JAMA Oncol. 2020; 6: 60-67
        • Massani M.
        • Bonariol L.
        • Stecca T.
        Hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma, a comprehensive review.
        J Clin Med. 2021; 10
        • Edeline J.
        • Lamarca A.
        • McNamara M.G.
        • Jacobs T.
        • Hubner R.A.
        • Palmer D.
        • et al.
        Locoregional therapies in patients with intrahepatic cholangiocarcinoma: a systematic review and pooled analysis.
        Cancer Treat Rev. 2021; 99102258
        • Ohaegbulam K.C.
        • Koethe Y.
        • Fung A.
        • Mayo S.C.
        • Grossberg A.J.
        • Chen E.Y.
        • et al.
        The multidisciplinary management of cholangiocarcinoma.
        Cancer, 2022
        • Normanno N.
        • Martinelli E.
        • Melisi D.
        • Pinto C.
        • Rimassa L.
        • Santini D.
        • et al.
        Role of molecular genetics in the clinical management of cholangiocarcinoma.
        ESMO Open. 2022; 7100505
        • Lamarca A.
        • Santos-Laso A.
        • Utpatel K.
        • La Casta A.
        • Stock S.
        • Forner A.
        • et al.
        Reply to Letter by Zhang et al.
        Hepatology. 2021; 74: 1129-1131
        • Lamarca A.
        • Santos-Laso A.
        • Utpatel K.
        • La Casta A.
        • Stock S.
        • Forner A.
        • et al.
        Reply to letter by Jansson and Sparrelid.
        Hepatology. 2021; 74: 2319-2321
        • Zhang X.F.
        • Xue F.
        • He J.
        • Alexandrescu S.
        • Marques H.P.
        • Aldrighetti L.
        • et al.
        Proposed modification of the eighth edition of the AJCC staging system for intrahepatic cholangiocarcinoma.
        HPB. 2021; 23: 1456-1466
        • Burgart L.
        • Chopp W.
        • Jain D.
        Protocol for the examination of specimens from patients with carcinoma of the intrahepatic bile ducts.
        College of American Pathologists, 2021 (. Published)
        • Addeo P.
        • Jedidi I.
        • Locicero A.
        • Faitot F.
        • Oncioiu C.
        • Onea A.
        • et al.
        Prognostic impact of tumor multinodularity in intrahepatic cholangiocarcinoma.
        J Gastrointest Surg. 2019; 23: 1801-1809
        • Bartsch F.
        • Hahn F.
        • Muller L.
        • Baumgart J.
        • Hoppe-Lotichius M.
        • Kloeckner R.
        • et al.
        Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging.
        Hepatobiliary Pancreat Dis Int. 2021; 20: 330
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • Boutron I.
        • Hoffmann T.C.
        • Mulrow C.D.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372: n71
        • Jansson H.
        • Sparrelid E.
        (PROSPERO 2021 CRD42021244952)Prognostic influence of multifocal tumor distribution in intrahepatic cholangiocarcinoma: a systematic review. 2021 (. Published)
        • Ouzzani M.
        • Hammady H.
        • Fedorowicz Z.
        • Elmagarmid A.
        Rayyan - a web and mobile app for systematic reviews.
        Syst Rev. 2016; 5: 210
        • Margulis A.V.
        • Pladevall M.
        • Riera-Guardia N.
        • Varas-Lorenzo C.
        • Hazell L.
        • Berkman N.D.
        • et al.
        Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank.
        Clin Epidemiol. 2014; 6: 359-368
        • Zeng X.
        • Zhang Y.
        • Kwong J.S.
        • Zhang C.
        • Li S.
        • Sun F.
        • et al.
        The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review.
        J Evid Base Med. 2015; 8: 2-10
      1. Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 10 January 2022.

        • Mitchell M.
        • Muftakhidinov B.
        • Winchen T.
        Engauge digitizer software.
        2019
        • Iorio A.
        • Spencer F.A.
        • Falavigna M.
        • Alba C.
        • Lang E.
        • Burnand B.
        • et al.
        Use of GRADE for assessment of evidence about prognosis: rating confidence in estimates of event rates in broad categories of patients.
        BMJ. 2015; 350: h870
      2. Review manager (RevMan) version 5.4 [computer program]. The Cochrane Collaboration, 2020
        • Parmar M.K.
        • Torri V.
        • Stewart L.
        Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.
        Stat Med. 1998; 17: 2815-2834
        • Tierney J.F.
        • Stewart L.A.
        • Ghersi D.
        • Burdett S.
        • Sydes M.R.
        Practical methods for incorporating summary time-to-event data into meta-analysis.
        Trials. 2007; 8: 16
        • Williamson P.R.
        • Smith C.T.
        • Hutton J.L.
        • Marson A.G.
        Aggregate data meta-analysis with time-to-event outcomes.
        Stat Med. 2002; 21: 3337-3351
        • Aherne E.A.
        • Pak L.M.
        • Goldman D.A.
        • Gonen M.
        • Jarnagin W.R.
        • Simpson A.L.
        • et al.
        Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics?.
        Abdominal Radiology. 2018; 43: 2665-2672
        • Chen Q.
        • Li F.
        • Gao Y.
        • Xue H.
        • Li Z.
        • Zou Q.
        • et al.
        Developing a selection-aided model to screen cirrhotic intrahepatic cholangiocarcinoma for hepatectomy.
        J Cancer. 2020; 11: 5623-5634
        • Fu K.
        • Yang X.
        • Wu H.
        • Gong J.
        • Li X.
        Diabetes and PKM2 affect prognosis in patients with intrahepatic cholangiocarcinoma.
        Oncol Lett. 2020; 20: 265
        • Kim S.H.
        • Park Y.N.
        • Lim J.H.
        • Choi G.H.
        • Choi J.S.
        • Kim K.S.
        Characteristics of combined hepatocellular-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.
        Eur J Surg Oncol. 2014; 40: 976-981
        • King M.J.
        • Hectors S.
        • Lee K.M.
        • Omidele O.
        • Babb J.S.
        • Schwartz M.
        • et al.
        Outcomes assessment in intrahepatic cholangiocarcinoma using qualitative and quantitative imaging features.
        Cancer Imag. 2020; 20: 43
        • Lee C.T.
        • Wu T.T.
        • Lohse C.M.
        • Zhang L.
        High-mobility group AT-hook 2: an independent marker of poor prognosis in intrahepatic cholangiocarcinoma.
        Hum Pathol. 2014; 45: 2334-2340
        • Liu L.Z.
        • Yang L.X.
        • Zheng B.H.
        • Dong P.P.
        • Liu X.Y.
        • Wang Z.C.
        • et al.
        CK7/CK19 index: a potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.
        J Surg Oncol. 2018; 117: 1531-1539
        • Lu C.D.
        • Wang K.
        • Zhang C.Z.
        • Zhou F.G.
        • Guo W.X.
        • Wu M.C.
        • et al.
        Outcomes of intrahepatic cholangiocarcinoma with portal vein tumor thrombus following hepatic resection.
        J Gastroenterol Hepatol. 2016; 31: 1330-1335
        • Nuzzo G.
        • Giuliante F.
        • Ardito F.
        • De Rose A.M.
        • Vellone M.
        • Clemente G.
        • et al.
        Intrahepatic cholangiocarcinoma: prognostic factors after liver resection.
        Updates in Surgery. 2010; 62: 11-19
        • Scheuermann U.
        • Kaths J.M.
        • Heise M.
        • Pitton M.B.
        • Weinmann A.
        • Hoppe-Lotichius M.
        • et al.
        Comparison of resection and transarterial chemoembolisation in the treatment of advanced intrahepatic cholangiocarcinoma--a single-center experience.
        Eur J Surg Oncol. 2013; 39: 593-600
        • Shen J.
        • Wen T.
        • Li C.
        • Yan L.
        • Li B.
        • Yang J.
        The prognostic prediction role of preoperative serum albumin level in patients with intahepatic cholangiocarcinoma following hepatectomy.
        Dig Dis. 2018; 36: 306-313
        • Tabrizian P.
        • Jibara G.
        • Hechtman J.F.
        • Franssen B.
        • Labow D.M.
        • Schwartz M.E.
        • et al.
        Outcomes following resection of intrahepatic cholangiocarcinoma.
        HPB. 2015; 17: 344-351
        • Tian M.
        • Liu W.
        • Tao C.
        • Tang Z.
        • Zhou Y.
        • Song S.
        • et al.
        Prediction of overall survival in resectable intrahepatic cholangiocarcinoma: ISICC-applied prediction model.
        Cancer Sci. 2020; 111: 1084-1092
        • Wang T.
        • Kong J.
        • Yang X.
        • Shen S.
        • Zhang M.
        • Wang W.
        Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
        J Surg Oncol. 2020; 121: 524-537
        • Wang Y.
        • Li J.
        • Xia Y.
        • Gong R.
        • Wang K.
        • Yan Z.
        • et al.
        Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
        J Clin Oncol. 2013; 31: 1188-1195
        • Yeh C.N.
        • Hsieh F.J.
        • Chiang K.C.
        • Chen J.S.
        • Yeh T.S.
        • Jan Y.Y.
        • et al.
        Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma.
        Drug Des Dev Ther. 2015; 9: 163-174
        • Zhou H.B.
        • Wang H.
        • Li Y.Q.
        • Li S.X.
        • Wang H.
        • Zhou D.X.
        • et al.
        Hepatitis B virus infection: a favorable prognostic factor for intrahepatic cholangiocarcinoma after resection.
        World J Gastroenterol. 2011; 17: 1292-1303
        • Zhu H.
        • Wang L.
        • Wang M.
        • He X.
        • Xu W.
        • Zhu W.
        • et al.
        Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.
        Am J Surg. 2021; 15: 15
        • Bednarsch J.
        • Czigany Z.
        • Heij L.R.
        • Liu D.
        • den Dulk M.
        • Wiltberger G.
        • et al.
        Compelling long-term results for liver resection in early cholangiocarcinoma.
        J Clin Med. 2021; 10
        • Brustia R.
        • Langella S.
        • Kawai T.
        • Fonseca G.M.
        • Schielke A.
        • Colli F.
        • et al.
        Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
        Eur J Surg Oncol. 2020; 46: 560-571
        • Buettner S.
        • Galjart B.
        • van Vugt J.L.A.
        • Bagante F.
        • Alexandrescu S.
        • Marques H.P.
        • et al.
        Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma.
        J Surg Oncol. 2017; 116: 1085-1095
        • Conci S.
        • Ruzzenente A.
        • Vigano L.
        • Ercolani G.
        • Fontana A.
        • Bagante F.
        • et al.
        Patterns of distribution of hepatic nodules (single, satellites or multifocal) in intrahepatic cholangiocarcinoma: prognostic impact after surgery.
        Ann Surg Oncol. 2018; 25: 3719-3727
        • De Rose A.M.
        • Cucchetti A.
        • Clemente G.
        • Ardito F.
        • Giovannini I.
        • Ercolani G.
        • et al.
        Prognostic significance of tumor doubling time in mass-forming type cholangiocarcinoma.
        J Gastrointest Surg. 2013; 17: 739-747
        • Moro A.
        • Paredes A.Z.
        • Farooq A.
        • Sahara K.
        • Tsilimigras D.I.
        • Mehta R.
        • et al.
        Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: a preoperative vs postoperative perspective.
        J Surg Oncol. 2019; 120: 946-955
        • Spolverato G.
        • Kim Y.
        • Alex
        • rescu S.
        • Popescu I.
        • Marques H.P.
        • et al.
        Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration.
        Ann Surg Oncol. 2015; 22: 2218-2225
        • Tsilimigras D.I.
        • Mehta R.
        • Moris D.
        • Sahara K.
        • Bagante F.
        • Paredes A.Z.
        • et al.
        A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
        Ann Surg Oncol. 2020; 27: 1110-1119
        • Zhang X.F.
        • Bagante F.
        • Chakedis J.
        • Moris D.
        • Beal E.W.
        • Weiss M.
        • et al.
        Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
        J Gastrointest Surg. 2017; 21: 1841-1850
        • Chen Y.
        • Liu H.
        • Zhang J.
        • Wu Y.
        • Zhou W.
        • Cheng Z.
        • et al.
        Prognostic value and predication model of microvascular invasion in patients with intrahepatic cholangiocarcinoma: a multicenter study from China.
        BMC Cancer. 2021; 21: 1299
        • Kudo M.
        • Izumi N.
        • Kokudo N.
        • Sakamoto M.
        • Shiina S.
        • Takayama T.
        • et al.
        Report of the 22nd nationwide follow-up survey of primary liver cancer in Japan (2012-2013).
        Hepatol Res. 2022;52(1):5-66;
        • Kudo M.
        • Izumi N.
        • Kokudo N.
        • Sakamoto M.
        • Shiina S.
        • Takayama T.
        • et al.
        Report of the 21st nationwide follow-up survey of primary liver cancer in Japan (2010-2011).
        Hepatol Res. 2021; 51: 355-405
        • Lee S.H.
        • Simoneau E.B.
        • Karpinets T.
        • Futreal P.A.
        • Zhang J.
        • Javle M.
        • et al.
        Genomic profiling of multifocal intrahepatic cholangiocarcinoma reveals intraindividual concordance of genetic alterations.
        Carcinogenesis. 2021; 42: 436-441
        • Franssen S.
        • Soares K.C.
        • Jolissaint J.S.
        • Tsilimigras D.I.
        • Buettner S.
        • Alexandrescu S.
        • et al.
        Comparison of hepatic arterial infusion pump chemotherapy vs resection for patients with multifocal intrahepatic cholangiocarcinoma.
        JAMA Surg. 2022; 157: 590-596
        • Wright G.P.
        • Perkins S.
        • Jones H.
        • Zureikat A.H.
        • Marsh J.W.
        • Holtzman M.P.
        • et al.
        Surgical resection does not improve survival in multifocal intrahepatic cholangiocarcinoma: a comparison of surgical resection with intra-arterial therapies.
        Ann Surg Oncol. 2018; 25: 83-90
        • Yin L.
        • Zhao S.
        • Zhu H.
        • Ji G.
        • Zhang X.
        Primary tumor resection improves survival in patients with multifocal intrahepatic cholangiocarcinoma based on a population study.
        Sci Rep. 2021; 1112166
        • Maithel S.K.
        • Javle M.M.
        • Mahipal A.
        • Lin B.S.-L.
        • Akce M.
        • Switchenko J.M.
        • et al.
        NEO-GAP: a phase II single-arm prospective feasibility study of neoadjuvant gemcitabine/cisplatin/nab-paclitaxel for resectable high-risk intrahepatic cholangiocarcinoma.
        J Clin Oncol. 2022; 40: 4097
        • Primrose J.N.
        • Fox R.P.
        • Palmer D.H.
        • Malik H.Z.
        • Prasad R.
        • Mirza D.
        • et al.
        Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.
        Lancet Oncol. 2019; 20: 663-673
        • Ikeda M.
        • Nakachi K.
        • Konishi M.
        • Nomura S.
        • Katayama H.
        • Kataoka T.
        • et al.
        Adjuvant S-1 versus observation in curatively resected biliary tract cancer: a phase III trial (JCOG1202: ASCOT).
        J Clin Oncol. 2022; 40: 382
        • Mavros M.N.
        • Economopoulos K.P.
        • Alexiou V.G.
        • Pawlik T.M.
        Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis.
        JAMA Surgery. 2014; 149: 565-574
        • Choi W.J.
        • Williams P.J.
        • Claasen M.
        • Ivanics T.
        • Englesakis M.
        • Gallinger S.
        • et al.
        Systematic review and meta-analysis of prognostic factors for early recurrence in intrahepatic cholangiocarcinoma after curative-intent resection.
        Ann Surg Oncol. 2022; 29: 4337-4353
        • Baheti A.D.
        • Tirumani S.H.
        • Shinagare A.B.
        • Rosenthal M.H.
        • Hornick J.L.
        • Ramaiya N.H.
        • et al.
        Correlation of CT patterns of primary intrahepatic cholangiocarcinoma at the time of presentation with the metastatic spread and clinical outcomes: retrospective study of 92 patients.
        Abdom Imag. 2014; 39: 1193-1201
        • Zhang X.F.
        • Xue F.
        • Dong D.H.
        • Weiss M.
        • Popescu I.
        • Marques H.P.
        • et al.
        Number and station of lymph node metastasis after curative-intent resection of intrahepatic cholangiocarcinoma impact prognosis.
        Ann Surg. 2020; 14: 14
        • Buettner S.
        • Ten Cate D.W.G.
        • Bagante F.
        • Alex
        • rescu S.
        • Marques H.P.
        • et al.
        Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
        J Gastrointest Surg. 2019; 23: 2239-2246
        • Conci S.
        • Vigano L.
        • Ercolani G.
        • Gonzalez E.
        • Ruzzenente A.
        • Isa G.
        • et al.
        Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
        Eur J Surg Oncol. 2020; 46: 1727-1733
        • Ikai I.
        • Kudo M.
        • Arii S.
        • Omata M.
        • Kojiro M.
        • Sakamoto M.
        • et al.
        Report of the 18th follow-up survey of primary liver cancer in Japan.
        Hepatol Res. 2010; 40: 1043-1059
        • Kudo M.
        • Izumi N.
        • Ichida T.
        • Ku Y.
        • Kokudo N.
        • Sakamoto M.
        • et al.
        Report of the 19th follow-up survey of primary liver cancer in Japan.
        Hepatol Res. 2016; 46: 372-390
        • Kudo M.
        • Izumi N.
        • Kubo S.
        • Kokudo N.
        • Sakamoto M.
        • Shiina S.
        • et al.
        Report of the 20th Nationwide follow-up survey of primary liver cancer in Japan.
        Hepatol Res. 2020; 50: 15-46
        • Liu H.
        • Lin L.
        • Lin Z.
        • Chen Y.
        • Huang Q.
        • Ding L.
        • et al.
        Impact of surgical margin width on long-term outcomes for intrahepatic cholangiocarcinoma: a multicenter study.
        BMC Cancer. 2021; 21: 840
        • Tian M.X.
        • Zhou Y.F.
        • Qu W.F.
        • Liu W.R.
        • Jin L.
        • Jiang X.F.
        • et al.
        Histopathology-based immunoscore predicts recurrence for intrahepatic cholangiocarcinoma after hepatectomy.
        Cancer Immunol Immunother. 2019; 68: 1369-1378
        • Wang L.
        • Deng M.
        • Ke Q.
        • Lou J.
        • Zheng S.
        • Bi X.
        • et al.
        Postoperative adjuvant therapy following radical resection for intrahepatic cholangiocarcinoma: a multicenter retrospective study.
        Cancer Med. 2020; 9: 2674-2685