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Cancers
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Perihilar Cholangiocarcinoma
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Perihilar Cholangiocarcinoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 28625

Special Issue Editors

Dr. Bas Groot Koerkamp

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Guest Editor
Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands
Interests: pancreatobiliary cancer; clinical trials; robotic surgery
Dr. Stefan Büttner

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Guest Editor
Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands
Interests: pancreatobiliary cancer; clinical trials; clinical epidemiology
Dr. Pim B. Olthof

E-Mail Website
Guest Editor
Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands
Interests: pancreatobiliary cancer; clinical trials; liver surgery

Special Issue Information

Dear Colleagues,

Perihilar cholangiocarcinoma (pCCA) is a rare disease, especially in Western countries, with a reported incidence of 2 cases per 100,000 per year. The treatment of pCCA patients requires a multidisciplinary approach and has numerous difficulties. Pathologic diagnosis is difficult and is only confirmed in about 50% of patients; as a result, up to 10% of patients are diagnosed with a benign disorder after curative resection. Curative resection is only possible in 10–20% of patients, and up to 50% of patients are unresectable at exploration, mainly due to limitations in the accuracy of preoperative staging, even with state-of-the-art imaging. When resection is feasible, these procedures are associated with high liver failure rates and a 90-day mortality rate among the highest of any elective cancer surgery. Preoperative biliary drainage has been the subject of debate for decades and is used to resolve preoperative obstructive cholestasis in order to reduce operative risks. Even a recent randomized trial on preoperative biliary drainage was not able to settle the debate. After surgery, survival varies greatly and is poorly predictable with currently known risk factors. Median survival after surgery is about 3 years.  While most literature is based on curative resections and biliary drainage, most patients are not amenable for surgery. Palliative systemic therapy has been shown to increase survival, yet prognosis remains dismal. Adjuvant systemic therapy has been investigated, but the benefit and ideal regimen are not elucidated. Many relevant research projects are yet to be initiated, but the complexity of the disease and its low incidence limit the feasibility of high-quality prospective research projects.

Dr. Bas Groot Koerkamp
Dr. Stefan Büttner
Dr. Pim B. Olthof
Guest Editors

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Keywords

  • cholangiocarcinoma
  • perihilar
  • Klatskin tumor
  • treatment
  • diagnosis

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Published Papers (8 papers)

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Research

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15 pages, 1608 KiB  
Article
Comparing Liver Venous Deprivation and Portal Vein Embolization for Perihilar Cholangiocarcinoma: Is It Time to Shift the Focus to Hepatic Functional Reserve Rather than Hypertrophy?
by Rebecca Marino, Francesca Ratti, Angelo Della Corte, Domenico Santangelo, Lucrezia Clocchiatti, Carla Canevari, Patrizia Magnani, Federica Pedica, Andrea Casadei-Gardini, Francesco De Cobelli and Luca Aldrighetti
Cancers 2023, 15(17), 4363; https://doi.org/10.3390/cancers15174363 - 1 Sep 2023
Cited by 5 | Viewed by 1489
Abstract
Purpose: Among liver hypertrophy technics, liver venous deprivation (LVD) has been recently introduced as an effective procedure to combine simultaneous portal inflow and hepatic outflow abrogation, raising growing clinical interest. The aim of this study is to investigate the role of LVD [...] Read more.
Purpose: Among liver hypertrophy technics, liver venous deprivation (LVD) has been recently introduced as an effective procedure to combine simultaneous portal inflow and hepatic outflow abrogation, raising growing clinical interest. The aim of this study is to investigate the role of LVD for preoperative optimization of future liver remnant (FLR) in perihilar cholangiocarcinoma (PHC), especially when compared with portal vein embolization (PVE). Methods: Between January 2013 and July 2022, all patients diagnosed with PHC and scheduled for preoperative optimization of FTR, through radiological hypertrophy techniques, prior to liver resection, were included. FTR volumetric assessment was evaluated at two distinct timepoints to track the progression of both early (T1, 10 days post-procedural) and late (T2, 21 days post-procedural) efficacy indicators. Post-procedural outcomes, including functional and volumetric analyses, were compared between the LVD and the PVE cohorts. Results: A total of 12 patients underwent LVD while 19 underwent PVE. No significant differences in either post-procedural or post-operative complications were found. Post-procedural FLR function, calculated with (99m) Tc-Mebrofenin hepatobiliary scintigraphy, and kinetic growth rate, at both timepoints, were greater in the LVD cohort (3.12 ± 0.55%/min/m2 vs. 2.46 ± 0.64%/min/m2, p = 0.041; 27.32 ± 16.86%/week (T1) vs. 15.71 ± 9.82%/week (T1) p < 0.001; 17.19 ± 9.88%/week (T2) vs. 9.89 ± 14.62%/week (T2) p = 0.034) when compared with the PVE cohort. Post-procedural FTR volumes were similar for both hypertrophy techniques. Conclusions: LVD is an effective procedure to effectively optimize FLR before liver resection for PHC. The faster growth rate combined with the improved FLR function, when compared to PVE alone, could maximize surgical outcomes by lowering post-hepatectomy liver failure rates. Full article
(This article belongs to the Special Issue Perihilar Cholangiocarcinoma)
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13 pages, 935 KiB  
Article
Impact of Positive Lymph Nodes and Resection Margin Status on the Overall Survival of Patients with Resected Perihilar Cholangiocarcinoma: The ENSCCA Registry
by Lynn E. Nooijen, Jesus M. Banales, Marieke T. de Boer, Chiara Braconi, Trine Folseraas, Alejandro Forner, Waclaw Holowko, Frederik J. H. Hoogwater, Heinz-Josef Klümpen, Bas Groot Koerkamp, Angela Lamarca, Adelaida La Casta, Flora López-López, Laura Izquierdo-Sánchez, Alexander Scheiter, Kirsten Utpatel, Rutger-Jan Swijnenburg, Geert Kazemier and Joris I. Erdmann
Cancers 2022, 14(10), 2389; https://doi.org/10.3390/cancers14102389 - 12 May 2022
Cited by 14 | Viewed by 2528
Abstract
Background: Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival (OS) and poor recurrence-free survival (RFS) for patients who underwent resection for perihilar cholangiocarcinoma (pCCA). However, the prognostic value of positive lymph nodes independently from [...] Read more.
Background: Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival (OS) and poor recurrence-free survival (RFS) for patients who underwent resection for perihilar cholangiocarcinoma (pCCA). However, the prognostic value of positive lymph nodes independently from resection margin status on OS has not been evaluated. Methods: From the European Cholangiocarcinoma (ENSCCA) registry, patients who underwent resection for pCCA between 1994 and 2021 were included in this retrospective cohort study. The primary outcome was OS stratified for resection margin and lymph node status. The secondary outcome was recurrence-free survival. Results: A total of 325 patients from 11 different centers and six European countries were included. Of these, 194 (59.7%) patients had negative resection margins. In 113 (34.8%) patients, positive lymph nodes were found. Lymph node status, histological grade, and ECOG performance status were independent prognostic factors for survival. The median OS for N0R0, N0R1, N+R0, and N+R1 was 38, 30, 18, and 12 months, respectively (p < 0.001). Conclusion: These data indicate that in the presence of positive regional lymph nodes, resection margin status does not determine OS or RFS in patients with pCCA. Achieving negative margins in patients with positive nodes should not come at the expense of more extensive surgery and associated higher mortality. Full article
(This article belongs to the Special Issue Perihilar Cholangiocarcinoma)
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15 pages, 3781 KiB  
Article
PD-1+ T-Cells Correlate with Nerve Fiber Density as a Prognostic Biomarker in Patients with Resected Perihilar Cholangiocarcinoma
by Xiuxiang Tan, Jan Bednarsch, Mika Rosin, Simone Appinger, Dong Liu, Georg Wiltberger, Juan Garcia Vallejo, Sven Arke Lang, Zoltan Czigany, Shiva Boroojerdi, Nadine T. Gaisa, Peter Boor, Roman David Bülow, Judith De Vos-Geelen, Liselot Valkenburg-van Iersel, Marian C. Clahsen-van Groningen, Evelien J. M. de Jong, Bas Groot Koerkamp, Michail Doukas, Flavio G. Rocha, Tom Luedde, Uwe Klinge, Shivan Sivakumar, Ulf Peter Neumann and Lara Rosaline Heijadd Show full author list remove Hide full author list
Cancers 2022, 14(9), 2190; https://doi.org/10.3390/cancers14092190 - 27 Apr 2022
Cited by 5 | Viewed by 2847
Abstract
Background and Aims: Perihilar cholangiocarcinoma (pCCA) is a hepatobiliary malignancy, with a dismal prognosis. Nerve fiber density (NFD)—a novel prognostic biomarker—describes the density of small nerve fibers without cancer invasion and is categorized into high numbers and low numbers of small nerve fibers [...] Read more.
Background and Aims: Perihilar cholangiocarcinoma (pCCA) is a hepatobiliary malignancy, with a dismal prognosis. Nerve fiber density (NFD)—a novel prognostic biomarker—describes the density of small nerve fibers without cancer invasion and is categorized into high numbers and low numbers of small nerve fibers (high vs low NFD). NFD is different than perineural invasion (PNI), defined as nerve fiber trunks invaded by cancer cells. Here, we aim to explore differences in immune cell populations and survival between high and low NFD patients. Approach and Results: We applied multiplex immunofluorescence (mIF) on 47 pCCA patients and investigated immune cell composition in the tumor microenvironment (TME) of high and low NFD. Group comparison and oncological outcome analysis was performed. CD8+PD-1 expression was higher in the high NFD than in the low NFD group (12.24 × 10−6 vs. 1.38 × 10−6 positive cells by overall cell count, p = 0.017). High CD8+PD-1 expression was further identified as an independent predictor of overall (OS; Hazard ratio (HR) = 0.41; p = 0.031) and recurrence-free survival (RFS; HR = 0.40; p = 0.039). Correspondingly, the median OS was 83 months (95% confidence interval (CI): 18–48) in patients with high CD8+PD-1+ expression compared to 19 months (95% CI: 5–93) in patients with low CD8+PD-1+ expression (p = 0.018 log rank). Furthermore, RFS was significantly lower in patients with low CD8+PD-1+ expression (14 months (95% CI: 6–22)) compared to patients with high CD8+PD-1+ expression (83 months (95% CI: 17–149), p = 0.018 log rank). Conclusions: PD-1+ T-cells correlate with high NFD as a prognostic biomarker and predict good survival; the biological pathway needs to be investigated. Full article
(This article belongs to the Special Issue Perihilar Cholangiocarcinoma)
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Review

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10 pages, 4533 KiB  
Review
Concomitant Hepatic Artery Resection for Advanced Perihilar Cholangiocarcinoma: A Narrative Review
by Takehiro Noji, Satoshi Hirano, Kimitaka Tanaka, Aya Matsui, Yoshitsugu Nakanishi, Toshimichi Asano, Toru Nakamura and Takahiro Tsuchikawa
Cancers 2022, 14(11), 2672; https://doi.org/10.3390/cancers14112672 - 27 May 2022
Cited by 5 | Viewed by 2757
Abstract
Perihilar cholangiocarcinoma (PHCC) is one of the most intractable gastrointestinal malignancies. These tumours lie in the core section of the biliary tract. Patients who undergo curative surgery have a 40–50-month median survival time, and a five-year overall survival rate of 35–45%. Therefore, curative [...] Read more.
Perihilar cholangiocarcinoma (PHCC) is one of the most intractable gastrointestinal malignancies. These tumours lie in the core section of the biliary tract. Patients who undergo curative surgery have a 40–50-month median survival time, and a five-year overall survival rate of 35–45%. Therefore, curative intent surgery can lead to long-term survival. PHCC sometimes invades the surrounding tissues, such as the portal vein, hepatic artery, perineural tissues around the hepatic artery, and hepatic parenchyma. Contralateral hepatic artery invasion is classed as T4, which is considered unresectable due to its “locally advanced” nature. Recently, several reports have been published on concomitant hepatic artery resection (HAR) for PHCC. The morbidity and mortality rates in these reports were similar to those non-HAR cases. The five-year survival rate after HAR was 16–38.5%. Alternative procedures for arterial portal shunting and non-vascular reconstruction (HAR) have also been reported. In this paper, we review HAR for PHCC, focusing on its history, diagnosis, procedures, and alternatives. HAR, undertaken by established biliary surgeons in selected patients with PHCC, can be feasible. Full article
(This article belongs to the Special Issue Perihilar Cholangiocarcinoma)
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15 pages, 2368 KiB  
Review
Current Perspectives on the Surgical Management of Perihilar Cholangiocarcinoma
by D. Brock Hewitt, Zachary J. Brown and Timothy M. Pawlik
Cancers 2022, 14(9), 2208; https://doi.org/10.3390/cancers14092208 - 28 Apr 2022
Cited by 11 | Viewed by 8475
Abstract
Cholangiocarcinoma (CCA) represents nearly 15% of all primary liver cancers and 2% of all cancer-related deaths worldwide. Perihilar cholangiocarcinoma (pCCA) accounts for 50–60% of all CCA. First described in 1965, pCCAs arise between the second-order bile ducts and the insertion of the cystic [...] Read more.
Cholangiocarcinoma (CCA) represents nearly 15% of all primary liver cancers and 2% of all cancer-related deaths worldwide. Perihilar cholangiocarcinoma (pCCA) accounts for 50–60% of all CCA. First described in 1965, pCCAs arise between the second-order bile ducts and the insertion of the cystic duct into the common bile duct. CCA typically has an insidious onset and commonly presents with advanced, unresectable disease. Complete surgical resection is technically challenging, as tumor proximity to the structures of the central liver often necessitates an extended hepatectomy to achieve negative margins. Intraoperative frozen section can aid in assuring negative margins and complete resection. Portal lymphadenectomy provides important prognostic and staging information. In specialized centers, vascular resection and reconstruction can be performed to achieve negative margins in appropriately selected patients. In addition, minimally invasive surgical techniques (e.g., robotic surgery) are safe, feasible, and provide equivalent short-term oncologic outcomes. Neoadjuvant chemoradiation therapy followed by liver transplantation provides a potentially curative option for patients with unresectable disease. New trials are needed to investigate novel chemotherapies, immunotherapies, and targeted therapies to better control systemic disease in the adjuvant setting and, potentially, downstage disease in the neoadjuvant setting. Full article
(This article belongs to the Special Issue Perihilar Cholangiocarcinoma)
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14 pages, 1507 KiB  
Review
Preoperative Management of Perihilar Cholangiocarcinoma
by Ryan J. Ellis, Kevin C. Soares and William R. Jarnagin
Cancers 2022, 14(9), 2119; https://doi.org/10.3390/cancers14092119 - 24 Apr 2022
Cited by 9 | Viewed by 3110
Abstract
Perihilar cholangiocarcinoma is a rare hepatobiliary malignancy that requires thoughtful, multidisciplinary evaluation in the preoperative setting to ensure optimal patient outcomes. Comprehensive preoperative imaging, including multiphase CT angiography and some form of cholangiographic assessment, is key to assessing resectability. While many staging systems [...] Read more.
Perihilar cholangiocarcinoma is a rare hepatobiliary malignancy that requires thoughtful, multidisciplinary evaluation in the preoperative setting to ensure optimal patient outcomes. Comprehensive preoperative imaging, including multiphase CT angiography and some form of cholangiographic assessment, is key to assessing resectability. While many staging systems exist, the Blumgart staging system provides the most useful combination of resectability assessment and prognostic information for use in the preoperative setting. Once resectability is confirmed, volumetric analysis should be performed. Upfront resection without biliary drainage or portal venous embolization may be considered in patients without cholangitis and an estimated functional liver remnant (FLR) > 40%. In patients with FLR < 40%, judicious use of biliary drainage is advised, with the goal of selective biliary drainage of the functional liver remnant. Percutaneous biliary drainage may avoid inadvertent contamination of the contralateral biliary tree and associated infectious complications, though the relative effectiveness of percutaneous and endoscopic techniques is an ongoing area of study and debate. Patients with low FLR also require intervention to induce hypertrophy, most commonly portal venous embolization, in an effort to reduce the rate of postoperative liver failure. Even with extensive preoperative workup, many patients will be found to have metastatic disease at exploration and diagnostic laparoscopy may reduce the rate of non-therapeutic laparotomy. Management of perihilar cholangiocarcinoma continues to evolve, with ongoing efforts to improve preoperative liver hypertrophy and to further define the role of transplantation in disease management. Full article
(This article belongs to the Special Issue Perihilar Cholangiocarcinoma)
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Other

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13 pages, 580 KiB  
Systematic Review
Comparison of Intraductal RFA Plus Stent versus Stent-Only Treatment for Unresectable Perihilar Cholangiocarcinoma—A Systematic Review and Meta-Analysis
by David M. de Jong, Jeska A. Fritzsche, Amber S. Audhoe, Suzanne S. L. Yi, Marco J. Bruno, Rogier P. Voermans and Lydi M. J. W. van Driel
Cancers 2022, 14(9), 2079; https://doi.org/10.3390/cancers14092079 - 21 Apr 2022
Cited by 15 | Viewed by 2434
Abstract
Background: One of the cornerstones of palliative treatment for unresectable perihilar cholangiocarcinoma is biliary stent placement in order to restore biliary drainage. In this review, the potential added value of RFA with stent placement in comparison to stent placement alone in patients with [...] Read more.
Background: One of the cornerstones of palliative treatment for unresectable perihilar cholangiocarcinoma is biliary stent placement in order to restore biliary drainage. In this review, the potential added value of RFA with stent placement in comparison to stent placement alone in patients with unresectable perihilar cholangiocarcinoma is analyzed. Methods: We performed a comprehensive online search for relevant articles in November 2021 (PROSPERO ID: CRD42021288180). The primary endpoint was difference in overall survival. Secondary endpoints included overall survival, stent patency and complications. Only studies comparing survival after RFA + stent placement with stent placement alone were included in the meta-analysis. Non-comparative studies or comparative studies describing stent patency only were included in the systematic review. Results: A total of nine studies, including 217 patients with pCCA who underwent RFA + stent placement and 294 patients who underwent stent-only treatment, met the inclusion criteria for the primary endpoint analysis. Direct comparison between the two treatment groups showed a significantly longer overall survival for RFA + stent treatment, with a pooled HR of 0.65 [95% CI, 0.50–0.84, I2 = 38%]. When all eligible studies were included, RFA + stent treatment revealed an overall survival of 9.5 months [95% CI, 6.3–12.6], whereas survival for stent-only treatment was 7.0 months [95% CI, 5.7–8.2]. Due to the heterogeneity of the data, no pooled data analysis could be performed on stent patency or complications. Conclusions: RFA + stent placement displays promising potential to prolong survival. However, further research incorporating confounding factors like use of palliative chemotherapy is necessary in order to validate these findings. Full article
(This article belongs to the Special Issue Perihilar Cholangiocarcinoma)
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14 pages, 4352 KiB  
Systematic Review
The Value of Platelet-to-Lymphocyte Ratio as a Prognostic Marker in Cholangiocarcinoma: A Systematic Review and Meta-Analysis
by Dong Liu, Zoltan Czigany, Lara R. Heij, Stefan A. W. Bouwense, Ronald van Dam, Sven A. Lang, Tom F. Ulmer, Ulf P. Neumann and Jan Bednarsch
Cancers 2022, 14(2), 438; https://doi.org/10.3390/cancers14020438 - 16 Jan 2022
Cited by 23 | Viewed by 3232
Abstract
The platelet-to-lymphocyte ratio (PLR), an inflammatory parameter, has shown prognostic value in several malignancies. The aim of this meta-analysis was to determine the impact of pretreatment PLR on the oncological outcome in patients with cholangiocarcinoma (CCA). A systematic literature search has been carried [...] Read more.
The platelet-to-lymphocyte ratio (PLR), an inflammatory parameter, has shown prognostic value in several malignancies. The aim of this meta-analysis was to determine the impact of pretreatment PLR on the oncological outcome in patients with cholangiocarcinoma (CCA). A systematic literature search has been carried out in the PubMed and Google Scholar databases for pertinent papers published between January 2000 and August 2021. Within a random-effects model, the pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated to investigate the relationships among the PLR, overall survival (OS), and disease-free survival (DFS). Subgroup analysis, sensitivity analysis, and publication bias were also conducted to further evaluate the relationship. A total of 20 articles comprising 5429 patients were included in this meta-analysis. Overall, the pooled outcomes revealed that a high PLR before treatment is associated with impaired OS (HR = 1.14; 95% CI = 1.06–1.24; p < 0.01) and DFS (HR = 1.57; 95% CI = 1.19–2.07; p < 0.01). Subgroup analysis revealed that this association is not influenced by the treatment modality (surgical vs. non-surgical), PLR cut-off values, or sample size of the included studies. An elevated pretreatment PLR is prognostic for the OS and DFS of CCA patients. More high-quality studies are required to investigate the pathophysiological basis of the observation and the prognostic value of the PLR in clinical management as well as for patient selection. Full article
(This article belongs to the Special Issue Perihilar Cholangiocarcinoma)
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