Characteristics of late recurrences after hepatectomy for perihilar cholangiocarcinoma: A single-center cohort study

Characteristics of late recurrences after hepatectomy for perihilar cholangiocarcinoma: A single-center cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Characteristics of late recurrences after hepatectomy for perihilar cholangiocarcinoma: A single-center cohort study Hideaki Sato, Shuichi Aoki, Masahiro Iseki, Mika Ando, Shuichiro Hayashi, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7306398/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jan, 2026 Read the published version in BMC Surgery → Version 1 posted 20 You are reading this latest preprint version Abstract Background: Surgical resection is the only curative treatment for perihilar cholangiocarcinoma (pCCA); however, the majority of patients experience postoperative recurrence. While recurrence typically occurs within five years after surgery, recurrence after prolonged relapse-free survival has been occasionally observed. This study aimed to investigate the clinicopathological factors associated with late recurrence of pCCA. Methods: Among the 258 consecutive patients who underwent radical hepatectomy with extrahepatic bile duct resection for pCCA at our institution between 1996 and 2019, 9 patients (3.4%) had postoperative recurrence more than five years after surgery. Clinicopathological characteristics of late recurrence (beyond five years) were analyzed and compared with those of the patients who remained recurrence-free for over 12 years (no recurrence group, n=14). Results: Among the nine cases of late recurrence, local recurrence was the most common, followed by liver metastasis. Chemotherapy was the primary treatment after recurrence, while surgical resection was performed in two cases. A comparison between the late recurrence and no recurrence groups revealed similar demographics; however, the late recurrence group exhibited significantly higher cases with pathological perineural invasion. Notably, all late recurrence cases demonstrated positive perineural invasion. Conclusions: The presence of pathological perineural invasion is significantly associated with late recurrence of pCCA. This finding provides significant insights for the long-term follow-up and managemant of pCCA patients. perihilar cholangiocarcinoma late recurrence hepatectomy long term survival perineural invasion Figures Figure 1 Figure 2 Figure 3 1 | BACKGROUND Perihilar cholangiocarcinoma (pCCA) arises from the bile duct epithelial cells that involves the hilar bifurcation, with its anatomical boundaries extending from the cystic duct origin to the second-order branches of the intrahepatic bile ducts [ 1 , 2 ]. pCCA constitutes approximately 3% of all gastrointestinal tumors [ 3 ], and has an estimated 5-year survival rate of only 10% [ 4 , 5 ]. Surgical resection remains the sole curative option for pCCA [ 6 ], but postoperative recurrence is common, and long-term survival outcomes remain poor [ 6 , 7 ]. Recurrence of pCCA most frequently occurs within five years following surgery and those patients are not expected to have a long-term prognosis [ 8 – 10 ]. In contrast, there are rare cases with recurrence after a prolonged disease-free period, such as a case of late recurrence as 10 years after curative resection [ 8 , 11 , 12 ]. While clinicopathological risk factors for early postoperative recurrence following radical resection of pCCA have been widely investigated [ 10 , 13 – 15 ], there is limited research on the causes and predictive factors for recurrence occurring more than five years after surgery. Such late recurrences have been primarily documented in case reports, leaving their characteristics insufficiently explored [ 8 , 9 , 11 , 12 ]. Furthermore, only a small proportion of patients survive beyond five years, and even fewer undergo extended follow-up. At our institution, we follow a policy of monitoring cholangiocarcinoma patients for more than 10 years after surgery. This approach has enabled us to compile a significant number of cases, including both early recurrences and those occurring more than five years after surgery. In this study, we aim to analyze the characteristics of pCCA cases with recurrences beyond five years following radical hepatectomy and compare them to patients with no recurrence beyond 12 years. 2 | METHODS 2.1 | Patients and study outline This study was a retrospective observational study. Consecutive patients with pCCA who underwent radical hepatectomy with extrahepatic bile duct resection at Tohoku University Hospital (Sendai, Japan) between 1996 and 2019 were enrolled. A total of 321 pCCA patients were initially enrolled in this study. Of these, 51 patients who died from other causes within 5 years and 12 patients with insufficient clinical data were excluded. Consequently, 258 patients were included in the final analysis. Among the 258 patients, 75 patients (29.1%) had no recurrence, while 183 patients (70.9%) experienced recurrence. Of the recurrence cases, 67 patients (26.0%) experienced recurrence within one year, 83 patients (32.2%) within three years, 24 patients (9.3%) within five years, and 9 patients (3.4%) beyond five years (Fig. 1 ). The median overall survival (OS) and relapse-free survival (RFS) of the 258 patients were 43.0 months and 27.3 months, respectively. Among the 258 patients, we compared the clinicopathological characteristics of the 9 patients who experienced late recurrence (beyond five years after surgery) with those of 14 patients who remained recurrence-free for more than 12 years (no recurrence group, selected from the 75 recurrence-free patients). We defined late recurrence as recurrence occurring within 12 years after surgery, based on the observation that the longest recurrence-free interval among our late recurrence cases was 12 years. 2.2 | Surgical treatment The surgical procedure for pCCA involved hemihepatectomy or trisectionectomy with caudate lobectomy, combined with extrahepatic bile duct resection [ 16 ]. All surgeries were performed after achieving a serum bilirubin level of < 2 mg/dL. Comprehensive lymph node dissection was conducted in all cases, targeting nodes at the hepatoduodenal ligament, around the pancreatic head, and near the common hepatic artery. Combined portal vein or hepatic artery resection was undertaken if the tumor had invaded these vessels [ 17 ]. Additionally, hepatopancreatoduodenectomy (HPD) was performed when necessary to achieve curative resection, particularly when intraoperative rapid diagnosis revealed positive bile duct resection margins [ 17 ]. Morbidity was defined according to the Clavien-Dindo Classification, which is commonly used for the assessment of postoperative complications [ 18 ]. 2.3 | Neoadjuvant therapy For resectable pCCA, surgery was typically the first-line treatment. However, in cases of extensive local progression or strong suspicion of lymph node metastasis, neoadjuvant chemotherapy with gemcitabine, S-1, and/or cisplatine, or radiation therapy might be considered in conjunction with surgery. 2.4 | Adjuvant therapy Since 2013, postoperative adjuvant chemotherapy with S-1 has been routinely administered [ 19 ]. Prior to this period, gemcitabine, S-1, uracil-tegafur (UFT), 5FU and/or cisplatin were selected as adjuvant chemotherapy, primarily for patients at high risk of postoperative recurrence, such as those with lymph node metastasis. In some cases, adjuvant chemotherapy was omitted based on the patient's performance status and pathological findings. 2.5 | Postoperative follow-up Physical examinations and blood tests, including tumor marker assessments, were conducted every three months postoperatively. CT scans were performed at least twice a year during the first five years. After this period, blood tests and CT scans are continued annually for as long as feasible. In cases of recurrence, surgical intervention, chemotherapy, and/or radiation therapy were selected based on the patient’s overall condition and clinical status. 2.6 | Statistical analysis All statistical analyses were performed with JMP Pro® 17.1.0 for Macintosh (SAS Institute Inc., Cary, NC, USA). Wilcoxon's signed-rank test was applied for continuous variables, and Fisher's exact test or chi-square test for categorical data. A p-value of less than 0.05 was considered as statistically significant. 3 | RESULTS 3.1 | Characteristics of the patients The characteristics of the 9 cases with late recurrence are summarized in Table 1. Local recurrence was the most common and was observed in six cases (five at the anastomotic site and one in a lymph node), followed by three cases of liver metastasis, two cases of peritoneal dissemination, and one case of pulmonary metastasis (some cases exhibited overlap). Histologically, four cases were classified as well-differentiated tubular adenocarcinoma, four as moderately differentiated tubular adenocarcinoma, and one as poorly differentiated adenocarcinoma. R0 resection was performed in five cases. Postoperative adjuvant chemotherapy was administered in seven cases, with two exceptions. After recurrence, chemotherapy was the primary treatment in most cases, while surgical resection was performed in two cases. In four cases, best supportive care (BSC) was chosen due to the patient’s age or personal preference. Five patients succumbed to the underlying disease; however, among them, two patients survived for more than two years after recurrence, and four patients are currently undergoing chemotherapy as part of their ongoing treatment. 3.2 | Comparison between no recurrence and late recurrence Among 9 cases with late recurrence after 5 years, the case with recurrence after 11.5 years represents the longest time to recurrence. Therefore, we compared the cases with late recurrence after 5 years with those who had no recurrence beyond 12 years. The results are summarized in Table 2 and 3. Table 2 shows the patients' clinical and surgical characteristics. There were no significant differences in the clinicodemographic data between the two groups, including sex, age, preoperative BMI, and adjuvant therapy. Similarly, no significant differences were observed in the surgical outcomes, such as operative time, blood loss volume, or combined vascular resection. Additionally, postoperative morbidity and length of hospital stay did not differ significantly between the two groups. However, neoadjuvant chemotherapy and HPD were performed significantly more frequently in the no recurrence group. Table 3 summarizes a comparison of the pathological findings between the two groups. No significant differences were identified between the groups regarding Bismuth type IV classification, TNM staging, vascular and lymphatic invasion, R1 resection (including hepatic, distal, and extrahepatic margins), or lymph node metastasis. However, perineural invasion was significantly more frequent in the late recurrence group. Notably, all cases of late recurrence exhibited positive perineural invasion. 3.3 | Case report Finally, we present the case of a patient with pCCA who experienced recurrence 11 years after surgery (Case 8 in Table 1). The patient, a 59-year-old man, was diagnosed in 2013 with Bismuth type IV pCCA and underwent extended right hepatectomy with with extrahepatic bile duct and portal vein resection following right portal vein embolization (Figure 2A,B,C). Intraoperative frozen section analysis revealed a positive resection margin on the hepatic side of the bile duct, resulting in an R1 resection. The final pathological diagnosis was well-differentiated tubular adenocarcinoma, classified as pT2N0M0, Stage II. Histopathological examination demonstrated lymphatic, venous, and perineural invasion. The hepatic resection margin remained positive, confirming an R1 resection. Postoperatively, the patient received adjuvant chemotherapy with S-1 and was regularly monitored during the follow-up. The patient remained recurrence-free for 11 years. However, tumor marker levels began to rise (Figure 3), and CT imaging revealed findings consistent with either a local recurrence or liver metastasis (Figure 2D, E). Although histological confirmation of recurrence was not obtained, gemcitabine + cisplatin + durvalumab (GCD) therapy was initiated. To date, the patient has completed five courses of treatment. During this time, the tumor marker levels of CA19-9 had normalized (Figure 3), and CT imaging demonstrated tumor shrinkage (Figure 2E), although the findings remained categorized as stable disease (SD). 4 | DISCUSSION pCCA is recognized as one of the most aggressive malignant tumors, with an exceptionally poor prognosis [ 4 – 7 ]. While surgical intervention is considered the only potentially curative treatment [ 6 ], the recurrence rate following curative-intent surgery for pCCA remains alarmingly high, ranging from 44–83.2% [ 15 , 20 ]. Notably, most recurrences occur relatively early, with approximately 24-45.4% of cases recurring within the first year after surgery [ 20 ]. Several prognostic factors for early recurrence have been identified, including poor tumor differentiation, vascular invasion, perineural invasion, lymph node metastases, elevated preoperative CA19-9 and bilirubin levels, positive resection margins, and advanced TNM staging [ 15 , 20 ]. While early recurrence has been extensively studied, with its clinicopathological features well-documented, the characteristics and prognosis of late recurrence remain poorly understood [ 8 – 12 ]. In this study, we identified the clinicopathological characteristics of late recurrence in pCCA patients for the first time, extending beyond previously published case reports by comparing them with cases that remained recurrence-free for more than 12 years. Notably, we clarified that perineural invasion, a factor associated with early recurrence, is also a significant risk factor for late recurrence. Previous case reports have described a wide spectrum of clinical courses for late recurrence, ranging from rapid fatal progression to favorable responses to treatment [ 8 , 9 , 11 , 12 ]. Similarly, among our nine cases, some experienced rapid deterioration after recurrence, while others achieved long-term disease control. Notably, cases in which therapeutic interventions beyond BSC were feasible demonstrated the potential for prolonged survival. These findings underscore the importance of early detection and timely management of recurrence. However, it remains unclear whether late recurrence universally results in rapid systemic deterioration, which raises critical issues for future research. Some studies suggest that late recurrences may exhibit varied clinical courses, potentially influenced by factors such as tumor dormancy, particularly in distant organs [ 22 , 23 ]. For example, lung metastases in pancreatic cancer are known to progress more slowly compared to other metastases [ 24 ]. In various cancers, prolonged dormancy has been associated with improved outcomes. Chemotherapy, in particular, may induce tumor dormancy, allowing patients to survive without significant disease progression despite the presence of residual tumors [ 21 – 23 ]. In this context, identifying minimal residual disease (MRD) and dormant tumor cells through biomarkers could be crucial for understanding late recurrence. Circulating free DNA (cfDNA), a key biomarker, has shown promise in detecting tumor-derived DNA in the bloodstream, providing a less invasive method for monitoring disease presence and progression [ 25 , 26 ]. cfDNA levels may reflect the burden of MRD, offering potential insights into dormant tumor cells that could contribute to late recurrence. Additionally, other biomarkers, such as exosomes and tumor-associated antigens, may aid in detecting these residual cells [ 27 ]. However, predicting the prognosis at the time of recurrence remains challenging. Further research is needed to determine how these biomarkers can guide treatment decisions. Currently, observation and treatment remain the primary strategies for managing late recurrence. On the other hand, in cases such as the present one, where recurrence occurs after a long interval following resection, the possibility of metachronous de novo carcinogenesis, rather than true recurrence, should also be considered. In our cases, this possibility cannot be entirely excluded. However, most cases of metachronous biliary tract carcinomas (BTCs) arising long after resection tend to follow an intraductal recurrence pattern rather than representing entirely new primary lesions. Comparative genomic analyses of BTCs have revealed that most metachronous BTCs are clonally related to their primary tumors, either through successional evolution or phylogenetic divergence [ 28 ]. From this perspective, we interpreted our case as a persistent recurrence. This study has several limitations. First, it is a single-center retrospective study, which introduces potential confounding factors and selection bias. Additionally, the small sample size, despite our institution's status as a leading center for cholangiocarcinoma treatment in Japan, limited the ability to identify factors associated with late recurrence through multivariate analysis. Furthermore, because previous reports and our cases have not identified recurrences in patients followed for more than 12 years after surgery, we compared cases with no recurrence for over 12 years to those with late recurrence. However, these cases may include patients who may experience recurrence in the future. As such, this comparison may be insufficient. To conduct a more comprehensive analysis, further accumulation of cases with even longer follow-up periods is necessary. Despite these limitations, this study is the first to investigate the clinicopathological characteristics of late recurrence in pCCA. While late recurrence is relatively rare, our findings highlight the importance of monitoring patients for more than 10 years postoperatively. In particular, vigilant follow-up of high-risk groups, such as those with perineural invasion, is essential for enabling early intervention and improving the prognosis. Accumulating additional cases in the future will allow for more detailed analyses and contribute to the development of refined management strategies for late recurrence. However, recent advancements in non-surgical treatments have provided new hope for improving patient outcomes [ 1 ]. These developments emphasize the growing importance of early detection and timely intervention. Among these, immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in the treatment of cholangiocarcinoma. The results of the TOPAZ-1 and KEYNOTE-966 trials have established ICIs as a viable therapeutic option for patients with unresectable cholangiocarcinoma [ 29 , 30 ]. These trials provide strong evidence supporting the integration of ICIs into treatment protocols, marking a significant shift in the management of this challenging disease. 5 | CONCLUSIONS This study is the first to identify clinicopathological factors associated with late recurrence of pCCA, providing valuable insights for long-term follow-up and management. Although late recurrence is rare, its occurrence underscores the need for vigilant monitoring beyond 10 years postoperatively. Moving forward, multicenter collaborative studies and the accumulation of additional cases will be essential for determining optimal follow-up durations and developing effective treatment strategies for recurrence. 6 | LIST OF ABBREVIATIONS perihilar cholangiocarcinoma, pCCA; overall survival, OS; relapse-free survival, RFS; hepatopancreatoduodenectomy, HPD; uracil-tegafur, UFT; computed tomography, CT; best supportive care, BSC; Body Mass Index, BMI; gemcitabine + cisplatin + durvalumab, GCD; stable disease, SD; minimal residual disease, MRD; circulating free DNA, cfDNA; biliary tract carcinomas, BTCs; immune checkpoint inhibitors, ICIs. 7 | DECLARATIONS Ethics Approval Statement and Clinical Trial Registration: The study protocol was conducted in accordance with the ethical standards outlined in the Declaration of Helsinki and was approved by the Institutional Review Board of Tohoku University (approval number: 2024-1-668). Written informed consent was obtained from all patients regarding the use of their clinical data. Consent for publicasion Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that there are no conflicts of interest related to this article. Funding This research did not receive any specific funding from public, commercial, or not-for-profit organizations. Authors' contributions Hideaki Sato and Shuichi Aoki: Manuscript writing, and drafting of the conception and design. Hideaki Sato, Shuichi Aoki, Masahiro Iseki, Mika Ando, Shuichiro Hayashi, Shingo Yoshimachi, Akiko Kusaka, Mitsuhiro Shimura, Daisuke Douchi, Takayuki Miura, Shimpei Maeda, Masaharu Ishida, Masamichi Mizuma and Michiaki Unno: Critical revision of the article for important intellectual content. Hideaki Sato and Shuichi Aoki: Analysis and interpretation of the data. Masamichi Mizuma, Atsushi Masamune and Michiaki Unno: Final approval of the article. Acknowledgements The authors would like to express their heartfelt gratitude to all the surgeons who performed surgical resections at our institution, especially Dr. Kei Nakagawa. They also extend their sincere thanks to the gastroenterologists and radiologists of the Departments of Gastroenterology and Diagnostic Radiology at Tohoku University Hospital for their invaluable contributions. Clinical trial number Not applicable. References van Keulen AM, Franssen S, van der Geest LG, et al. Nationwide treatment and outcomes of perihilar cholangiocarcinoma. Liver Int. 2021 Aug;41(8):1945-1953. Mueller M, Breuer E, Mizuno T, et al. Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers. Ann Surg. 2021 Nov 1;274(5):780-788. Ilyas SI, Gores GJ. 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Supplementary Files TABLE0702.docx Cite Share Download PDF Status: Published Journal Publication published 07 Jan, 2026 Read the published version in BMC Surgery → Version 1 posted Editorial decision: Revision requested 08 Sep, 2025 Reviews received at journal 31 Aug, 2025 Reviews received at journal 28 Aug, 2025 Reviews received at journal 25 Aug, 2025 Reviews received at journal 23 Aug, 2025 Reviewers agreed at journal 19 Aug, 2025 Reviews received at journal 19 Aug, 2025 Reviewers agreed at journal 19 Aug, 2025 Reviewers agreed at journal 19 Aug, 2025 Reviews received at journal 17 Aug, 2025 Reviewers agreed at journal 17 Aug, 2025 Reviews received at journal 17 Aug, 2025 Reviewers agreed at journal 16 Aug, 2025 Reviewers agreed at journal 16 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviewers invited by journal 14 Aug, 2025 Editor assigned by journal 13 Aug, 2025 Submission checks completed at journal 13 Aug, 2025 First submitted to journal 06 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shimpei","middleName":"","lastName":"Maeda","suffix":""},{"id":502844075,"identity":"04f51d8c-f853-47f6-ba76-eb1b969fa7b1","order_by":11,"name":"Masaharu Ishida","email":"","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masaharu","middleName":"","lastName":"Ishida","suffix":""},{"id":502844078,"identity":"ce5d6612-b774-43ec-a8f5-2347fcce2a7b","order_by":12,"name":"Masamichi Mizuma","email":"","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masamichi","middleName":"","lastName":"Mizuma","suffix":""},{"id":502844079,"identity":"f5ba6fc1-b167-46dd-bd80-3d68a7777219","order_by":13,"name":"Atsushi Masamune","email":"","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Masamune","suffix":""},{"id":502844080,"identity":"649c29c5-4a71-45ca-b5b3-a138750cbdcf","order_by":14,"name":"Michiaki Unno","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIie3RsUrEMBzH8V8pxCXQNUWpTyDkCMRB0VdJOegt9RBuuUFQOOhtzn0MQXAuBOJScL3NgnCTQydxUuPplQNzp24i+Q7ln8KnJCng8/3FQhAoKLpcn0ewb1B9rPhPiIqL78jimxZ1hJsV4mpvGs6b5izbATsxTYvDobif2KHWiKYVRqdfidRknyuTU7DhoFciG0lD7DDTYLWCKF2EEqbI2JJcblPo4MZQO7QamAGCriMvHXkNrotPsruJpEW+JFV6Rd6J3RhfS4hk6WVGCX2Uccn7gpksi8t6QHt1euE8y52ex89P/eNoK5esHR8l0UQb1pqDJLnVRjhurIssniu/zm4pKMQG4S58+DXx+Xy+f9gbHn1aO9OtRloAAAAASUVORK5CYII=","orcid":"","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Michiaki","middleName":"","lastName":"Unno","suffix":""}],"badges":[],"createdAt":"2025-08-06 06:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7306398/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7306398/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12893-025-03374-x","type":"published","date":"2026-01-07T15:58:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89972516,"identity":"a9447141-809f-421a-8352-1eee9b62f3c4","added_by":"auto","created_at":"2025-08-27 05:45:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":17276,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of case selection.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-7306398/v1/897f6c11ad2c7ae0fa1d4583.png"},{"id":89971403,"identity":"8d2643ba-4300-45e5-b7ac-98e753a29b49","added_by":"auto","created_at":"2025-08-27 05:37:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":291559,"visible":true,"origin":"","legend":"\u003cp\u003eImaging findings from the case report.\u003c/p\u003e\n\u003cp\u003eA, B: Preoperative CT scans showing wall thickening at the confluence of the right and left hepatic ducts.\u003c/p\u003e\n\u003cp\u003eC: Preoperative MRI revealing strictures at the confluence of the right and left hepatic ducts, consistent with Bismuth type IV classification.\u003c/p\u003e\n\u003cp\u003eD, E: CT scans at the time of recurrence showing recurrent lesions near the anastomotic site and in segment 4 (S4).\u003c/p\u003e\n\u003cp\u003eF: CT scan after five courses of GCD therapy showing tumor shrinkage, categorized as stable disease (SD).\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-7306398/v1/6bfa4cefa54ffa4db5e2924d.png"},{"id":89974153,"identity":"6729c188-d1fe-4f18-a007-0d9ed910730d","added_by":"auto","created_at":"2025-08-27 05:53:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30441,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in CA19-9 levels.\u003c/p\u003e\n\u003cp\u003ePre: CA19-9 level immediately before surgery.\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-7306398/v1/8f4fc56d00118820f127661a.png"},{"id":100069987,"identity":"938f698b-e5dd-474d-a60a-fef16b82a2af","added_by":"auto","created_at":"2026-01-12 16:15:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":969089,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7306398/v1/4910e5c7-8dde-4636-9fb3-ccd7bee234fc.pdf"},{"id":89971399,"identity":"d01377ae-3cea-4be7-81e1-83e30a55aaed","added_by":"auto","created_at":"2025-08-27 05:37:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":83145,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"TABLE0702.docx","url":"https://assets-eu.researchsquare.com/files/rs-7306398/v1/adf78594871eac2971545b01.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Characteristics of late recurrences after hepatectomy for perihilar cholangiocarcinoma: A single-center cohort study","fulltext":[{"header":"1 | BACKGROUND","content":"\u003cp\u003ePerihilar cholangiocarcinoma (pCCA) arises from the bile duct epithelial cells that involves the hilar bifurcation, with its anatomical boundaries extending from the cystic duct origin to the second-order branches of the intrahepatic bile ducts [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. pCCA constitutes approximately 3% of all gastrointestinal tumors [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and has an estimated 5-year survival rate of only 10% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Surgical resection remains the sole curative option for pCCA [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], but postoperative recurrence is common, and long-term survival outcomes remain poor [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecurrence of pCCA most frequently occurs within five years following surgery and those patients are not expected to have a long-term prognosis [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In contrast, there are rare cases with recurrence after a prolonged disease-free period, such as a case of late recurrence as 10 years after curative resection [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. While clinicopathological risk factors for early postoperative recurrence following radical resection of pCCA have been widely investigated [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], there is limited research on the causes and predictive factors for recurrence occurring more than five years after surgery. Such late recurrences have been primarily documented in case reports, leaving their characteristics insufficiently explored [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, only a small proportion of patients survive beyond five years, and even fewer undergo extended follow-up.\u003c/p\u003e\u003cp\u003eAt our institution, we follow a policy of monitoring cholangiocarcinoma patients for more than 10 years after surgery. This approach has enabled us to compile a significant number of cases, including both early recurrences and those occurring more than five years after surgery. In this study, we aim to analyze the characteristics of pCCA cases with recurrences beyond five years following radical hepatectomy and compare them to patients with no recurrence beyond 12 years.\u003c/p\u003e"},{"header":"2 | METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 | Patients and study outline\u003c/h2\u003e\u003cp\u003eThis study was a retrospective observational study. Consecutive patients with pCCA who underwent radical hepatectomy with extrahepatic bile duct resection at Tohoku University Hospital (Sendai, Japan) between 1996 and 2019 were enrolled. A total of 321 pCCA patients were initially enrolled in this study. Of these, 51 patients who died from other causes within 5 years and 12 patients with insufficient clinical data were excluded. Consequently, 258 patients were included in the final analysis. Among the 258 patients, 75 patients (29.1%) had no recurrence, while 183 patients (70.9%) experienced recurrence. Of the recurrence cases, 67 patients (26.0%) experienced recurrence within one year, 83 patients (32.2%) within three years, 24 patients (9.3%) within five years, and 9 patients (3.4%) beyond five years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median overall survival (OS) and relapse-free survival (RFS) of the 258 patients were 43.0 months and 27.3 months, respectively. Among the 258 patients, we compared the clinicopathological characteristics of the 9 patients who experienced late recurrence (beyond five years after surgery) with those of 14 patients who remained recurrence-free for more than 12 years (no recurrence group, selected from the 75 recurrence-free patients). We defined late recurrence as recurrence occurring within 12 years after surgery, based on the observation that the longest recurrence-free interval among our late recurrence cases was 12 years.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 | Surgical treatment\u003c/h2\u003e\u003cp\u003eThe surgical procedure for pCCA involved hemihepatectomy or trisectionectomy with caudate lobectomy, combined with extrahepatic bile duct resection [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. All surgeries were performed after achieving a serum bilirubin level of \u0026lt;\u0026thinsp;2 mg/dL. Comprehensive lymph node dissection was conducted in all cases, targeting nodes at the hepatoduodenal ligament, around the pancreatic head, and near the common hepatic artery. Combined portal vein or hepatic artery resection was undertaken if the tumor had invaded these vessels [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, hepatopancreatoduodenectomy (HPD) was performed when necessary to achieve curative resection, particularly when intraoperative rapid diagnosis revealed positive bile duct resection margins [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Morbidity was defined according to the Clavien-Dindo Classification, which is commonly used for the assessment of postoperative complications [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 | Neoadjuvant therapy\u003c/h2\u003e\u003cp\u003eFor resectable pCCA, surgery was typically the first-line treatment. However, in cases of extensive local progression or strong suspicion of lymph node metastasis, neoadjuvant chemotherapy with gemcitabine, S-1, and/or cisplatine, or radiation therapy might be considered in conjunction with surgery.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 | Adjuvant therapy\u003c/h2\u003e\u003cp\u003eSince 2013, postoperative adjuvant chemotherapy with S-1 has been routinely administered [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Prior to this period, gemcitabine, S-1, uracil-tegafur (UFT), 5FU and/or cisplatin were selected as adjuvant chemotherapy, primarily for patients at high risk of postoperative recurrence, such as those with lymph node metastasis. In some cases, adjuvant chemotherapy was omitted based on the patient's performance status and pathological findings.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 | Postoperative follow-up\u003c/h2\u003e\u003cp\u003ePhysical examinations and blood tests, including tumor marker assessments, were conducted every three months postoperatively. CT scans were performed at least twice a year during the first five years. After this period, blood tests and CT scans are continued annually for as long as feasible. In cases of recurrence, surgical intervention, chemotherapy, and/or radiation therapy were selected based on the patient\u0026rsquo;s overall condition and clinical status.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6 | Statistical analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed with JMP Pro\u0026reg; 17.1.0 for Macintosh (SAS Institute Inc., Cary, NC, USA). Wilcoxon's signed-rank test was applied for continuous variables, and Fisher's exact test or chi-square test for categorical data. A p-value of less than 0.05 was considered as statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 | RESULTS","content":"\u003cp\u003e\u003cstrong\u003e3.1 | Characteristics of the patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe characteristics of the 9 cases with late recurrence are summarized in Table 1. Local recurrence was the most common and was observed in six cases (five at the anastomotic site and one in a lymph node), followed by three cases of liver metastasis, two cases of peritoneal dissemination, and one case of pulmonary metastasis (some cases exhibited overlap). Histologically, four cases were classified as well-differentiated tubular adenocarcinoma, four as moderately differentiated tubular adenocarcinoma, and one as poorly differentiated adenocarcinoma. R0 resection was performed in five cases. Postoperative adjuvant chemotherapy was administered in seven cases, with two exceptions. After recurrence, chemotherapy was the primary treatment in most cases, while surgical resection was performed in two cases. In four cases, best supportive care (BSC) was chosen due to the patient’s age or personal preference. Five patients succumbed to the underlying disease; however, among them, two patients survived for more than two years after recurrence, and four patients are currently undergoing chemotherapy as part of their ongoing treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 | Comparison between no recurrence and late recurrence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 9 cases with late recurrence after 5 years, the case with recurrence after 11.5 years represents the longest time to recurrence. Therefore, we compared the cases with late recurrence after 5 years with those who had no recurrence beyond 12 years. The results are summarized in Table 2 and 3.\u003c/p\u003e\n\u003cp\u003eTable 2 shows the patients' clinical and surgical characteristics. There were no significant differences in the clinicodemographic data between the two groups, including sex, age, preoperative BMI, and adjuvant therapy. Similarly, no significant differences were observed in the surgical outcomes, such as operative time, blood loss volume, or combined vascular resection. Additionally, postoperative morbidity and length of hospital stay did not differ significantly between the two groups.\u0026nbsp;However, neoadjuvant chemotherapy and HPD were performed significantly more frequently in the no recurrence group.\u003c/p\u003e\n\u003cp\u003eTable 3 summarizes a comparison of the pathological findings between the two groups. No significant differences were identified between the groups regarding Bismuth type IV classification, TNM staging, vascular and lymphatic invasion, R1 resection (including hepatic, distal, and extrahepatic margins), or lymph node metastasis. However, perineural invasion was significantly more frequent in the late recurrence group. Notably, all cases of late recurrence exhibited positive perineural invasion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 | Case report\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinally, we present the case of a patient with pCCA who experienced recurrence 11 years after surgery (Case 8 in Table 1). The patient, a 59-year-old man, was diagnosed in 2013 with Bismuth type IV pCCA and underwent extended right hepatectomy with with extrahepatic bile duct and portal vein resection following right portal vein embolization (Figure 2A,B,C). Intraoperative frozen section analysis revealed a positive resection margin on the hepatic side of the bile duct, resulting in an R1 resection. The final pathological diagnosis was well-differentiated tubular adenocarcinoma, classified as pT2N0M0, Stage II. Histopathological examination demonstrated lymphatic, venous, and perineural invasion. The hepatic resection margin remained positive, confirming an R1 resection. Postoperatively, the patient received adjuvant chemotherapy with S-1 and was regularly monitored during the follow-up. The patient remained recurrence-free for 11 years. However, tumor marker levels began to rise (Figure 3), and CT imaging revealed findings consistent with either a local recurrence or liver metastasis (Figure 2D, E). Although histological confirmation of recurrence was not obtained, gemcitabine + cisplatin + durvalumab (GCD) therapy was initiated. To date, the patient has completed five courses of treatment. During this time, the tumor marker levels of CA19-9 had normalized (Figure 3), and CT imaging demonstrated tumor shrinkage (Figure 2E), although the findings remained categorized as stable disease (SD).\u003c/p\u003e"},{"header":"4 | DISCUSSION","content":"\u003cp\u003epCCA is recognized as one of the most aggressive malignant tumors, with an exceptionally poor prognosis [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. While surgical intervention is considered the only potentially curative treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], the recurrence rate following curative-intent surgery for pCCA remains alarmingly high, ranging from 44\u0026ndash;83.2% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Notably, most recurrences occur relatively early, with approximately 24-45.4% of cases recurring within the first year after surgery [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Several prognostic factors for early recurrence have been identified, including poor tumor differentiation, vascular invasion, perineural invasion, lymph node metastases, elevated preoperative CA19-9 and bilirubin levels, positive resection margins, and advanced TNM staging [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. While early recurrence has been extensively studied, with its clinicopathological features well-documented, the characteristics and prognosis of late recurrence remain poorly understood [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, we identified the clinicopathological characteristics of late recurrence in pCCA patients for the first time, extending beyond previously published case reports by comparing them with cases that remained recurrence-free for more than 12 years. Notably, we clarified that perineural invasion, a factor associated with early recurrence, is also a significant risk factor for late recurrence. Previous case reports have described a wide spectrum of clinical courses for late recurrence, ranging from rapid fatal progression to favorable responses to treatment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Similarly, among our nine cases, some experienced rapid deterioration after recurrence, while others achieved long-term disease control. Notably, cases in which therapeutic interventions beyond BSC were feasible demonstrated the potential for prolonged survival. These findings underscore the importance of early detection and timely management of recurrence.\u003c/p\u003e\u003cp\u003eHowever, it remains unclear whether late recurrence universally results in rapid systemic deterioration, which raises critical issues for future research. Some studies suggest that late recurrences may exhibit varied clinical courses, potentially influenced by factors such as tumor dormancy, particularly in distant organs [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. For example, lung metastases in pancreatic cancer are known to progress more slowly compared to other metastases [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In various cancers, prolonged dormancy has been associated with improved outcomes. Chemotherapy, in particular, may induce tumor dormancy, allowing patients to survive without significant disease progression despite the presence of residual tumors [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this context, identifying minimal residual disease (MRD) and dormant tumor cells through biomarkers could be crucial for understanding late recurrence. Circulating free DNA (cfDNA), a key biomarker, has shown promise in detecting tumor-derived DNA in the bloodstream, providing a less invasive method for monitoring disease presence and progression [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. cfDNA levels may reflect the burden of MRD, offering potential insights into dormant tumor cells that could contribute to late recurrence. Additionally, other biomarkers, such as exosomes and tumor-associated antigens, may aid in detecting these residual cells [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, predicting the prognosis at the time of recurrence remains challenging. Further research is needed to determine how these biomarkers can guide treatment decisions. Currently, observation and treatment remain the primary strategies for managing late recurrence.\u003c/p\u003e\u003cp\u003eOn the other hand, in cases such as the present one, where recurrence occurs after a long interval following resection, the possibility of metachronous de novo carcinogenesis, rather than true recurrence, should also be considered. In our cases, this possibility cannot be entirely excluded. However, most cases of metachronous biliary tract carcinomas (BTCs) arising long after resection tend to follow an intraductal recurrence pattern rather than representing entirely new primary lesions. Comparative genomic analyses of BTCs have revealed that most metachronous BTCs are clonally related to their primary tumors, either through successional evolution or phylogenetic divergence [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. From this perspective, we interpreted our case as a persistent recurrence.\u003c/p\u003e\u003cp\u003eThis study has several limitations. First, it is a single-center retrospective study, which introduces potential confounding factors and selection bias. Additionally, the small sample size, despite our institution's status as a leading center for cholangiocarcinoma treatment in Japan, limited the ability to identify factors associated with late recurrence through multivariate analysis. Furthermore, because previous reports and our cases have not identified recurrences in patients followed for more than 12 years after surgery, we compared cases with no recurrence for over 12 years to those with late recurrence. However, these cases may include patients who may experience recurrence in the future. As such, this comparison may be insufficient. To conduct a more comprehensive analysis, further accumulation of cases with even longer follow-up periods is necessary.\u003c/p\u003e\u003cp\u003eDespite these limitations, this study is the first to investigate the clinicopathological characteristics of late recurrence in pCCA. While late recurrence is relatively rare, our findings highlight the importance of monitoring patients for more than 10 years postoperatively. In particular, vigilant follow-up of high-risk groups, such as those with perineural invasion, is essential for enabling early intervention and improving the prognosis. Accumulating additional cases in the future will allow for more detailed analyses and contribute to the development of refined management strategies for late recurrence.\u003c/p\u003e\u003cp\u003eHowever, recent advancements in non-surgical treatments have provided new hope for improving patient outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These developments emphasize the growing importance of early detection and timely intervention. Among these, immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in the treatment of cholangiocarcinoma. The results of the TOPAZ-1 and KEYNOTE-966 trials have established ICIs as a viable therapeutic option for patients with unresectable cholangiocarcinoma [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. These trials provide strong evidence supporting the integration of ICIs into treatment protocols, marking a significant shift in the management of this challenging disease.\u003c/p\u003e"},{"header":"5 | CONCLUSIONS","content":"\u003cp\u003eThis study is the first to identify clinicopathological factors associated with late recurrence of pCCA, providing valuable insights for long-term follow-up and management. Although late recurrence is rare, its occurrence underscores the need for vigilant monitoring beyond 10 years postoperatively. Moving forward, multicenter collaborative studies and the accumulation of additional cases will be essential for determining optimal follow-up durations and developing effective treatment strategies for recurrence.\u003c/p\u003e"},{"header":"6 | LIST OF ABBREVIATIONS","content":"\u003cp\u003eperihilar cholangiocarcinoma, pCCA; overall survival, OS; relapse-free survival, RFS; hepatopancreatoduodenectomy, HPD; uracil-tegafur, UFT; computed tomography, CT; best supportive care, BSC; Body Mass Index, BMI; gemcitabine + cisplatin + durvalumab, GCD; stable disease, SD; minimal residual disease, MRD; circulating free DNA, cfDNA; biliary tract carcinomas, BTCs; immune checkpoint inhibitors, ICIs.\u003c/p\u003e"},{"header":"7 | DECLARATIONS","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval Statement and Clinical Trial Registration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was conducted in accordance with the ethical standards outlined in the Declaration of Helsinki and was approved by the Institutional Review Board of Tohoku University (approval number: 2024-1-668). Written informed consent was obtained from all patients regarding the use of their clinical data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publicasion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no conflicts of interest related to this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific funding from public, commercial, or not-for-profit organizations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHideaki Sato and Shuichi Aoki: Manuscript writing, and drafting of the conception and design.\u003c/p\u003e\n\u003cp\u003eHideaki Sato, Shuichi Aoki, Masahiro Iseki, Mika Ando, Shuichiro Hayashi, Shingo Yoshimachi, Akiko Kusaka, Mitsuhiro Shimura,\u0026nbsp;Daisuke Douchi, Takayuki Miura, Shimpei Maeda, Masaharu Ishida,\u0026nbsp;Masamichi Mizuma and Michiaki Unno: Critical revision of the article for important intellectual content.\u003c/p\u003e\n\u003cp\u003eHideaki Sato and Shuichi Aoki: Analysis and interpretation of the data.\u003c/p\u003e\n\u003cp\u003eMasamichi Mizuma, Atsushi Masamune and Michiaki Unno: Final approval of the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their heartfelt gratitude to all the surgeons who performed surgical resections at our institution, especially Dr. Kei Nakagawa. They also extend their sincere thanks to the gastroenterologists and radiologists of the Departments of Gastroenterology and Diagnostic Radiology at Tohoku University Hospital for their invaluable contributions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003evan Keulen AM, Franssen S, van der Geest LG, et al. Nationwide treatment and outcomes of perihilar cholangiocarcinoma. Liver Int. 2021 Aug;41(8):1945-1953.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMueller M, Breuer E, Mizuno T, et al. Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers. Ann Surg. 2021 Nov 1;274(5):780-788.\u003c/li\u003e\n \u003cli\u003eIlyas SI, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013 Dec;145(6):1215-29. doi: 10.1053/j.gastro.2013.10.013. Epub 2013 Oct 15.\u003c/li\u003e\n \u003cli\u003eEverhart JE, Ruhl CE. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology. 2009 Feb;136(2):376-86.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011 Jul;54(1):173-84.\u003c/li\u003e\n \u003cli\u003eJarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001 Oct;234(4):507-17; discussion 517-9.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKimura N, Young AL, Toyoki Y, et al. Radical operation for hilar cholangiocarcinoma in comparable Eastern and Western centers: Outcome analysis and prognostic factors. Surgery. 2017 Sep;162(3):500-514.\u003c/li\u003e\n \u003cli\u003eMachimoto T, Doi R, Ogawa K, Masui T, Seo S, Uemoto S. Abdominal wall recurrence of Hilar bile duct cancer 12 years after a curative resection: report of a case. Surg Today. 2009;39(1):72-6.\u003c/li\u003e\n \u003cli\u003eSasaki T, Kondo S, Ambo Y, et al. Local recurrence at hepaticojejunostomy 9 years after resection of bile duct cancer with superficial flat spread. J Hepatobiliary Pancreat Surg. 2006;13(5):458-62.\u003c/li\u003e\n \u003cli\u003ePeng DZ, Lu J, Li B, et al. A simple scoring system to predict early recurrence of Bismuth-Corlette type IV perihilar cholangiocarcinoma. Gastroenterol Rep (Oxf). 2019 Apr 21;7(5):345-353.\u003c/li\u003e\n \u003cli\u003eMitsuura C, Okabe H, Yamashita YI, et al. A case of chest wall recurrence of hilar cholangiocarcinoma 10\u0026nbsp;years after R1 surgery with positive ductal margin of carcinoma in situ. Int Cancer Conf J. 2020 Feb 15;9(2):77-81.\u003c/li\u003e\n \u003cli\u003eOta Y, Matsuyama R, Taniguchi K, et al. Solitary rib recurrence of hilar cholangiocarcinoma 10 years after resection: report of a case. Clin J Gastroenterol. 2013 Dec;6(6):485-9.\u003c/li\u003e\n \u003cli\u003eZhao J, Zhang W, Zhang J, et al. Independent Risk Factors of Early Recurrence After Curative Resection for Perihilar Cholangiocarcinoma: Adjuvant Chemotherapy May Be Beneficial in Early Recurrence Subgroup. Cancer Manag Res. 2020 Dec 22;12:13111-13123.\u003c/li\u003e\n \u003cli\u003eMargies R, Gr\u0026ouml;ger LK, Straub BK, Bartsch F, Lang H. Influence of Perineural (Pn), Lymphangio (L) and Vascular (V) Invasion on Survival after Resection of Perihilar Cholangiocarcinoma. Cancers (Basel). 2024 Oct 12;16(20):3463.\u003c/li\u003e\n \u003cli\u003eTian Y, Wen N, Li B, et al. A meta-analysis of prognostic factors for early recurrence in perihilar cholangiocarcinoma after curative-intent resection. Eur J Surg Oncol. 2023 Nov;49(11):106982.\u003c/li\u003e\n \u003cli\u003eNagino M, Ebata T, Yokoyama Y, et al. Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Ann Surg. 2013 Jul;258(1):129-40.\u003c/li\u003e\n \u003cli\u003eNagino M, Ebata T, Yokoyama Y, et al. Hepatopancreatoduodenectomy with simultaneous resection of the portal vein and hepatic artery for locally advanced cholangiocarcinoma: Short- and long-term outcomes of superextended surgery. J Hepatobiliary Pancreat Sci. 2021 Apr;28(4):376-386.\u003c/li\u003e\n \u003cli\u003eDindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNakachi K, Ikeda M, Konishi M, et al. Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2023 Jan 21;401(10372):195-203.\u003c/li\u003e\n \u003cli\u003eZhang XF, Beal EW, Chakedis J, et al. Defining Early Recurrence of Hilar Cholangiocarcinoma After Curative-intent Surgery: A Multi-institutional Study from the US Extrahepatic Biliary Malignancy Consortium. World J Surg. 2018 Sep;42(9):2919-2929.\u003c/li\u003e\n \u003cli\u003eHolmgren L, O\u0026apos;Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995 Feb;1(2):149-53.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTakahashi Y, Mai M, Taguchi T, Urushizaki I, Nishioka K. Prolonged stable disease effects survival in patients with solid gastric tumor: analysis of phase II studies of doxifluridine. Int J Oncol. 2000 Aug;17(2):285-9.\u003c/li\u003e\n \u003cli\u003eNaumov GN, MacDonald IC, Weinmeister PM, et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 2002 Apr 1;62(7):2162-8.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eZheng B, Ohuchida K, Yan Z, Okumura T, Ohtsuka T, Nakamura M. Primary Recurrence in the Lung is Related to Favorable Prognosis in Patients with Pancreatic Cancer and Postoperative Recurrence. World J Surg. 2017 Nov;41(11):2858-2866.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eModing EJ, Nabet BY, Alizadeh AA, Diehn M. Detecting Liquid Remnants of Solid Tumors: Circulating Tumor DNA Minimal Residual Disease. Cancer Discov. 2021 Dec 1;11(12):2968-2986.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePellini B, Chaudhuri AA. Circulating Tumor DNA Minimal Residual Disease Detection of Non-Small-Cell Lung Cancer Treated With Curative Intent. J Clin Oncol. 2022 Feb 20;40(6):567-575.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHe C, Zheng S, Luo Y, Wang B. Exosome Theranostics: Biology and Translational Medicine. Theranostics. 2018 Jan 1;8(1):237-255. doi: 10.7150/thno.21945. PMID: 29290805; PMCID: PMC5743472.\u003c/li\u003e\n \u003cli\u003eOmori Y, Aoki S, Ono Y, et al. Clonal analysis of metachronous double biliary tract cancers. J Pathol. 2024 May;263(1):113-127.\u003c/li\u003e\n \u003cli\u003eOh DY, Ruth He A, Qin S, et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid. 2022 Aug;1(8):EVIDoa2200015.\u003c/li\u003e\n \u003cli\u003eKelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 Jun 3;401(10391):1853-1865.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bsur","sideBox":"Learn more about [BMC Surgery](http://bmcsurg.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bsur/default.aspx","title":"BMC Surgery","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"perihilar cholangiocarcinoma, late recurrence, hepatectomy, long term survival, perineural invasion","lastPublishedDoi":"10.21203/rs.3.rs-7306398/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7306398/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eSurgical resection is the only curative treatment for perihilar cholangiocarcinoma (pCCA); however, the majority of patients experience postoperative recurrence. While recurrence typically occurs within five years after surgery, recurrence after prolonged relapse-free survival has been occasionally observed. This study aimed to investigate the clinicopathological factors associated with late recurrence of pCCA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eAmong the 258 consecutive patients who underwent radical hepatectomy with extrahepatic bile duct resection for pCCA at our institution between 1996 and 2019, 9 patients (3.4%) had postoperative recurrence more than five years after surgery. Clinicopathological characteristics of late recurrence (beyond five years) were analyzed and compared with those of the patients who remained recurrence-free for over 12 years (no recurrence group, n=14).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong the nine cases of late recurrence, local recurrence was the most common, followed by liver metastasis. Chemotherapy was the primary treatment after recurrence, while surgical resection was performed in two cases. A comparison between the late recurrence and no recurrence groups revealed similar demographics; however, the late recurrence group exhibited significantly higher cases with pathological perineural invasion. Notably, all late recurrence cases demonstrated positive perineural invasion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe presence of pathological perineural invasion is significantly associated with late recurrence of pCCA. This finding provides significant insights for the long-term follow-up and managemant of pCCA patients.\u003c/p\u003e","manuscriptTitle":"Characteristics of late recurrences after hepatectomy for perihilar cholangiocarcinoma: A single-center cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 05:37:27","doi":"10.21203/rs.3.rs-7306398/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-08T12:32:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-31T16:34:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-28T16:39:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-26T02:57:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-23T14:44:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146266577095053285309055395967440821818","date":"2025-08-20T03:04:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-20T01:58:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"176152191496160758976862733814957032916","date":"2025-08-20T01:03:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"179367042397717728772091818925027140051","date":"2025-08-20T00:30:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-18T01:07:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"107534145283600424974545497927967671496","date":"2025-08-17T22:53:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-17T06:55:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8020332241056933640804189931999050482","date":"2025-08-17T02:25:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"195722882949236478495039899343689184471","date":"2025-08-16T14:52:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76558194038266941976481863905339214165","date":"2025-08-15T23:46:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"305449044014195439891932958676109253108","date":"2025-08-14T15:10:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-14T14:48:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-13T05:56:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-13T05:53:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Surgery","date":"2025-08-06T06:29:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bsur","sideBox":"Learn more about [BMC Surgery](http://bmcsurg.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bsur/default.aspx","title":"BMC Surgery","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d50a568-5b61-4d77-a906-1c28c7e807d1","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:09:05+00:00","versionOfRecord":{"articleIdentity":"rs-7306398","link":"https://doi.org/10.1186/s12893-025-03374-x","journal":{"identity":"bmc-surgery","isVorOnly":false,"title":"BMC Surgery"},"publishedOn":"2026-01-07 15:58:26","publishedOnDateReadable":"January 7th, 2026"},"versionCreatedAt":"2025-08-27 05:37:27","video":"","vorDoi":"10.1186/s12893-025-03374-x","vorDoiUrl":"https://doi.org/10.1186/s12893-025-03374-x","workflowStages":[]},"version":"v1","identity":"rs-7306398","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7306398","identity":"rs-7306398","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}