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肝门部胆管癌意向根治性切除术后腹膜转移危险因素研究
刘钦钦, 施祥德, 唐启彬, 余先焕, 张锐, 刘超
中国实用外科杂志 ›› 2025, Vol. 45 ›› Issue (12) : 1443-1448.
PDF(1428 KB)
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肝门部胆管癌意向根治性切除术后腹膜转移危险因素研究
Risk factors for peritoneal metastasis after curative-intent resection for perihilar cholangiocarcinoma
目的 探讨肝门部胆管癌（pCCA）意向根治性切除术后腹膜转移的发生情况及其危险因素。方法 回顾性分析中山大学孙逸仙纪念医院胆胰外科2014 年 1 月至 2023 年 6 月期间接受意向根治性切除的75例pCCA病人临床资料，比较腹膜转移组与非腹膜转移组的临床特征，采用Cox回归模型分析术后腹膜转移的独立危险因素。结果 75例病人术后1年、3年、5年复发率分别为34.7%、58.2%、74.9%，腹膜为最常见远处复发部位，共11例（14.7%）病人发生腹膜转移，术后平均转移时间为（18.2±13.4）个月，中位总体生存时间为17.1（11.8~47.8）个月。Cox单因素分析提示Bismuth-Corlette分型、淋巴结转移及肿瘤分化程度与腹膜转移相关（P<0.05）；多因素分析显示肿瘤低分化为独立危险因素（HR=4.022，95% CI：1.110~14.566，P=0.034）。术前胆道引流方式、肿瘤大小、切缘及血管侵犯与腹膜转移差异无统计学意义（P>0.05）。结论 肿瘤低分化是pCCA意向根治性切除术后腹膜转移的独立危险因素。pCCA病人术后腹膜转移常在术后1.5年左右出现，预后较差。术前行经皮经肝穿刺胆道引流术（PTCD）虽非独立危险因素，但潜在种植风险需审慎评估。针对低分化pCCA病人，应加强术后密切随访与个体化辅助治疗，以减少腹膜转移的发生并改善长期生存。
Objective To investigate the incidence and risk factors of peritoneal metastasis after curative-intent resection for perihilar cholangiocarcinoma (pCCA). Methods Clinical data of 75 pCCA cases undergoing curative-intent resection at the Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, from 2014-01 to 2023-06 were retrospectively analyzed. Clinicopathological characteristics were compared between the peritoneal-metastasis and non-peritoneal-metastasis groups. Cox proportional hazards regression was used to identify independent risk factors for postoperative peritoneal metastasis. Results The cumulative recurrence rates at 1, 3, and 5 years after surgery were 34.7%, 58.2%, and 74.9%, respectively. The peritoneum was the most common site of distant recurrence: 11/75 patients (14.7%) developed peritoneal metastasis, with a mean time to metastasis of (18.2±13.4) months. The median overall survival was 17.1 (11.8-47.8) months. Univariate Cox analysis indicated associations between Bismuth-Corlette classification, lymph-node metastasis, tumor differentiation and peritoneal metastasis (P<0.05). Multivariable analysis identified poor tumor differentiation as an independent risk factor (HR=4.022;95%CI: 1.110-14.566; P=0.034). Preoperative biliary drainage approach, tumor size, margin status, and vascular invasion were not significantly associated with peritoneal metastasis (P>0.05). Conclusion Poor tumor differentiation is an independent risk factor for peritoneal metastasis after curative-intent resection for pCCA. Peritoneal metastasis tends to occur at approximately 18 months postoperatively and portends a poor prognosis. Although preoperative percutaneous transhepatic biliary drainage (PTCD) was not an independent risk factor, its potential for tumor seeding warrants careful clinical consideration. For poorly differentiated pCCA, closer postoperative surveillance and individualized adjuvant strategies are warranted to reduce peritoneal metastasis and improve long-term survival.
perihilar cholangiocarcinoma / peritoneal metastasis / risk factors / tumor differentiation
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Cholangiocarcinoma is a type of hepatobiliary tumor. For perihilar cholangiocarcinoma (pCCA), patients who experience early recurrence (ER) have a poor prognosis. Preoperative accurate prediction of postoperative ER can avoid unnecessary operation; however, prediction is challenging.
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Biliary tract cancers (BTC) are a disease entity comprising diverse epithelial tumors, which are categorized according to their anatomical location as intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinomas, and gallbladder carcinomas (GBC), with distinct epidemiology, biology, and prognosis. Complete surgical resection is the mainstay in operable BTC as it is the only potentially curative treatment option. Nevertheless, even after curative (R0) resection, the 5-year survival rate ranges between 20 and 40% and the disease free survival rates (DFS) is approximately 48–65% after one year and 23–35% after three years without adjuvant treatment. Improvements in adjuvant chemotherapy have improved the DFS, but the role of adjuvant radiotherapy is unclear. On the other hand, more than 50% of the patients present with unresectable disease at the time of diagnosis, which limits the prognosis to a few months without treatment. Herein, we review the role of radiotherapy in the treatment of cholangiocarcinoma in the curative and palliative setting.
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There is little information regarding the clinical behaviour of hilar cholangiocarcinoma after curative resection.A retrospective study was undertaken of 79 consecutive patients with hilar cholangiocarcinoma who had undergone major hepatectomy (three or more Couinaud segments) concomitant with caudate lobectomy, and had negative resection margins. Sites of initial disease recurrence were classified as locoregional (porta hepatis) or distant (intrahepatic, peritoneal, para-aortic lymph nodal or extra-abdominal). Univariable and multivariable analyses were performed to determine the factors potentially related to recurrence.Disease recurrence was observed in 42 (53 per cent) of the 79 patients. Cumulative recurrence rates at 3 and 4 years after surgery were 52 and 56 per cent respectively. Locoregional recurrence alone was observed in eight (10 per cent) and distant metastasis in 34 (43 per cent) of the 79 patients after R0 resection. Positive nodal involvement and high International Union Against Cancer tumour (T) stage were independent prognostic factors associated with distant metastasis.Distant metastases are more common than locoregional recurrence after R0 resection for hilar cholangiocarcinoma, and associated with nodal involvement and high T stage.Copyright 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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Pancreatic cancer is the third leading cause of cancer death in the USA, and pancreatic ductal adenocarcinoma (PDA) constitutes 85% of pancreatic cancer diagnoses. PDA frequently metastasizes to the peritoneum, but effective treatment of peritoneal metastasis remains a clinical challenge. Despite this unmet need, understanding of the biological mechanisms that contribute to development and progression of PDA peritoneal metastasis is sparse. By contrast, a vast number of studies have investigated mechanisms of peritoneal metastasis in ovarian and gastric cancers. Here, we contrast similarities and differences between peritoneal metastasis in PDA as compared with those in gastric and ovarian cancer by outlining molecular mediators involved in each step of the peritoneal metastasis cascade. This review aims to provide mechanistic insights that could be translated into effective targeted therapies for patients with peritoneal metastasis from PDA.
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Hyaluronic acid (HA) is known to play an important role in motility of tumor cells. However, the molecular mechanisms associated with HA-promoted melanoma cell motility are not fully understood. Treatment of cells with HA was shown to increase the production of reactive oxygen species (ROS) in a CD44-dependent manner. Antioxidants, such as N-acetyl-l-cysteine and seleno-l-methionine, prevented HA from enhancing cell motility. Protein kinase C (PKC)-alpha and PKCdelta were responsible for increased Rac1 activity, production of ROS, and mediated HA-promoted cell motility. HA increased Rac1 activity via CD44, PKCalpha, and PKCdelta. Transfection with dominant negative and constitutive active Rac1 mutants demonstrated that Rac1 was responsible for the increased production of ROS and cell motility by HA. Inhibition of NADPH oxidase by diphenylene iodonium and down-regulation of p47Phox and p67Phox decreased the ROS level, suggesting that NADPH oxidase is the main source of ROS production. Rac1 increased phosphorylation of FAK. FAK functions downstream of and is necessary for HA-promoted cell motility. Secretion and expression of MMP-2 were increased by treatment with HA via the action of PKCalpha, PKCdelta, and Rac1 and the production of ROS and FAK. Ilomastat, an inhibitor of MMP-2, exerted a negative effect on HA-promoted cell motility. HA increased interaction between CD44 and epidermal growth factor receptor (EGFR). AG1478, an inhibitor of EGFR, decreased phosphorylation of PKCalpha, PKCdelta, and Rac1 activity and suppressed induction of p47Phox and p67Phox. These results suggest that CD44-EGFR interaction is necessary for HA-promoted cell motility by regulating PKC signaling. EGFR-Akt interaction promoted by HA was responsible for the increased production of ROS and HA-promoted cell motility. In summary, HA promotes CD44-EGFR interaction, which in turn activates PKC signaling, involving Akt, Rac1, Phox, and the production of ROS, FAK, and MMP-2, to enhance melanoma cell motility.
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Peritoneal dissemination is a distinct form of metastasis in ovarian cancer that precedes hematogenic or lymphatic metastasis. Exosomes are extracellular vesicles of 30–150 nm in diameter secreted by different cell types and internalized by target cells. There is emerging evidence that exosomes facilitate the peritoneal dissemination of ovarian cancer by mediating intercellular communication between cancer cells and the tumor microenvironment through the transfer of nucleic acids, proteins, and lipids. Furthermore, therapeutic applications of exosomes as drug cargo delivery are attracting research interest because exosomes are stabilized in circulation. This review highlights the functions of exosomes in each process of the peritoneal dissemination of ovarian cancer and discusses their potential for cancer therapeutics.
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Although there are many studies on technical outcomes of endoscopic nasobiliary drainage (ENBD), no authors reported on preoperative course of patients undergoing ENBD. The aim of this study was to investigate the course of patients with ENBD during the waiting period.Patients who underwent resection of perihilar cholangiocarcinoma (PHCC) between January 2013 and September 2017 were retrospectively reviewed.During the study period, 191 consecutive patients underwent surgical resection of PHCC after ENBD. Of the study patients, 154 (80.6%) patients were discharged, returned to their home, then re-admitted for surgery. The remaining 37 patients were continuously hospitalized. The number of cholangitis events during the waiting period was 0 in 120 patients, 1 in 59 patients, 2 ≤ in 12 patients. Endoscopic re-intervention was needed in 52 patients. The median length between the first admission and surgery was 37 days (range 12-197 days) in the entire cohort; it was longer in patients with portal vein embolization than in those without (43 vs. 27 days, P < 0.001).In patients undergoing resection of PHCC, ENBD is widely tolerable with relatively low incidence of cholangitis and thus recommended for preoperative biliary drainage.© 2019 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
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李斌, 姜小清. 肝门部胆管癌外科诊疗难点、争议及团队23年实践体会[J]. 中国实用外科杂志, 2024, 44(3): 261-266. DOI: 10.19538/j.cjps.issn1005-2208.2024.03.02.
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刘颖斌, 邵子雨, 吴文广. 胆管恶性肿瘤术前减黄研究进展[J]. 中国实用外科杂志, 2020, 40(8): 969-972. DOI: 10.19538/j.cjps.issn1005-2208.2020.08.26.
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Cytologic examination of bile obtained during surgery from intrahepatic bile ducts in patients with malignant proximal bile duct obstruction has shown a high incidence of tumor cells. Spill of bile occurs frequently during these operations and postoperative bile leakage often occurs. Typical implantation metastases were detected in three patients who underwent resective surgery for bile duct cancer. In addition, peritoneal spread of bile duct carcinoma was found on postmortem examination in seven of ten patients who died 6 to 27 months after resection of the hilar tumor. A relation between tumor-positive bile cytologic findings, tumor spill, and seeding during surgery is likely to exist. It is recommended that during surgery the utmost care should be taken to prevent spill of bile.
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Due to advances in endoscopic equipment and techniques, preoperative endoscopic biliary drainage (EBD) has been developed to serve as an alternative to percutaneous transhepatic biliary drainage (PTBD). This study sought to clarify the benefit of EBD in comparison to PTBD in patients who underwent radical resections of hilar cholangiocarcinoma. One hundred and forty-one patients underwent radical surgery for hilar cholangiocarcinoma between 2000 and 2008 were retrospectively divided into two groups based on the type of preoperative biliary drainage, PTBD (n = 67) or EBD (n = 74). We investigated if the different biliary drainage methods affected postoperative survival and mode of recurrence after median observation period of 82 months. The survival rate for patients who underwent EBD was significantly higher than those who had PTBD (P = 0.004). Multivariate analysis revealed that PTBD was one of the independent factors predictive of poor survival (hazard ratio: 2.075, P = 0.003). Patients with PTBD more frequently developed peritoneal seeding in comparison to those who underwent EBD (P = 0.0003). PTBD was the only independent factor predictive of peritoneal seeding. In conclusion, EBD might confer an improved prognosis over PTBD due to prevention of peritoneal seeding, and is recommended as the initial procedure for preoperative biliary drainage in patients with hilar cholangiocarcinoma. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
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To review our 34-year experience with 574 consecutive resections for perihilar cholangiocarcinoma and to evaluate the progress made in surgical treatment of this disease.Few studies have reported improved surgical outcomes for perihilar cholangiocarcinoma; therefore, it is still unclear whether surgical treatment of this intractable disease has progressed.Between April 1977 and December 2010, a total of 754 consecutive patients with perihilar cholangiocarcinoma were treated, of whom 574 (76.1%) underwent resection. The medical records of these resected patients were retrospectively reviewed.The incidence of major hepatectomies has increased, and limited resections, including central hepatectomies and bile duct resections, were rarely performed. Combined vascular resection was being used more often. Operative time has become shorter, and intraoperative blood loss has also decreased significantly. Because of refinements in surgical techniques and perioperative management, morbidity decreased significantly but was still high, with a rate of 43.1% in the last 5 years. Mortality rate has also decreased significantly (P < 0.001) from 11.1% (8/72) before 1990 to 1.4% (3/218) in the last 5 years. The ratio of advanced disease defined as pStage IVA and IVB has increased significantly from 49.4% before 2000 to 61.4% after 2001. The disease-specific survival for the 574 study patients (including all deaths) was 44.3% at year 3, 32.5% at year 5, and 19.9% at year 10. The survival was significantly better in the later period of 2001 to 2010 than in the earlier period of 1977 to 2000 (38.1% vs 23.1% at year 5, P < 0.001). For pM0, R0, and pN0 patients (n = 243), the survival in the later period was good with 67.1% at year 5, which was significantly better than that of the earlier period (P < 0.001). For pM0, R0, and pN1 patients (n = 142), however, the survival in the later period was similar to that of the earlier period (22.1% vs 14.6% at year 5, P = 0.647). Multivariate analysis revealed that lymph node metastasis was the strongest prognostic indicator.Surgical treatment of perihilar cholangiocarcinoma has been evolving steadily, with expanded surgical indication, decreased mortality, and increased survival. Survival for R0 and pN0 patients was satisfactory, whereas survival for pN1 patients was still poor, suggesting that establishment of effective adjuvant chemotherapy is needed.
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Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has survival benefits in patients with intraperitoneal malignant lesions, but there is no study specific to intrahepatic cholangiocarcinoma (ICC).To compare the prognosis of patients with advanced ICC undergoing CRS + HIPEC compared with CRS alone.This study was a retrospective cohort study of patients with advanced ICC treated at the Shanghai Eastern Hepatobiliary Surgery Hospital between 01/2014 and 12/2018. The patients were divided into either CRS + HIPEC or CRS group based on the treatment they received. Overall survival (OS), complications, hospital stay, biochemical indicators, tumor markers, and number of HIPEC were examined.There were 51 and 61 patients in the CRS + HIPEC and CRS groups, respectively. There were no differences between the groups regarding preoperative CA19-9 levels (421 ± 381 vs. 523 ± 543 U/mL, P = 0.208). The hospital stay was longer in the CRS + HIPEC group (22.2 ± 10.0 vs. 18.6 ± 7.6 days, P = 0.033). The occurrence of overall complications was similar in the two groups (37.2% vs. 34.4%, P = 0.756). The postoperative CA19-9 levels were lower in the CRS + HIPEC group compared with the CRS group (196 ± 320 vs. 337 ± 396 U/mL, P = 0.044). The median OS was longer in the CRS + HIPEC group than in the CRS group (25.53 vs. 11.17 months, P < 0.001). Compared with the CRS group, the CRS + HIPEC group showed a higher occurrence of leukopenia (7.8% vs. 0, P = 0.040) but a lower occurrence of total bilirubin elevation (15.7% vs. 37.7%, P = 0.032).CRS + HIPEC could be a treatment option for patients with advanced ICC, with improved OS and similar complications and adverse events compared with CRS alone.Copyright © 2021. Published by Elsevier Ltd.
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Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal hepatobiliary neoplasm whose incidence is increasing. Largely neglected for decades as a rare malignancy and frequently misdiagnosed as carcinoma of unknown primary, considerable clinical and investigative attention has recently been focused on iCCA worldwide. The established standard of care includes first-line (gemcitabine and cisplatin), second-line (FOLFOX) and adjuvant (capecitabine) systemic chemotherapy. Compared to hepatocellular carcinoma, iCCA is genetically distinct with several targetable genetic aberrations identified to date. Indeed, FGFR2 and NTRK fusions, and IDH1 and BRAF targetable mutations have been comprehensively characterised and clinical data is emerging on targeting these oncogenic drivers pharmacologically. Also, the role of immunotherapy has been examined and is an area of intense investigation. Herein, in a timely and topical manner, we will review these advances and highlight future directions of research.Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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Recently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.
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Immune checkpoint inhibitors monotherapy has been studied in patients with advanced biliary tract cancer (BTC). The aim of this study was to assess the efficacy and safety of camrelizumab, plus gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC and explored the potential biomarkers associated with response.
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