Intrahepatic Cholangiocarcinoma: An International Multi-Institutional Analysis of Prognostic Factors and Lymph Node Assessment
Mechteld C. de JongHari NathanGeorgios C. SotiropoulosAndreas PaulSorin AlexandrescuHugo P. MarquesCarlo PulitanòEduardo BarrosoBryan M. ClaryLuca AldrighettiCristina R. FerroneAndrew X. ZhuTodd W. BauerDustin M. WaltersT. Clark GamblinKevin T. NguyenRyan S. TurleyIrinel PopescuCatherine HubertStephanie MeyerRichard D. SchulickMichael A. ChotiJ. F. GigotGilles MenthaTimothy M. Pawlik
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Purpose To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. Patients and Methods From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. Results Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). Conclusion Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.Keywords:
Intrahepatic Cholangiocarcinoma
Lymphadenectomy
Surgical margin
ABSTRACT Introduction The mainstay treatment for intrahepatic cholangiocarcinoma is surgical resection, the impact of lymph node dissection and the scope of lymph node dissection for intrahepatic cholangiocarcinoma surgery is controversial. However, research on the comparative of regional lymphadenectomy and extended lymphadenectomy is still limited. This study will explore the effect of regional lymphadenectomy and extended lymphadenectomy in intrahepatic cholangiocarcinoma surgery patients to provide reliable evidence for further standardize the scope of lymph node dissection for intrahepatic cholangiocarcinoma surgery. Methods and analysis This is a prospective, multicentre, randomised controlled trial in intrahepatic cholangiocarcinoma surgery patients. A total of 174 patients will be enrolled at the first clinic visit in sites from China. Participants will be allocated randomly to the regional lymphadenectomy group and extended lymphadenectomy group (1:1 ratio). Patients in different groups undergo the corresponding surgery. Primary study outcome is disease-free survival (DFS). Secondary study outcomes include incidence of severe Clavien–Dindo complications (≥II), safety of operation, overall survival (OS), three-year survival rate, five-year survival rate and median mortality. Participants will be followed up at baseline, post-operation, every 3 months for the first 2 years and 6 months for the next 3 years to evaluate the impact of different surgery types. The analysis will be done according to protocol cohorts, adjusted by variables associated with intrahepatic cholangiocarcinoma. Ethics and dissemination This study was approved by the ethical review committee of the second affiliated hospital Zhejiang University school of medicine (2019-261) and will provide reference for standardize the scope of lymph node dissection for intrahepatic cholangiocarcinoma surgery. Trial registration ClinicalTrials.gov , NCT04078230 . Registered on September 6, 2019. The study is expected to last for more than five years, and the first patient was enrolled on August 22, 2020, and a total of 17 patients have been enrolled so far.
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Although lymph node metastasis (LNM) is one of the most important contributory factors to the overall survival of ICC patients, the role of lymph node dissection(LND) is still under research. Some researchers thought hepatectomy combined with extended lymphadenectomy is the standard surgical treatment for ICC. However, not all the clinical centers approved routine LND. Some centers have reported the use of selective LND and limited routine LND. This review will mainly concern lymph node metastasis and lymph node dissection.
Key words:
Intrahepatic cholangiocarcinoma; Lymphatic metastasis; Lymph node dissection; Lymph node ratio
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It is unclear whether gastric cancer prognosis is improved by extended lymph node dissection more than by lymph node dissection limited to the contiguous N1 perigastric lymph nodes.Four hundred and thirty-eight patients treated by curative gastrectomy were evaluated. Outcomes of D1/D1.5 lymphadenectomy, limited lymph node dissection and of D2/D2.5 lymphadenectomy, extended lymph node dissection and histopathological prognostic factors as in the 1993 TNM staging classification supplement were analyzed.Estimated overall 5-year survival was 54.9%. Five-year survival was 58.4% in the limited lymph node dissection group and 54% in the extended lymph node dissection (P n.s.). Stage I 5-year survival was 59% after D2.5 lymph node dissection, 58% after D1.5 and 50% after D2 dissection (P n.s.). Stage II 5-year survival was 86% in D2.5 group and 56% in D1.5 group (P = 0.041). Stage IIIa survival was 61% in the D2.5 group and 22% in the D1.5 group (P = 0.001). Stage IIIb 5-year survival was 42% after D2.5 resection and 0% in D1.5 group (P = 0.001). In the pT3 group 5-year survival was 72% after D2.5 dissection and 33% after D2 dissection (P = 0.001). In the positive N1 lymph nodes group 5-year survival was better after extended lymph node dissection than after limited lymph node dissection. In pN2a patients 5-year survival was 57% after D2.5 resection and 0% after D2 resection (P < 0.001). In pN2b and pN2c patients extended lymph node dissection did not statistically improve survival.Even if no statistical differences were found in overall survival, prognosis was improved by extended lymph node dissection in stage II and III, particularly in T2 and T3 subgroups and in N1 and N2a subgroups. When large numbers of positive nodes were found, improved survival was dependent upon resection of extragastric nodes distal to the uppermost echelon of positive nodes.
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Intrahepatic cholangiocarcinoma(ICC) is the second common primary liver cancer originated from epithelium of the sub-branches of intrahepatic bile ducts with extremely poor prognosis and lack of effective treatment.The prognosis of ICC is mostly affected by the origin,the type and the size of the tumor as well as the intrahepatic metastasis(satellite lesion) and lymph node metastasis etc.Surgical resection remains the first choice of treatment to patients with ICC.However, there are multiple issues in surgical treatment of ICC, which have not been reached a consensus.Among them, the value of systematic lymphadenectomy during hepatic resection for ICC patient remains one of the hot spot issues.Given the heterogeneity of ICC,we recommend planning the procedure of the radical resection and lymphadenectomy personally, according to the type and origin of the tumor, the number and locationof the lesion.The pre-operation imaging examination and the intra-operation lymph node tracing technique could provide valuable information to help the surgeon decide the range of systematic lymphadenectomy.Routine systematic lymphadenectomy is recommended in the surgical treatment of ICC patients by experienced surgeons even without evidence of lymph node metastasis.The resected lymph tissue should be labeled by the provenance for further study.肝内胆管癌（ICC）恶性程度高，预后与肿瘤类型、大小、数目、分期及淋巴结转移等密切相关，根治性手术是患者获得治愈的唯一方法，但ICC的外科治疗尚有较多问题未达成共识，其中是否常规淋巴结清扫及清扫范围的确定是争议热点。建议根据肿瘤性质和大小、肝内肿瘤数目、范围等规划手术方式及确定是否需联合淋巴结清扫等。不同部位ICC的淋巴结转移途径存在差异，淋巴结清扫范围也应相应调整。术前影像学检查及术中淋巴结示踪技术对决定淋巴结清扫范围有一定帮助。鉴于ICC的异质性特征，对于术前未发现淋巴结转移的ICC，为了精确分期，建议有条件的单位常规开展淋巴结清扫术，并标记部位。.
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Lymph node (LN) metastasis is well recognized as a poor prognostic factor in intrahepatic cholangiocarcinoma (ICC); however, the efficacy of LN dissection for ICC remains unclear. We clarify a targeted papulation of ICC to evaluate it in this study. A retrospective study of patients who underwent liver resection without the extrahepatic bile duct for ICC was conducted. The pattern of LN recurrence and the location of the primary tumor were evaluated. Between January 2003 and July 2014, 52 patients with ICC underwent surgery. Fourteen patients had LN recurrence, 6 of whom had LN recurrence only. Excluding patients with LN dissection at surgery, the primary tumor was limited to the perihilar surrounding area in patients with LN recurrence only. Recurrence rate in LNs was 50% in patients with primary tumors originating in the perihilar surrounding area, which was significantly higher than the rate of 13% in patients with primary tumors originating in other areas. Primary tumors in the perihilar surrounding area have a high risk of LN recurrence. Regional lymphadenectomy combined with hepatectomy should be carried out in patients with ICC located in this area. The incidence of LN metastasis and the possibility of preventing LN recurrence could be effectively revealed by regional lymphadenectomy in selected patients.
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Abstract Lymph node status is a key prognostic indicator in patients with bladder cancer, so lymphadenectomy is important for accurate staging. Moreover, lymphadenectomy is curative for some patients with nodal metastases. Although there is evidence that the quality of regional node dissection is associated with oncologic outcome, controversy exists because other factors may also explain this observation. Consequently, there is no consensus regarding the optimal extent of lymphadenectomy and number of nodes that should be assessed. J. Surg. Oncol. 2009;99:225–231. © 2009 Wiley‐Liss, Inc.
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