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性别对经典型混合型肝细胞癌-胆管癌手术病人生存预后影响研究
刘羽鸣, 高强, 王晓颖, 丁振斌, 史颖弘, 叶青海, 孙惠川, 邱双健, 周俭, 樊嘉
中国实用外科杂志 ›› 2026, Vol. 46 ›› Issue (8) : 1103-1110.
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性别对经典型混合型肝细胞癌-胆管癌手术病人生存预后影响研究
Analysis of the impact of sex on survival outcomes after surgical resection for classical combined hepatocellular-cholangiocarcinoma
目的 探讨性别对经典型混合型肝细胞癌-胆管癌（简称混合癌）手术病人生存预后的影响，分析CA19-9在不同性别间的生存预后预测价值差异，并对比中国肝癌分期系统（CNLC）和第八版美国癌症联合委员会（AJCC）肝内胆管癌TNM分期系统在混合癌手术病人中的适用性。方法 回顾性分析2016年1月至2023年12月在复旦大学附属中山医院肝胆肿瘤与肝移植外科行手术切除并经病理学检查结果证实的440例混合癌病人的临床资料。用Cox比例风险回归分析评估影响混合癌病人总体生存期（OS）的影响因素。使用Kaplan-Meier法绘制按CNLC分期系统及第八版AJCC肝内胆管癌TNM分期系统构建的生存曲线，使用log-rank检验比较组间差异。采用倾向评分匹配（PSM）平衡性别间基线差异，通过交互作用分析评价性别对CA19-9水平与OS关联的效应修饰作用，应用最大选择秩统计量探索性别特异性CA19-9水平截断值。结果 所有纳入病人中，女性的OS显著长于男性（P=0.005）。相比于CNLC分期系统，第八版AJCC肝内胆管癌TNM分期在区分Ⅱ期与Ⅲ期病人OS方面表现出更好的效能（CNLC 3、5年OS Ⅱ期vs. Ⅲ期，P>0.05；AJCC TNM 3、5年OS Ⅱ期vs. Ⅲ期，P<0.05）。PSM后，交互作用分析结果显示，性别对CA19-9水平与OS的关联存在显著的效应修饰作用（交互项，P=0.012）。CA19-9水平预测混合癌病人预后的潜在性别特异性截断值分别为女性19.5 kU/L、男性61.4 kU/L。结论 经典型混合癌病人中，第八版AJCC肝内胆管癌TNM分期较CNLC分期表现出更好的生存风险分层能力；女性病人OS优于男性，且性别对CA19-9水平与OS之间的关联具有显著的修饰作用。
Objective To investigate the impact of sex on survival outcomes after surgical resection for classical combined hepatocellular-cholangiocarcinoma (cHCC-CCA), to evaluate whether the prognostic value of carbohydrate antigen 19-9 (CA19-9) differs between sexes, and to compare the prognostic performance of the China Liver Cancer (CNLC) staging system and the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system for intrahepatic cholangiocarcinoma in patients with cHCC-CCA. Methods A retrospective analysis was conducted on the clinical data of 440 patients with pathologically confirmed classical cHCC-CCA who underwent surgical resection at the Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, between January 2016 and December 2023. Overall survival (OS) was evaluated using Cox proportional hazards regression analysis. Kaplan-Meier survival curves were generated according to the CNLC and the eighth edition AJCC TNM staging systems and compared using the log-rank test. Propensity score matching (PSM) was performed to balance baseline characteristics between sexes. Interaction analysis was conducted to evaluate whether sex modified the association between CA19-9 and OS. Sex-specific CA19-9 cutoff values were explored using maximally selected rank statistics. Results Among all included patients, women had significantly longer OS than men (P=0.005). Compared with the CNLC staging system, the eighth edition AJCC TNM staging system demonstrated superior discrimination between stage Ⅱ and stage Ⅲ patients (CNLC stage Ⅱ vs. Ⅲ, 3-/5-year OS: P>0.05; AJCC stage Ⅱ vs. Ⅲ, 3-/5-year OS: P<0.05). In the propensity score-matched cohort, interaction analysis demonstrated that sex significantly modified the association between CA19-9 and OS (interaction P=0.012). The potential sex-specific optimal cutoff values of CA19-9 for prognostic stratification were 19.5 kU/L in women and 61.4 kU/L in men. Conclusion In this cohort of patients with classical cHCC-CCA, the eighth edition AJCC TNM staging system for intrahepatic cholangiocarcinoma provided better prognostic stratification than the CNLC staging system. Female patients had superior OS compared with male patients, and sex significantly modified the association between CA19-9 and OS.
混合型肝细胞癌-胆管癌 / 性别 / 分期 / 预后 / CA19-9
combined hepatocellular-cholangiocarcinoma / sex / staging / prognosis / carbohydrate antigen 19-9
| [1] |
|
| [2] |
|
| [3] |
|
| [4] |
张倩男. 混合型肝细胞癌-胆管细胞癌新的分期和预后系统的建立与验证[D]. 东南大学, 2021.
|
| [5] |
|
| [6] |
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further.Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria.Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031).The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).
|
| [7] |
王大林. 基于临床及分子特征的混合型肝癌预后影响因素分析及模型构建[D]. 中国人民解放军空军军医大学, 2022.
|
| [8] |
| [9] |
韦宇轩. 97例混合型肝癌患者的临床特点及预后分析[D]. 右江民族医学院, 2023.
|
| [10] |
| [11] |
张戈. 混合型肝癌的预后因素和系统治疗分析[D]. 北京协和医学院, 2023.
|
| [12] |
|
| [13] |
|
| [14] |
中华人民共和国国家卫生健康委员会医政司. 原发性肝癌诊疗指南(2026年版)[J]. 中国实用外科杂志, 2026, 46(5):545-598. DOI:10.19538/j.cjps.issn1005-2208.2026.05.01.
|
| [15] |
陈骏, 毛谅, 何健, 等. 第8版《美国癌症联合会肿瘤分期手册》肝内胆管细胞癌TNM分期解读[J]. 中华消化外科杂志, 2017, 16(4):330-335. DOI:10.3760/cma.j.issn.1673-9752.2017.04.003.
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| [16] |
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| [17] |
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a primary liver carcinoma with both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) components. We examined the clinicopathological characteristics and recurrence patterns of cHCC-CCA. Because of the rarity of cHCC-CCA, its etiology, clinicopathological features, and prognosis in comparison with other primary liver carcinoma remain unknown. Its recurrence pattern and sites in particular also need to be elucidated.All patients who underwent hepatectomy for primary liver malignancies between 2005 and 2015 were retrospectively included in this study.Eight hundred and ninety-four hepatectomies were performed. Nineteen cases of cHCC-CCA (2.1%) in 16 patients were enrolled. Three patients underwent re-hepatectomy. The background of hepatitis viruses and tumor marker patterns of cHCC-CCA were similar to those of HCC and dissimilar to those of intrahepatic CCA (iCCA). Biliary invasion was common in cHCC-CCA and iCCA. The 5-year overall survival values of the cHCC-CCA, HCC, and iCCA patients were 44.7%, 56.6%, and 38.5%, respectively. The 5-year recurrence-free survival values of the cHCC-CCA, HCC, and iCCA patients were 12.2%, 28.7%, and 32.9%, respectively. The liver was the most common recurrence site. Unlike HCC, however, the lymph node was the second-most common recurrence site in both cHCC-CCA and iCCA. Pathological samples of the recurrent lesions were obtained in six patients, and four had cHCC-CCA recurrence pathologically.cHCC-CCA had a mixture of characteristics of HCC and iCCA. Many cases of cHCC-CCA remained cHCC-CCA pathologically even after recurrence.
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| [18] |
Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary liver cancer that has rarely been reported in large-scale clinical studies. The aim of this study was to clarify the clinical features, treatment modalities, and prognosis of cHCC-CC.Included in this study were 113 patients who were histologically diagnosed as having Allen type C cHCC-CC, 103 of whom received liver resection, 6 transarterial chemoembolization treatment, 3 radiofrequency ablation, and 1 palliative supportive treatment. Clinicopathologic features and prognosis of 103 cHCC-CC patients after liver resection were compared with those of 6,679 patients with hepatocellular carcinoma (HCC) and 386 patients with intrahepatic cholangiocarcinoma (ICC) who underwent liver resection during the same period.The proportion of cHCC-CC in primary liver cancers was 1.5 %. The 103 cases of cHCC-CC were characterized by male predominance, infection with hepatitis virus or presence of liver cirrhosis, and elevated alfa-fetoprotein-findings similar to HCC. However, serum CA19-9 elevation, incomplete capsules, and lymph node involvement were similar to ICC. The 1-, 3-, and 5-year overall survival rates after liver resection were 73.9, 41.4, and 36.4 %, respectively, for patients with cHCC-CC versus 77.5, 53.3, and 41.4 % for HCC patients, and 58.0, 29.1, and 22.3 % for ICC patients (χ(2) = 137.5, P < 0.001). Tumor, node, metastasis system stage (hazard ratio 1.27, 95 % confidence interval 1.08-1.49, P = 0.003) and radical liver resection (hazard ratio 0.31, 95 % confidence interval 0.14-0.68, P = 0.004) were independent prognostic factors for overall survival.cHCC-CC has biological behavior and prognosis that are intermediate between HCC and ICC. Radical liver resection can provide a better outcome for this uncommon malignancy.
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| [19] |
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| [20] |
Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti–PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell–mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response.
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| [21] |
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| [22] |
Sex-based differences have been observed in the incidence and prognosis of various cancers, as well as in the response to immune check point inhibitors (ICIs). These disparities are partially attributed to sex-based differences in the molecular characteristics of the anticancer immune response, which are largely influenced by sex hormones. Here, we provide a comprehensive overview on how sex hormones affect innate and adaptive immunity and contribute to shaping the features of tumor immune microenvironment and response to anticancer immunotherapy. We also discuss the promising potential and challenges of combining sex hormone manipulation with anticancer immunotherapy as new therapeutic strategy. We surmise that a sex-based perspective should be part of precision medicine approaches, and sex hormones manipulation provides opportunities for innovative immune therapeutic approaches.Copyright © 2025 Elsevier Inc. All rights reserved.
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| [23] |
|
| [24] |
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| [25] |
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| [26] |
|
| [27] |
|
| [28] |
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