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基于超声造影LI-RADS特征的肝细胞癌微血管侵犯列线图模型的构建及验证
DOI: 10.3969/j.issn.1001-5256.2022.11.016
伦理学声明：本研究方案于2016年12月17日经由江苏大学附属武进医院伦理委员会审批，批号：2016-P2-010，所纳入患者均签署知情同意书。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：奚静负责课题设计，资料分析，撰写论文；顾美琴、包作伟参与收集数据，修改论文。
Construction and validation of a nomogram model for microvascular invasion in hepatocellular carcinoma based on the characteristics on contrast-enhanced ultrasound Liver Imaging Reporting and Data System
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摘要:
目的 基于肝细胞癌(HCC)患者的超声造影(CEUS)肝脏成像报告和数据系统(LI-RADS)特征建立预测微血管侵犯(MVI)的列线图模型并进行验证。 方法 选取2017年1月—2020年7月在江苏大学附属武进医院确诊的HCC患者共262例，按照1∶ 1比例随机分为建模组和验证组各131例，以术后镜下病理结果确诊MVI，其中建模组MVI 70例和验证组MVI 56例。采用超声造影评估两组的LI-RADS特征。两组间计量资料比较采用独立样本t检验；两组间计数资料比较采用χ2检验。采用单因素和多因素Logistic回归分析筛选建模组MVI的危险因素；绘制受试者工作特征曲线(ROC曲线)，计算模型预测MVI的曲线下面积(AUC)，评估预测准确度；应用决策曲线分析模型的一致性，比较模型预测MVI的校正曲线与标准曲线的离散度。 结果 建模组与验证组患者的临床资料和CEUS检查结果比较，差异均无统计学意义(P值均＞0.05)。单因素分析显示，与MVI阴性患者相比，MVI阳性患者血清AFP水平显升高，肿瘤直径增大，LI-RADS显示LR-5“后出”和LR-M“先出”增多，LI-RADS分级较高，差异均有统计学意义(P值均＜0.05)。多因素分析显示，AFP 20~400 ng/mL(OR=2.65，P＜0.001)、AFP≥400 ng/mL(OR=3.98，P＜0.001)、肿瘤直径≥30 mm(OR=2.12，P＜0.001)和CEUS显示LR-M(OR=3.24，P＜0.001) 是MVI的独立危险因素。ROC曲线显示，列线图预测建模组和验证组MVI的AUC分别为0.867和0.821。列线图模型的一致性指数C-Index为0.765(95%CI：0.701~0.834)。在建模组和验证组，列线图模型的预测校准曲线与标准曲线均接近。 结论 利用CEUS得出LI-RADS，并结合AFP和肿瘤直径建立的列线图模型有较好的应用价值，有助于指导临床术前筛选MVI高危患者，制订恰当的手术方案。 Abstract:Objective To construct and validate a nomogram model for predicting microvascular invasion (MVI) based on the characteristics on contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) in patients with hepatocellular carcinoma (HCC). Methods A total of 262 patients with HCC who were diagnosed in Wujin Hospital Affiliated to Jiangsu University from January 2017 to July 2020 were enrolled and randomly divided into modeling group and validation group at a ratio of 1∶ 1, with 131 patients in each group. MVI was confirmed by postoperative microscopic pathological results, and there were 70 patients with MVI in the modeling group and 56 patients with MVI in the validation group. CEUS was used to evaluate LI-RADS characteristics for the two groups. The independent samples t-test was used for comparison of continuous data between the two groups, and the chi-square test was used for comparison of categorical data between the two groups. Univariate and multivariate Logistic regression analyses were used to identify the risk factors for MVI in the modeling group; the receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated for the model in predicting MVI to evaluate the accuracy of prediction; a decision curve analysis was used to evaluate the consistency of the model, and dispersion was compared between the calibration curve and the standard curve for the model in predicting MVI. Results There were no significant differences in clinical data and CEUS findings between the modeling group and the validation group (all P > 0.05). The univariate analysis showed that compared with the MVI-negative patients, the MVI-positive patients had significant increases in serum alpha fetoprotein (AFP) level, tumor diameter, and LR-5 "late and mild washout" and LR-M "early washout" on LI-RADS, as well as a significantly higher LI-RADS grade (all P < 0.05). The multivariate analysis showed that AFP 20-400 ng/mL (odds ratio [OR]=2.65, P < 0.001), AFP≥400 ng/mL (OR=3.98, P < 0.001), tumor diameter ≥30 mm (OR=2.12, P < 0.001), and LR-M on CEUS (OR=3.24, P < 0.001) were independent risk factors for MVI. The ROC curve analysis showed that the nomogram had an AUC of 0.867 and 0.821 in predicting MVI in the modeling group and the validation group, respectively. The nomogram model had a C-Index of 0.765 (95% confidence interval: 0.701-0.834). The calibration curves of the nomogram model were close to the standard curve in both groups. Conclusion The nomogram model based on LI-RADS obtained by CEUS in combination with AFP and tumor diameter has a good application value and can guide the preoperative screening for patients at a high risk of MVI and the development of appropriate surgical plans in clinical practice. -
注：a，肝硬化患者超声显示肿瘤直径35.5 mm，低回声(虚线处)；b，MVI阴性，LR-5动脉期增强和“后出”征象(虚线处)；c，MVI阳性，LR-M边缘增强和“先出”征象(虚线处)；d，病理标本显示分化良好，无MVI (HE染色，×100)。
图 1 HCC的CEUS图像分析
Figure 1. CEUS image of HCC
注：a，建模组；b，验证组。
图 3 列线图模型预测建模组和验证组MVI的ROC曲线分析
Figure 3. ROC analysis of nomograph model for predicting MVI in model group and validation group
注：a，建模组；b，验证组。
图 4 建模组与验证组的列线图预测曲线
Figure 4. Nomograph predictive curve of model group and validation group
表 1 建模组与验证组的临床资料和CEUS特征比较
Table 1. Comparison of clinical datas and CEUS characteristics between model group and validation group
指标 建模组(n=131) 验证组(n=131) 统计值 P值 男/女(例) 78/53 70/61 χ2=0.994 0.319 年龄(岁) 58.2±6.7 57.2±6.3 t=1.052 0.198 乙型肝炎[例(%)] 115(87.8) 110(84.0) χ2=0.787 0.375 肝硬化[例(%)] 80(61.1) 84(64.1) χ2=0.261 0.610 肿瘤TNM分期[例(%)] χ2=0.138 0.710 Ⅰ~Ⅱ 60(45.8) 63(48.1) Ⅲ~Ⅳ 71(54.2) 68(51.9) 分化级别[例(%)] χ2=0.245 0.621 低 65(49.6) 61(46.6) 中高 66(50.4) 70(53.4) MVI[例(%)] 70(53.4) 56(42.7) χ2=2.997 0.083 血生化指标 PT＞14 s[例(%)] 42(32.1) 33(25.2) χ2=1.513 0.219 AFP(ng/mL) 365±74 349±68 t=0.795 0.302 PLT(×109/L) 201±32 212±39 t=0.632 0.348 TBil(μmol/L) 15.6±3.8 13.9±3.2 t=0.469 0.521 Alb(g/L) 35.9±4.5 33.2±4.3 t=0.396 0.627 ALT(U/L) 40.2±5.3 43.9±5.7 t=0.559 0.501 二维超声 肿瘤直径≥30 mm[例(%)] 92(70.2) 81(61.8) χ2=2.059 0.151 回声类型[例(%)] χ2=0.177 0.674 低 95(72.5) 98(74.8) 等或高 36(27.5) 33(25.2) 边缘不清[例(%)] 101(77.1) 93(71.0) χ2=1.271 0.260 不规则外形[例(%)] 92(70.2) 94(71.8) χ2=0.074 0.785 Halo征[例(%)] 32(24.4) 28(21.4) χ2=0.346 0.556 血管分布[例(%)] χ2=0.078 0.780 少 97(74.0) 95(72.5) 多 34(26.0) 36(27.5) CEUS特征[例(%)] LR-5动脉期增强 93(71.0) 89(67.9) χ2=0.288 0.592 “后出”征象 57(43.5) 51(38.9) χ2=0.567 0.451 LR-M边缘增强 19(14.5) 22(16.8) χ2=0.260 0.610 “先出”征象 78(59.5) 71(54.2) χ2=0.762 0.383 LI-RADS分级[例(%)] χ2=0.492 0.782 3~4 16(12.3) 19(14.5) 5 48(36.6) 50(38.2) M 67(51.1) 62(47.3) 镶嵌图形征[例(%)] 23(17.6) 25(19.1) χ2=0.102 0.749 结节内结节征[例(%)] 20(15.3) 17(13.0) χ2=0.283 0.595 
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表 2 MVI的危险因素分析
Table 2. Risk factor analysis of MVI
因素 单因素分析 多因素分析 OR 95%CI P值 OR 95%CI P值 AFP 20~400 ng/mL 3.19 2.66~3.42 ＜0.001 2.65 2.13~3.23 ＜0.001 ≥400 ng/mL 4.45 3.78~4.79 ＜0.001 3.98 3.32~4.39 ＜0.001 肿瘤直径≥30 mm 2.76 2.23~3.16 ＜0.001 2.12 1.69~2.58 ＜0.001 LR-5“后出” 2.09 1.56~2.54 ＜0.001 LR-M“先出” 3.96 3.46~4.49 ＜0.001 3.24 2.78~3.65 ＜0.001 LI-RADS分级 2.01 1.48~2.43 ＜0.001
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