肝内胆管细胞癌根治性切除术后临床预后影响因素的研究

doi:10.3877/cma.j.issn.1674-0793.2019.02.004

目的

探讨肝内胆管细胞癌（ICC）行根治性切除（R0切除）术后的独立预后影响因素。

方法

回顾性分析中山大学附属第一医院自2002年1月至2018年8月行R0切除并经病理确诊的237例ICC患者的临床病理及随访资料，采用Kaplan-Meier法构建生存曲线；单因素及多因素COX回归分析筛选影响患者生存预后的独立因素。一致性指数（C-index）、时间依赖性受试者工作特征曲线（ROC曲线）、曲线下面积（AUC）及校准曲线用于评价COX回归模型的预测效能。

结果

237例ICC患者的中位生存期为19.93个月（95%CI=14.31~26.21），术后1、2、3年生存率分别为62.3%、45.0%及35.6%。单因素及多因素回归分析显示谷氨酰转移酶（GGT） >53 U/L（P=0.001）、CA125>17.4 U/ml（P<0.001）、淋巴结转移（P=0.039）、肿瘤分化不良（P<0.001）是ICC患者行R0切除术后预后不良的独立危险因素。按照删除概率P>0.1的标准，纳入癌胚抗原（CEA）（P=0.092）后的预后模型C-index为0.74（95%CI=0.68~0.78），不同随访时间点对应的AUC值均在0.8左右，模型具有良好的预测效能。

结论

GGT、CEA、CA125、淋巴结转移情况及肿瘤分化程度可作为ICC患者R0切除术后临床预后的预测指标。

关键词: 癌，胆管细胞, 肝切除术, 预后, 因素分析，统计学

Objective

To identify the independent prognostic factors of intrahepatic cholangiocarcinoma (ICC) patients after receiving curative (R0) resection.

Methods

From January 2002 to August 2018, the clinicopathological and prognosis data of two hundred and thirty-seven patients with the pathological diagnosis of ICC in the First Affiliated Hospital of Sun Yat-sen University who underwent curative resection were analyzed retrospectively. The survival curve was constructed by Kaplan-Meier method. Univariate and multivariate COX regression analysis were used to screen independent factors affecting survival and prognosis of patients. C-index, ROC curve, AUC curve and calibration curve were used to evaluate the predictive effectiveness of COX regression model.

Results

The median survival time of ICC patients was 19.93 months (95%CI=14.31-26.21), and the 1-, 2-, and 3-year survival rates were 62.3%, 45.0%, and 35.6%, respectively. Univariate and multivariate regression analysis demonstrated that gamma-glutamyl transpeptidase (GGT) >53 U/L (P=0.001), CA125>17.4 U/ml (P<0.001), lymph node metastasis (P=0.039) and poor tumor differentiation (P<0.001) were the adverse factors of prognosis after R0 resection in ICC patients. According to the criteria for deleting probability: P>0.1, the C-index of the prognostic model containing CEA (P=0.092) was 0.74 (95%CI=0.68-0.78). The AUC values corresponding to different follow-up time points were all around 0.8, and the model had good prediction efficiency.

Conclusion

GGT, CEA, CA125, lymph node metastasis and poor tumor differentiation are prognostic predictors of ICC patients after receiving R0 resection.

Key words: Carcinoma, cholangiocellular, Hepatectomy, Prognosis, Factor analysis, statistical

表1 237例行R0切除术的ICC患者临床病理特征分析

项目		例数(%)	项目		例数(%)	项目		例数(%)
年龄(岁)		?	INR		1.0(0.1~2.0)^a	肿瘤大小(cm)		6.0(0.1~16)^a
?	≤60	128(54.0)	?	≤1.07	171(72.2)	?	≤5	81(35.8)
?	>60	109(46.0)	?	>1.07	66(27.8)	?	>5	145(64.2)
性别		?	CA19-9(U/ml)		111.0(0~12 000)^a	肿瘤个数		?
?	男	138(58.2)	?	≤51.4	83(35.0)	?	1	172(75.8)
?	女	99(41.8)	?	>51.4	154(65.0)	?	2~3	19(8.4)
Hb(g/L)		130.0(3.8~178.0)^a	CEA(μg/L)		3.0(0.6~3 203.5)^a	?	>3	36(15.8)
?	≤122	77(32.5)	?	≤3	119(50.2)	血管侵犯		?
?	>122	160(67.5)	?	>3	118(49.8)	?	无	152(64.1)
ALB(g/L)		39.9(20.3~59.0)^a	CA125(U/ml)		20.7(2.6~6 197.6)^a	?	有	85(35.9)
?	≤40	127(53.6)	?	≤17.4	87(36.7)	胆管侵犯		?
?	>40	110(46.4)	?	>17.4	150(63.3)	?	无	197(83.8)
TBIL(μmol/L)		12.0(2.4~412.7)^a	HBsAg		?	?	有	38(16.2)
?	≤18.6	187(78.9)	?	阴性	165(69.6)	局部侵犯		?
?	>18.6	50(21.1)	?	阳性	72(30.4)	?	无	178(75.1)
ALT(U/L)		25.0(5.0~560.0)^a	丙型肝炎		?	?	有	59(24.9)
?	≤49	181(76.4)	?	阴性	227(96.6)	淋巴结转移		?
?	>49	56(23.6)	?	阳性	8(3.4)	?	无	158(66.7)
GGT(U/L)		91.0(12.0~1 776.0)^a	肝硬化		?	?	有	79(33.3)
?	≤53	61(25.7)	?	无	201(84.8)	分化程度		?
?	>53	176(74.3)	?	有	36(15.2)	?	Ⅰ~Ⅱ	115(59.6)
PT(s)		11.9(10.2~131.0)^a	胆管结石		?	?	Ⅲ	78(40.4)
?	≤12.5	180(75.9)	?	无	154(66.7)	术中输血		?
?	>12.5	57(24.1)	?	有	77(33.3)	?	无	157(66.2)
?	?	?	?	?	?	?	有	80(33.8)

表1 237例行R0切除术的ICC患者临床病理特征分析

项目		例数(%)	项目		例数(%)	项目		例数(%)
年龄(岁)		?	INR		1.0(0.1~2.0)^a	肿瘤大小(cm)		6.0(0.1~16)^a
?	≤60	128(54.0)	?	≤1.07	171(72.2)	?	≤5	81(35.8)
?	>60	109(46.0)	?	>1.07	66(27.8)	?	>5	145(64.2)
性别		?	CA19-9(U/ml)		111.0(0~12 000)^a	肿瘤个数		?
?	男	138(58.2)	?	≤51.4	83(35.0)	?	1	172(75.8)
?	女	99(41.8)	?	>51.4	154(65.0)	?	2~3	19(8.4)
Hb(g/L)		130.0(3.8~178.0)^a	CEA(μg/L)		3.0(0.6~3 203.5)^a	?	>3	36(15.8)
?	≤122	77(32.5)	?	≤3	119(50.2)	血管侵犯		?
?	>122	160(67.5)	?	>3	118(49.8)	?	无	152(64.1)
ALB(g/L)		39.9(20.3~59.0)^a	CA125(U/ml)		20.7(2.6~6 197.6)^a	?	有	85(35.9)
?	≤40	127(53.6)	?	≤17.4	87(36.7)	胆管侵犯		?
?	>40	110(46.4)	?	>17.4	150(63.3)	?	无	197(83.8)
TBIL(μmol/L)		12.0(2.4~412.7)^a	HBsAg		?	?	有	38(16.2)
?	≤18.6	187(78.9)	?	阴性	165(69.6)	局部侵犯		?
?	>18.6	50(21.1)	?	阳性	72(30.4)	?	无	178(75.1)
ALT(U/L)		25.0(5.0~560.0)^a	丙型肝炎		?	?	有	59(24.9)
?	≤49	181(76.4)	?	阴性	227(96.6)	淋巴结转移		?
?	>49	56(23.6)	?	阳性	8(3.4)	?	无	158(66.7)
GGT(U/L)		91.0(12.0~1 776.0)^a	肝硬化		?	?	有	79(33.3)
?	≤53	61(25.7)	?	无	201(84.8)	分化程度		?
?	>53	176(74.3)	?	有	36(15.2)	?	Ⅰ~Ⅱ	115(59.6)
PT(s)		11.9(10.2~131.0)^a	胆管结石		?	?	Ⅲ	78(40.4)
?	≤12.5	180(75.9)	?	无	154(66.7)	术中输血		?
?	>12.5	57(24.1)	?	有	77(33.3)	?	无	157(66.2)
?	?	?	?	?	?	?	有	80(33.8)

图1 237例ICC患者R0切除术后生存曲线

表2 237例行R0切除术的ICC患者OS的单因素COX回归分析

项目	HR	95%CI	P值	项目	HR	95%CI	P值
年龄(>60岁)	0.92	0.65~1.31	0.639	丙型肝炎(阳性)	0.73	0.27~1.99	0.542
性别(女)	0.88	0.62~1.26	0.491	合并肝硬化(有)	0.91	0.54~1.52	0.711
Hb(>122 g/L)	0.59	0.41~0.85	0.005^a	胆管结石(有)	1.30	0.90~1.88	0.155
ALB(>40 g/L)	0.65	0.45~0.92	0.017^a	肿瘤大小(>5 cm)	1.68	1.13~2.51	0.011^a
TBIL(>18.6 μmol/L)	1.42	0.94~2.13	0.096	肿瘤数目(个)	?	?	?
ALT(>49 U/L)	1.40	0.96~2.06	0.083	2~3	1.19	0.65~2.19	0.564
GGT(>53 U/L)	2.51	1.56~4.06	<0.001^a	>3	1.82	1.16~2.84	0.009^a
PT(>12.5 s)	1.61	1.10~2.37	0.015^a	血管侵犯(有)	1.89	1.31~2.72	0.001^a
INR(>1.07)	1.45	1.00~2.12	0.051	胆管侵犯(有)	1.01	0.61~1.67	0.967
CA19-9(>51.4 U/ml)	1.89	1.27~2.80	0.002^a	局部侵犯(有)	1.25	0.84~1.86	0.264
CEA(>3 μg/L)	1.68	1.18~2.40	0.004^a	淋巴结转移(有)	1.99	1.39~2.85	<0.001^a
CA125(>17.4 U/ml)	2.65	1.77~3.96	<0.001^a	分化程度(Ⅲ级)	1.67	1.12~2.48	0.012^a
HBsAg(阳性)	1.10	0.76~1.59	0.612	术中输血(有)	1.99	1.40~2.83	<0.001^a

表2 237例行R0切除术的ICC患者OS的单因素COX回归分析

项目	HR	95%CI	P值	项目	HR	95%CI	P值
年龄(>60岁)	0.92	0.65~1.31	0.639	丙型肝炎(阳性)	0.73	0.27~1.99	0.542
性别(女)	0.88	0.62~1.26	0.491	合并肝硬化(有)	0.91	0.54~1.52	0.711
Hb(>122 g/L)	0.59	0.41~0.85	0.005^a	胆管结石(有)	1.30	0.90~1.88	0.155
ALB(>40 g/L)	0.65	0.45~0.92	0.017^a	肿瘤大小(>5 cm)	1.68	1.13~2.51	0.011^a
TBIL(>18.6 μmol/L)	1.42	0.94~2.13	0.096	肿瘤数目(个)	?	?	?
ALT(>49 U/L)	1.40	0.96~2.06	0.083	2~3	1.19	0.65~2.19	0.564
GGT(>53 U/L)	2.51	1.56~4.06	<0.001^a	>3	1.82	1.16~2.84	0.009^a
PT(>12.5 s)	1.61	1.10~2.37	0.015^a	血管侵犯(有)	1.89	1.31~2.72	0.001^a
INR(>1.07)	1.45	1.00~2.12	0.051	胆管侵犯(有)	1.01	0.61~1.67	0.967
CA19-9(>51.4 U/ml)	1.89	1.27~2.80	0.002^a	局部侵犯(有)	1.25	0.84~1.86	0.264
CEA(>3 μg/L)	1.68	1.18~2.40	0.004^a	淋巴结转移(有)	1.99	1.39~2.85	<0.001^a
CA125(>17.4 U/ml)	2.65	1.77~3.96	<0.001^a	分化程度(Ⅲ级)	1.67	1.12~2.48	0.012^a
HBsAg(阳性)	1.10	0.76~1.59	0.612	术中输血(有)	1.99	1.40~2.83	<0.001^a

表3 ICC患者R0切除术后OS的多因素COX回归模型

变量	Coef.	Std.Err	HR	95%CI	P值
GGT(>53 U/L)	0.98	2.89	2.68	1.52~4.71	0.001
CEA(>3 μg/L)	0.36	0.22	1.44	0.94~2.20	0.092
CA125(>17.4 U/ml)	0.96	0.24	2.61	1.63~4.17	<0.001
淋巴结转移	0.44	0.21	1.55	1.02~2.36	0.039
分化程度(Ⅲ级)	0.84	0.21	2.31	1.52~3.50	<0.001

表3 ICC患者R0切除术后OS的多因素COX回归模型

变量	Coef.	Std.Err	HR	95%CI	P值
GGT(>53 U/L)	0.98	2.89	2.68	1.52~4.71	0.001
CEA(>3 μg/L)	0.36	0.22	1.44	0.94~2.20	0.092
CA125(>17.4 U/ml)	0.96	0.24	2.61	1.63~4.17	<0.001
淋巴结转移	0.44	0.21	1.55	1.02~2.36	0.039
分化程度(Ⅲ级)	0.84	0.21	2.31	1.52~3.50	<0.001

图2 237例ICC患者根治术后生存的COX回归模型时间依赖性AUC曲线拟合图　实线是拟合线，两边的虚线是95%CI

图3 237例ICC患者根治术后生存的COX回归模型校准曲线

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Prognostic factors of intrahepatic cholangiocarcinoma patients undergoing curative resection

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Prognostic factors of intrahepatic cholangiocarcinoma patients undergoing curative resection