5种淋巴结转移分期标准预测肝门部胆管癌预后的应用价值

陈潇远; 毛谅; 杨翼飞; 伏旭; 严笑鹏; 蔡正华; 周铁; 凡银银; 张静; 仇毓东

doi:10.3760/cma.j.cn115610-20201208-00767

5种淋巴结转移分期标准预测肝门部胆管癌预后的应用价值

Application value of five lymph node staging methods in predicting prognosis of perihilar cholangiocarcinoma

摘要

摘要:
目的探讨美国癌症联合会（AJCC）第8版肿瘤TNM分期系统N分期、阳性淋巴结数目（pLN）、阴性淋巴结数目（nLN）、淋巴结转移率（LNR）和阳性淋巴结对数比（LODDS）5种淋巴结转移分期标准预测肝门部胆管癌（PHCC）预后的应用价值。
方法采用回顾性队列研究方法。收集2004―2015年美国监测、流行病学和最终结果（SEER）数据库669例PHCC病人的临床病理资料；男406例,女263例；年龄为（66±11）岁,年龄范围为29～92岁。观察指标：（1）PHCC病人预后影响因素分析。（2）PHCC病人随访和生存情况。（3）5种淋巴结转移分期标准N1期和N2期病人预后比较。（4）5种淋巴结转移分期标准预测病人预后的准确性。正态分布的计量资料以x±s表示,偏态分布的计量资料以M（范围）表示。计数资料以绝对数和百分比表示。采用Kaplan⁃Meier法计算生存率并绘制生存曲线。单因素生存分析采用Log⁃rank检验,多因素生存分析采用COX比例风险模型。采用X⁃tile 3.6.1软件确定pLN、nLN、LNR和LODDS的最佳截断值并将其转化为分类变量。将有区域淋巴结转移病人,根据AJCC第8版肿瘤TNM分期系统N分期及由X⁃tile软件计算5种分期标准的最佳截断值分别分为N1期和N2期。计算赤池信息量准则（AIC）、一致性指数（C⁃index）和1、3、5年受试者工作特征曲线下面积（AUC）比较不同分期标准的评估效能。
结果（1）PHCC病人预后影响因素分析。单因素分析结果显示：肿瘤分化程度、肿瘤长径、T分期、区域淋巴结转移是影响PHCC病人预后的相关因素（χ²=17.893,10.196,25.177,76.707,P<0.05）；多因素分析结果显示：肿瘤为低⁃未分化、T分期为pT3～pT4期、区域淋巴结转移是病人预后的独立危险因素（风险比=1.384,1.262,2.067,95%可信区间为1.145～1.673,1.032～1.543,1.698～2.515,P<0.05）。（2）PHCC病人随访及生存情况：669例病人均获得随访。病人肿瘤特异性生存时间为1～167个月,中位生存时间为26个月,1、3、5年肿瘤特异性生存率分别为76.5%、40.7%、32.1%。669例病人中,359例无区域淋巴结转移,其肿瘤特异性生存时间为1～167个月,中位生存时间为45个月,1、3、5年肿瘤特异性生存率分别为84.2%、54.1%、45.0%；310例有区域淋巴结转移,其肿瘤特异性生存时间为1～160个月,中位生存时间为17个月,1、3、5年肿瘤特异性生存率分别为67.3%、25.0%、16.7%。两者肿瘤特异性生存率比较,差异有统计学意义（χ²=76.707,P<0.05）。（3）5种淋巴结转移分期标准N1期和N2期病人预后比较：310例有区域淋巴结转移病人中,AJCC第8版N分期（N1期为1枚≤pLN≤3枚、N2期为pLN≥4枚）分别为228例和82例,1、3、5年肿瘤特异性生存率分别为69.0%、26.6%、18.1%和62.3%、20.1%、12.3%,两者比较,差异无统计学意义（χ²=2.294,P>0.05）。pLN分期（N1期为1枚≤pLN≤4枚、N2期为pLN≥5枚）分别为251例和59例,1、3、5年肿瘤特异性生存率分别为69.1%、27.1%、19.3%和59.2%、15.2%、3.8%,两者比较,差异有统计学意义（χ²=7.213,P<0.05）。nLN分期（N1期为nLN≥16枚、N2期nLN≤15枚）分别为70例和240例,1、3、5年肿瘤特异性生存率分别为73.9%、31.9%、22.2%和65.3%、22.9%、15.0%,两者比较,差异有统计学意义（χ²=4.805,P<0.05）。LNR分期（N1期为LNR≤0.32、N2期为LNR>0.32）分别为184例和126例,1、3、5年肿瘤特异性生存率分别为74.2%、29.7%、19.9和56.9%、18.0%、11.9%,两者比较,差异有统计学意义（χ²=9.273,P<0.05）。LODDS分期（N1期为LODDS≤-0.65、N2期为LODDS>-0.65）分别为185例和125例,1、3、5年肿瘤特异性生存率分别为74.3%、29.5%、18.4%和56.6%、19.8%、12.1%,两者比较,差异有统计学意义（χ²=9.584,P<0.05）。（4）5种淋巴结转移分期标准预测病人预后的准确性：根据AJCC第8版肿瘤TNM分期系统N分期、pLN、nLN、LNR、LODDS标准绘制PHCC病人术后1、3、5年肿瘤特异性生存率受试者工作特征曲线,其AUC分别为0.530、0.534、0.534、0.594、0.597,0.534、0.549、0.542、0.571、0.575,0.531、0.568、0.553、0.566、0.570。AIC分别为2 472.768、2 468.430、2 469.987、2 466.035、2 465.737。C⁃index分别为0.529、0.531、0.535、0.563、0.564。根据LODDS行淋巴结转移分期,病人1、3、5年肿瘤特异性生存率受试者工作特征曲线AUC值和C⁃index值最大,AIC值最小。
结论肿瘤为低⁃未分化、T分期为pT3～pT4期、区域淋巴结转移是PHCC病人预后的独立危险因素。采用LODDS分期标准绘制PHCC病人肿瘤特异性生存率受试者工作特征曲线AUC值和C⁃index值最大,AIC值最小。

Abstract:
Objective To investigate the application value of 5 different lymph node staging methods in predicting prognosis of perihilar cholangiocarcinoma(PHCC), including the pN stage of American Joint Committee on Cancer (AJCC) 8th edition TNM staging system, the number of positive lymph nodes(pLN), the number of negative lymph nodes(pLN), lymph node ratio(LNR), and log odds of metastatic lymph nodes(LODDS).
Methods The retrospective cohort study was conducted. The clinicopathological data of 669 PHCC patients from 2004 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database of America were collected. There were 406 males and 263 females, aged (66±11) years, with a range from 29 to 92 years. Observation indicators: (1) prognostic factor analysis of PHCC patients; (2) follow-up and survival of PHCC patients; (3) comparison of prognosis between patients in N1 stage and patients in N2 stage grouped by 5 different lymph node staging methods; (4) accuracy of 5 different lymph node staging methods in predicting prognosis of PHCC patients. Measurement data with normal distribution were represented as Mean±SD, and measurement data with skewed distribution were represented as M (range). Count data were described as absolute numbers and percentages. The Kaplan-Meier method was used to calculate survival rates and draw survival curves. The Log-rank test was used for univariate survival analysis. Multivariate survival analysis was performed using the COX proportional hazard model. X-tile 3.6.1 software was used to determine the optimal cut-off values of pLN, nLN, LNR and LODDS, and they were converted to categorical variables. Patients with regional lymph node metastasis were divided into patients in N1 stage and N2 stage based on pN stage of the AJCC 8th edition TNM staging system and optimal cut-off values of pLN, nLN, LNR and LODDS in X-tile software. Akaike information criterion (AIC), Harrell's Consistency Index (C-index) and 1-, 3-, 5-year area under receiver operating curve (AUROC) were calculated to compare prognostic performance of different staging methods.
Results (1) Prognostic factor analysis of PHCC patients: results of univariate analysis showed that tumor differentiation degree, tumor length, pT stage, regional lymph node metastasis were related factors for prognosis of PHCC patients (χ²=17.893, 10.196, 25.177, 76.707, P<0.05). Results of multivariate analysis showed that poorly differentiated or undifferentiated tumor, pT3-pT4 stage, regional lymph node metastasis were independent risk factors for prognosis of patients (hazard ratio=1.384, 1.262, 2.067, 95% confidence interval as 1.145-1.673, 1.032-1.543, 1.698-2.515, P<0.05). (2) Follow-up and survival of PHCC patients: all the 669 patients received the follow-up. In the cohort, the cancer-specific survival time was 1-167 months, with a median survival time of 26 months, and the 1-, 3-, 5-year cancer-specific survival rates were 76.5%, 40.7%, 32.1%, respectively. For 359 of the 669 patients without regional lymph node metastasis, the cancer-specific survival time was 1-167 months, with a median survival time of 45 months, and the 1-, 3-, 5-year cancer-specific survival rates were 84.2%, 54.1%, 45.0%, respectively. For 310 of the 669 patients with regional lymph node metastasis, the cancer-specific survival time was 1-160 months, with a median survival time of 17 months, and the 1-, 3-, 5-year cancer-specific survival rates were 67.3%, 25.0%, 16.7%, respectively. There was a significant difference in the cancer-specific survival rate between the two groups (χ²=76.707, P<0.05). (3) Comparison of prognosis between patients in N1 stage and patients in N2 stage grouped by 5 different lymph node staging methods: of the 310 patients with regional lymph node metastasis, according to the pN stage of AJCC 8th edition TNM staging system, 228 patients in N1 stage (1≤pLN≤3) had 1-, 3-, 5-year cancer-specific survival rates of 69.0%, 26.6%,18.1%, 82 patients in N2 stage (pLN≥4) had 1-, 3-, 5-year cancer-specific survival rates of 62.3%,20.1%, 12.3%, respectively, showing no significant difference between the two groups (χ²=2.294, P>0.05). According to the pLN, 251 patients in N1 stage (1≤pLN≤4) had 1-, 3-, 5-year cancer-specific survival rates of 69.1%, 27.1%, 19.3%, 59 patients in N2 stage (pLN≥5) had 1-, 3-, 5-year cancer-specific survival rates of 59.2%,15.2%,3.8%, respectively, showing a significant difference between the two groups (χ²=7.213, P<0.05). According to the nLN, 70 patients in N1 stage (nLN≥16) had 1-, 3-, 5-year cancer-specific survival rates of 73.9%, 31.9%, 22.2%, 240 patients in N2 stage (nLN≤15) had 1-, 3-, 5-year cancer-specific survival rates of 65.3%,22.9%,15.0%, respectively, showing a significant difference between the two groups (χ²=4.805, P<0.05). According to the LNR, 184 patients in N1 stage (LNR≤0.32) had 1-, 3-, 5-year cancer-specific survival rates of 74.2%, 29.7%,19.9%, 126 patients in N2 stage (LNR>0.32) had 1-, 3-, 5-year cancer-specific survival rates of 56.9%,18.0%,11.9%, respectively, showing a significant difference between the two groups (χ²=9.273, P<0.05). According to the LODDS, 185 patients in N1 stage (LODDS≤-0.65) had 1-, 3-, 5-year cancer-specific survival rates of 74.3%, 29.5%, 18.4%, 125 patients in N2 stage (LODDS>-0.65) had 1-, 3-, 5-year cancer-specific survival rates of 56.6%, 19.8%,12.1%, respectively, showing a significant difference between the two groups (χ²=9.584, P<0.05). (4) Accuracy of 5 different lymph node staging methods in predicting prognosis of PHCC patients: the AUROC for 1-year cancer-specific survival rates were 0.530, 0.534, 0.534, 0.594,0.597 based on the AJCC 8th edition pN stage, pLN, nLN, LNR, LODDS, the AUROC for 3-year cancer-specific survival rates were 0.534, 0.549, 0.542, 0.571,0.575, and the AUROC for 5-year cancer-specific survival rates were 0.531, 0.568, 0.553, 0.566, 0.570, respectively. The AIC values were 2 472.768, 2 468.430, 2 469.987, 2 466.035, 2 465.737, and the C-index were 0.529, 0.531, 0.535, 0.563, 0.564, respectievly. LODDS had the maximum AUROC for 1-, 3-, 5-year cancer-specific survival rates and C-index score but the minimum AIC value, showing the highest accuracy in predicting prognosis of PHCC patients.
Conclusion Poorly differentiated or undifferen-tiated tumor, pT3-pT4 stage, regional lymph node metastasis are independent risk factors for prognosis of patients. LODDS has the maximum AUROC for cancer-specific survival rates in PHCC patients and C-index score but the minimum AIC value.

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