肝细胞癌组织HepPar-1表达临床意义倾向评分匹配研究
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摘要
目的肝细胞抗原(hepatocyte paraffin,Hep Par-1)是肝细胞癌(hepatocellular carcinoma,HCC)诊断最常用的免疫组化标志物,但其表达情况对预后的影响尚罕见报道。本研究旨在探讨Hep Par-1不同表达HCC患者的临床病理学特征差异及其对预后的影响。方法收集2009-12-01—2010-03-31东方肝胆外科医院收治的582例肝切除术治疗的HCC患者的临床病理资料,无瘤生存期和总生存期用于进行生存分析,并采用倾向评分匹配平衡组间差异。结果 HCC患者中Hep Par-1阴性率为14.4%(84/582)。Hep Par-1阴性HCC患者的5年无瘤生存率(25.2%)和5年总生存率(41.1%)均低于Hep Par-1阳性患者的34.1%和54.5%,P值分别为0.016和0.002。在倾向评分匹配队列中结果相似,5年无瘤生存率分别为25.2%和36.9%,5年总生存率分别为41.1%和51.6%,P值分别为0.041和0.046。总研究队列多因素分析显示,甲胎蛋白>400ng/mL、乙肝表面抗原阳性、肝门阻断、肿瘤直径>2cm、肿瘤无包膜以及Hep Par-1阴性是无瘤生存期的独立风险因素。丙氨酸氨基转移酶≥40U/L、甲胎蛋白>400ng/mL、Child Pugh肝功能分级B级、肿瘤直径>2cm、肿瘤多发、肿瘤无包膜、Hep Par-1阴性是总生存期的独立风险因素。倾向评分匹配研究队列多因素分析显示,乙肝表面抗原阳性、肿瘤无包膜、Hep Par-1阴性是无瘤生存期的相关风险因素;门冬氨酸转氨酶≥40U/L、甲胎蛋白>400ng/mL、Hep Par-1阴性是总生存期的相关风险因素。结论 Hep Par-1阴性HCC是一种新的临床病理学分型,其肿瘤生物学行为恶性程度高,临床预后差,Hep Par-1有潜力成为HCC个体化治疗的新分子靶点。
OBJECTIVE AIM Hepatocyte paraffin(Hep Par-1)is the most commonly used immunohistochemical marker for the diagnosis of hepatocellular carcinoma(HCC),but the effect of its expression on prognosis has not been reported.The purpose of this study was to explore the difference of clinicopathological features and the effect on survival prognosis of HCC patients with different expression of Hep Par-1.METHODS A retrospective cohort of 582 HCC patients from Dec.2009 to Mar.2010 in Eastern Hepatobiliary Surgery Hospital was performed on the surgicopathologic features in this study.The Disease-free survival(DFS)and overall survival(OS)were compared.Propensity score matching(PSM)was used to overcome potential confounding factors between two groups.RESULTS Hep Par-1 negative patients accounted for 14.4%(n=84)of total HCCs.Compared to patients with Hep Par-1 positive,patients with Hep Par-1 negative had significantly lower DFS and OS.Similar results were(5-year DFS rate 25.2%and 34.1%,P=0.016;5-year OS rate 41.1% and 54.5%,P=0.002)obtained in the PSM cohort(5-year DFS rate 25.2% and 36.9%,P=0.041;5-year OS rate 41.1% and 51.6%,P =0.046).Multivariate Cox regression analyses identified that AFP>400 ng/mL,HBsAg positive,portal trad clamping,tumor diameter>2 cm,without capsule and Hep Par-1 negative were risk factors for DFS;AST≥40 U/L,AFP>400 ng/mL,Child Pugh classification grade B,diameter>2 cm,multiple tumors,without capsule and Hep Par-1 negative were risk factors for OS.In PSM cohort,multivariable Cox regression performed that HBsAg positive,without capsule and Hep Par-1 negative were independent risk factor of DFS.AST >40 U/L,AFP >400 ng/mL and Hep Par-1 were independent risk factor of OS.CONCLUSIONS Hep Par-1 negative HCC is a novel pathological entity that has a highly aggressive behavior and worse postoperative prognosis.The expression of Hep Par-1 should be emphasized,and it has the potential to be a new molecular target for the individualized treatment of HCC.
OBJECTIVE AIM Hepatocyte paraffin(Hep Par-1)is the most commonly used immunohistochemical marker for the diagnosis of hepatocellular carcinoma(HCC),but the effect of its expression on prognosis has not been reported.The purpose of this study was to explore the difference of clinicopathological features and the effect on survival prognosis of HCC patients with different expression of Hep Par-1.METHODS A retrospective cohort of 582 HCC patients from Dec.2009 to Mar.2010 in Eastern Hepatobiliary Surgery Hospital was performed on the surgicopathologic features in this study.The Disease-free survival(DFS)and overall survival(OS)were compared.Propensity score matching(PSM)was used to overcome potential confounding factors between two groups.RESULTS Hep Par-1 negative patients accounted for 14.4%(n=84)of total HCCs.Compared to patients with Hep Par-1 positive,patients with Hep Par-1 negative had significantly lower DFS and OS.Similar results were(5-year DFS rate 25.2%and 34.1%,P=0.016;5-year OS rate 41.1% and 54.5%,P=0.002)obtained in the PSM cohort(5-year DFS rate 25.2% and 36.9%,P=0.041;5-year OS rate 41.1% and 51.6%,P =0.046).Multivariate Cox regression analyses identified that AFP>400 ng/mL,HBsAg positive,portal trad clamping,tumor diameter>2 cm,without capsule and Hep Par-1 negative were risk factors for DFS;AST≥40 U/L,AFP>400 ng/mL,Child Pugh classification grade B,diameter>2 cm,multiple tumors,without capsule and Hep Par-1 negative were risk factors for OS.In PSM cohort,multivariable Cox regression performed that HBsAg positive,without capsule and Hep Par-1 negative were independent risk factor of DFS.AST >40 U/L,AFP >400 ng/mL and Hep Par-1 were independent risk factor of OS.CONCLUSIONS Hep Par-1 negative HCC is a novel pathological entity that has a highly aggressive behavior and worse postoperative prognosis.The expression of Hep Par-1 should be emphasized,and it has the potential to be a new molecular target for the individualized treatment of HCC.
引文
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[14]Shen J,Liu J,Li C,et al.The impact of tumor differentiation on the prognosis of HBV-associated solitary hepatocellular carcinoma following hepatectomy:A propensity score matching analysis[J].Dig Dis Sci,2018,63(7):1962-1969.
[15]Sia D,Villanueva A,Friedman SL,et al.Liver cancer cell of origin,molecular class,and effects on ptient prognosis[J].Gastroenterology,2017,152(4):745-761.
[2]Islami F,Miller KD,Siegel RL,et al.Disparities in liver cancer occurrence in the United States by race/ethnicity and state[J].CA Cancer J Clin,2017,67(4):273-289.
[3]Choi WT,Kakar S.Immunohistochemistry in the diagnosis of hepatocellular carcinoma[J].Gastroenterol Clin North Am,2017,46(2):311-325.
[4]Cong WM,Bu H,Chen J,et al.Practice guidelines for the pathological diagnosis of primary liver cancer:2015update[J].World JGastroenterol,2016,22(42):9279-9287.
[5]Forner A,Reig M,Bruix J.Hepatocellular carcinoma[J].Lancet,2018,391(10127):1301-1314.
[6]Lin DC,Mayakonda A,Dinh HQ,et al.Genomic and epigenomic heterogeneity of hepatocellular carcinoma[J].Cancer Res,2017,77(9):2255-2265.
[7]Cong WM,Wu MC.New insights into molecular diagnostic pathology of primary liver cancer:Advances and challenges[J].Cancer Lett,2015,368(1):14-19.
[8]Fu SJ,Qi CY,Xiao WK,et al.Glypican-3is a potential prognostic biomarker for hepatocellular carcinoma after curative resection[J].Surgery,2013,154(3):536-544.
[9]Lu XY,Xi T,Lau WY,et al.Hepatocellular carcinoma expressing cholangiocyte phenotype is a novel subtype with highly aggressive behavior[J].Ann Surg Oncol,2011,18(8):2210-2217.
[10]Torbenson MS.Morphologic Subtypes of Hepatocellular Carcinoma[J].Gastroenterol Clin North Am,2017,46(2):365-391.
[11]Hanif R,Mansoor S.Hep par-1:a novel immunohistochemical marker for differentiating hepatocellular carcinoma from metastatic carcinoma[J].J Coll Physicians Surg Pak,2014,24(3):186-189.
[12]李桂梅,侯宁,杨志慧,等.glypican-3、HepPar1和CD34在肝细胞癌中的表达及临床意义[J].诊断病理学杂志,2015,22(2):95-98.
[13]Mondada D,Bosman FT,Fontolliet C,et al.Elevated hepatocyte paraffin 1and neprilysin expression in hepatocellular carcinoma are correlated with longer survival[J].Virchows Arch,2006,448(1):35-45.
[14]Shen J,Liu J,Li C,et al.The impact of tumor differentiation on the prognosis of HBV-associated solitary hepatocellular carcinoma following hepatectomy:A propensity score matching analysis[J].Dig Dis Sci,2018,63(7):1962-1969.
[15]Sia D,Villanueva A,Friedman SL,et al.Liver cancer cell of origin,molecular class,and effects on ptient prognosis[J].Gastroenterology,2017,152(4):745-761.