馬 燕， 陳 艷， 安林靜， 曲建慧， 王春平， 楊永平

(北京大學(xué)解放軍三〇二醫(yī)院教學(xué)醫(yī)院 肝臟腫瘤診療與研究中心， 北京 100039)

論著/肝臟腫瘤

HBsAg陰性HBV相關(guān)肝細(xì)胞癌的臨床特點(diǎn)

馬 燕， 陳 艷， 安林靜， 曲建慧， 王春平， 楊永平

(北京大學(xué)解放軍三〇二醫(yī)院教學(xué)醫(yī)院 肝臟腫瘤診療與研究中心， 北京 100039)

目的 探討HBsAg陰性HBV相關(guān)肝細(xì)胞癌(HCC)臨床特點(diǎn)。方法 收集2005年1月-2012年1月于解放軍三○二醫(yī)院初診為HCC患者。根據(jù)HBV相關(guān)血清學(xué)標(biāo)志物的表現(xiàn)將患者分為HBsAg陰性HBV相關(guān)HCC組(HBsAg陰性組)和乙型肝炎相關(guān)HCC組(乙型肝炎組)?；仡櫺苑治鋈脒x患者初次診斷時(shí)的臨床數(shù)據(jù)，包括性別、年齡、HBV血清標(biāo)志物、TBil、Alb、AFP、HBV DNA、BMI、飲酒史、糖尿病史、治療方法以及隨訪結(jié)果。符合正態(tài)分布的計(jì)量資料2組間比較采用t檢驗(yàn)；不符合正態(tài)分布的計(jì)量資料2組間比較采用Wilcoxon秩和檢驗(yàn)；計(jì)數(shù)資料組間比較采用χ2檢驗(yàn)。生存曲線統(tǒng)計(jì)采用log-rank檢驗(yàn)，生存差異采用Kaplan-Meier檢驗(yàn)。結(jié)果 HBsAg陰性組患者的平均(59.42±11.13)歲、年齡>60歲比例(46.85%)、體質(zhì)量過輕比例(12.24%)、超重比例(20.98%)均明顯高于乙型肝炎組和總體患者，差異有統(tǒng)計(jì)學(xué)意義(P值均<0.01)。HBsAg陰性組患者男女比例(2.86∶1)、每年參加健康體檢定期篩查比例(10.41%)、HBV DNA陽性率(1.77%)、吸煙史、飲酒史比例均明顯低于總體患者和乙型肝炎組，差異有統(tǒng)計(jì)學(xué)意義(P值均<0.01)。HBsAg陰性組患者中以抗-HBs、抗-HBe和抗-HBc均為陽性的患者居多(64.08%)，抗-HBe和抗-HBc均為陽性次之(21.13%)，僅抗-HBc陽性者最少(14.79%)。HBsAg陰性組患者的AFP水平明顯低于總體患者和乙型肝炎組，差異有統(tǒng)計(jì)學(xué)意義(P=0.039)。且HBsAg陰性組患者初診時(shí)的多發(fā)病灶所占比例、腫瘤平均最大直徑以及腫瘤肝外轉(zhuǎn)移例數(shù)均明顯高于總體患者和乙型肝炎組，差異有統(tǒng)計(jì)學(xué)意義(P值均<0.001)。HBsAg陰性組患者初診時(shí)ECOG-PS評分為0者占17.69%，高于乙型肝炎組患者，且BCLC分期中早期(A、B)患者占30.26%，明顯低于乙型肝炎組(51.60%)，其晚期(C、D)患者例數(shù)是乙型肝炎組的1.83倍，差異有統(tǒng)計(jì)學(xué)意義(P值均<0.001)。HBsAg陰性組患者中位生存期15.22個(gè)月，低于總體患者(25.98個(gè)月)和乙型肝炎組(26.55個(gè)月)，差異有統(tǒng)計(jì)學(xué)意義(P=0.024、0.031)。預(yù)后方面，HBsAg陰性組的1、3年生存率(56.0%、24.0%)明顯低于總體患者(61.7%、45.2%)、乙型肝炎組患者(66.2%、44.1%)(χ2=4.93、6.87，P=0.026、0.009)。結(jié)論 HBsAg陰性HBV相關(guān)HCC多發(fā)生于抗-HBs、抗-HBe和抗-HBc均為陽性的60歲以上人群，建議將60歲以上的HBV感染后人群確立為HCC高危險(xiǎn)人群，推薦每6個(gè)月行HCC篩查，以提高HBsAg陰性HBV相關(guān)HCC的早期診斷率。

肝炎病毒, 乙型； 肝炎表面抗原， 乙型； 癌， 肝細(xì)胞； 疾病特征

肝細(xì)胞癌(HCC)是全球常見惡性腫瘤之一，其發(fā)生率逐年增高[1]，約占全球的55%，5年生存率差[2-3]。我國約90%HCC患者有HBV感染的背景，HBV高病毒載量[4]及C型HBV[5]感染被視為慢性乙型肝炎是否會進(jìn)展至HCC的主要預(yù)測因素[6]。在自然人群中將既往有急慢性乙型肝炎病史，且HBsAg陰性、抗-HBs陽性/陰性、抗-HBc 陽性、HBV DNA低于檢測下限、ALT水平在正常范圍者定義為乙型肝炎康復(fù)人群[7]。研究[8-10]發(fā)現(xiàn)該人群若干年后罹患HCC明顯高于正常人群，認(rèn)為HBV相關(guān)抗體與肝癌的發(fā)生相關(guān)。但關(guān)于HBsAg陰性HBV相關(guān)HCC的患病率及臨床特征鮮有深入研究，筆者就此進(jìn)行臨床分析。1 資料與方法

1.1 研究對象 收集本院肝臟腫瘤診療與研究中心2005年1月-2012年1月住院初診為HCC的患者。肝硬化診斷基于臨床特點(diǎn)及肝臟影像學(xué)特征、食道胃內(nèi)鏡特點(diǎn)和生化指標(biāo)與外周血常規(guī)。HCC的病因描述基于血清病毒抗原/抗體、自身免疫學(xué)抗體及酒精攝入史。參考2011年原發(fā)性肝癌診療規(guī)范[11]、2009年美國肝病學(xué)會原發(fā)性膽汁性肝硬化實(shí)踐指南[12]、2010年酒精性肝病診療指南[13]等診斷標(biāo)準(zhǔn)確定診斷，并排除其他部位腫瘤肝臟轉(zhuǎn)移及肝占位病變未確診為HCC病例，就病因及臨床特點(diǎn)進(jìn)行初步探討。1.2 研究方法 回顧性分析入選患者初次診斷時(shí)的臨床數(shù)據(jù)，包括性別、年齡、HBV血清標(biāo)志物、TBil、Alb、AFP、HBV DNA、BMI、飲酒史、糖尿病史和治療方法等。BMI>25 kg/m2定義為超重，BMI<18.5 kg/m2為偏瘦。AFP超過20 μg/L定義為陽性。采用BCLC分期系統(tǒng)進(jìn)行HCC分期、體力狀況評分(ECOG-PS)評價(jià)患者的體力活動(dòng)狀態(tài)、MELD評分系統(tǒng)評價(jià)嚴(yán)重程度?；颊叩拇婊顮顟B(tài)及死亡時(shí)間通過本中心肝癌患者隨訪系統(tǒng)獲得，生存時(shí)間的計(jì)算為首次治療日至死亡日(或最后隨訪截止日)。隨訪時(shí)間為2005年1月-2016年5月，隨訪率為70.9%。

2 結(jié)果

2.1 納入、分組情況 共納入患者5021例，其中乙型肝炎相關(guān)HCC患者4163例(82.91%)、HBsAg陰性HBV感染相關(guān)HCC患者286例(5.70%)，丙型肝炎相關(guān)HCC患者350例(6.97%)，HBV/HCV重疊感染相關(guān)HCC患者37例(0.74%)、原發(fā)性膽汁性肝硬化相關(guān)HCC患者10例(0.20%)，酒精性HCC患者59例(1.18%)，其他病因HCC患者116例(2.31%)。由于本研究中乙型肝炎相關(guān)HCC病例數(shù)遠(yuǎn)遠(yuǎn)大于HBsAg陰性HBV感染相關(guān)HCC樣本量，為避免樣本差異影響檢驗(yàn)效能，采用SPSS24.0軟件的SELECT CASES模塊從HBsAg陽性HCC患者中隨機(jī)抽樣500例。根據(jù)HBV相關(guān)血清學(xué)標(biāo)志物的表現(xiàn)將患者分為:(1)HBsAg陰性HBV相關(guān)HCC組(HBsAg陰性組),即HBsAg陰性、抗-HBc陽性，286例；(2)乙型肝炎相關(guān)HCC組(乙型肝炎組)，即HBsAg陽性，500例。2.2 臨床特點(diǎn) HBsAg陰性組患者的平均年齡、年齡>60歲比例、體質(zhì)量過輕比例、超重比例均明顯高于乙型肝炎組，差異有統(tǒng)計(jì)學(xué)意義(P值均<0.01)。HBsAg陰性組患者男女比例(2.86∶1)、每年參加健康體檢定期篩查比例、HBV DNA陽性率、吸煙史、飲酒史、HBV感染家族史比例均明顯低于乙型肝炎組，差異有統(tǒng)計(jì)學(xué)意義(P值均<0.01)。2組患者在糖尿病史和肝癌家族史方面的差異無統(tǒng)計(jì)學(xué)意義(P值均>0.05)(表1)。2.3 血清病毒學(xué)標(biāo)志物特點(diǎn) 乙型肝炎組患者中HBeAg陽性者占32.66%，HBeAg陰性者占67.34%；HBsAg陰性組患者中以抗-HBs、抗-HBe和抗-HBc均為陽性的患者居多(64.08%)，抗-HBe和抗-HBc均為陽性次之(21.13%)，僅抗-HBc陽性者最少(14.79%)。

2.4 腫瘤特性 HBsAg陰性組患者的AFP水平明顯低于乙型肝炎組，差異有統(tǒng)計(jì)學(xué)意義(P=0.039)。且HBsAg陰性組患者初診時(shí)以多發(fā)病灶所占比例、腫瘤平均最大直徑以及腫瘤肝外轉(zhuǎn)移例數(shù)均明顯高于乙型肝炎患者，差異有統(tǒng)計(jì)學(xué)意義(P值均<0.001)(表2)。

2.5 腫瘤評分、分期及預(yù)后 HBsAg陰性組患者初診時(shí)ECOG-PS評分為0者占17.69%，高于乙型肝炎組患者，且BCLC分期中早期(A、B)患者占30.26%，明顯低于乙型肝炎組(51.60%)，其晚期(C、D)患者例數(shù)是乙型肝炎組的1.83倍，差異有統(tǒng)計(jì)學(xué)意義(P值均<0.001)(表3)。MELD評分結(jié)果顯示乙型肝炎組和HBsAg陰性組的生存率差異無統(tǒng)計(jì)學(xué)意義。HBsAg陰性組患者中位生存期15.22個(gè)月，乙型肝炎組26.55個(gè)月，差異有統(tǒng)計(jì)學(xué)意義(P=0.031)；預(yù)后方面，HBsAg陰性組的1、3年生存率(56.0%、24.0%)明顯低于乙型肝炎組(66.2%、44.1%)(χ2值分別為4.93、6.87，P值分別為0.026、0.009)(圖1)。

表1 患者臨床特征比較

注：因部分患者臨床數(shù)據(jù)缺失，故各項(xiàng)目間總例數(shù)存在差異

圖1 HCC患者生存曲線

3 討論

近年HCC的發(fā)病率呈持續(xù)上升趨勢，Schutte等[14]研究結(jié)果提示HBV感染與HCC的發(fā)生發(fā)展密切相關(guān)，認(rèn)為HBV感染是HCC發(fā)生的獨(dú)立影響因素。目前，關(guān)于HBsAg陰性HBV感染者發(fā)生HCC的臨床特點(diǎn)相關(guān)研究較少，本研究通過對5021例初診HCC患者的臨床資料進(jìn)行分析發(fā)現(xiàn)，HBsAg陰性HBV相關(guān)HCC患者具有獨(dú)特的臨床特點(diǎn)，對該群體患者的HCC防治具有重要的指導(dǎo)意義。

表2 2組患者實(shí)驗(yàn)室檢查及腫瘤相關(guān)指標(biāo)比較

表3 2組患者腫瘤評分和分期比較

本研究中，HBsAg陰性HBV相關(guān)HCC患者在整體HCC患者構(gòu)成中占5.7%，僅次于乙型肝炎相關(guān)性HCC和丙型肝炎相關(guān)性HCC，明顯高于酒精性、脂肪肝性和代謝性疾病相關(guān)性HCC，提示在HBV感染高發(fā)地區(qū)應(yīng)重視HBsAg陰性HBV感染患者的HCC防治。研究結(jié)果顯示該人群發(fā)生HCC的平均年齡為59.42歲，高于乙型肝炎相關(guān)性HCC患者的平均年齡；64.08%的HBV感染相關(guān)HCC患者的抗-HBs、抗-HBe和抗-HBc均為陽性，男女比例為2.86∶1，低于吳孟超等[15]報(bào)道的7∶1與Shariff等[16]指出的5∶1，提示HBV感染被人體清除后，HBsAg陰性人群的HCC發(fā)生風(fēng)險(xiǎn)與雄激素等誘發(fā)肝癌因素的關(guān)聯(lián)性降低。在HBsAg陰性HBV相關(guān)HCC患者中肥胖患者占20.98%，因此認(rèn)為肥胖可能是發(fā)生HCC的促進(jìn)因素。

初診HCC時(shí)，早期HCC患者比例明顯低于乙型肝炎相關(guān)性HCC患者，且晚期HCC患者較多(43.17%)，肝外轉(zhuǎn)移的患者高達(dá)30.28%，腫瘤平均直徑較大，主要源于HBsAg陰性HBV感染后人群定期健康體檢者比例明顯低于慢性乙型肝炎患者(10.4% vs 63.60%)，錯(cuò)過早期發(fā)現(xiàn)的機(jī)會，確診時(shí)有條件接受根治性治療(肝癌切除術(shù)、肝移植)的患者較少，導(dǎo)致該群體的平均生存期較短，1、3年的生存率較低，預(yù)后較差。

綜上所述，HBsAg陰性HBV相關(guān)HCC多發(fā)生于抗-HBs、抗-HBe和抗-HBc均為陽性的60歲以上人群，在總體HCC患者構(gòu)成中僅次于慢性HBV、HCV感染者。該群體定期篩查HCC較少，早期診斷率低，接受根治性治療的機(jī)會少，預(yù)后差。建議將60歲以上的HBsAg陰性HBV感染后人群定義為HCC的高危險(xiǎn)人群，每6個(gè)月定期篩查HCC，以提高早期診斷率，對延長該群體患者的中位生存期具有重要意義。

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引證本文：MA Y, CHEN Y, AN LJ, et al. Clinical features of HBsAg-negative HBV-related hepatocellular carcinoma[J]. J Clin Hepatol, 2017, 33(4): 674-678. (in Chinese) 馬燕， 陳艷， 安林靜， 等. HBsAg陰性HBV相關(guān)肝細(xì)胞癌的臨床特點(diǎn)[J]. 臨床肝膽病雜志, 2017, 33(4): 674-678.

(本文編輯：邢翔宇)

Clinical features of HBsAg-negative HBV-related hepatocellular carcinoma

MAYan,CHENYan,ANLinjing,etal.

(LiverCancerTreatmentandResearchCenter,TeachingHospitalof302HospitalofPLA,PekingUniversity,Beijing100039,China)

Objective To investigate the clinical features of HBsAg-negative HBV-related hepatocellular carcinoma (HCC). MethodsThe patients who were newly diagnosed with HCC from January 2005 to January 2012 were enrolled. According to the HBV-related serological markers, the patients were divided into HBsAg-negative HBV-related HCC group and hepatitis B-related HCC group. A retrospective analysis was performed for the clinical and laboratory examination data at initial diagnosis, including sex, age, hepatitis B virus markers, total bilirubin (TBil), albumin (Alb), alpha-fetoprotein (AFP), HBV DNA, body mass index (BMI), drinking history, history of diabetes, therapies, and follow-up results. Thet-test was used for comparison of normally distributed continuous data between groups; the non-normally distributed data were expressed as median and interquartile range (Q1 and Q3), and the Wilcoxon rank sum test was used for comparison of non-normally distributed continuous data between groups; the chi-square test or Fisher′s exact test were used for comparison of categorical data. The log-rank test was used to compare survival curves between the two groups, and the Kaplan-Meier method was used to calculate survival rates. Results Compared with the hepatitis B group and all patients, the HBsAg-negative group had a significantly higher mean age (59.42±11.13 years) and significantly higher proportions of patients with age >60 years (46.85%), low body weight (12.24%), and overweight (20.98%)(allP<0.01). Compared with all patients and the hepatitis B group, the HBsAg-negative group had a significantly lower male-to-female ratio (2.86∶1), a significantly lower proportion of patients regularly undergoing physical examination every year (10.41%), a significantly lower HBV DNA positive rate (1.77%), and significantly lower proportions of patients with smoking and drinking histories (allP<0.01). Of all patients in the HBsAg-negative group, 64.08% had positive anti-HBs, anti-HBe, and anti-HBc, 21.13% had positive anti-HBe and anti-HBc, and 14.79% only had positive anti-HBc. The HBsAg-negative group had a significantly lower AFP level than all patients and the hepatitis B group (P=0.039). Compared with the hepatitis B group and all patients, the HBsAg-negative group had a significantly higher proportion of multiple lesions, a significantly greater mean maximum tumor diameter, and a significantly higher number of patients with extrahepatic metastasis (allP<0.001). Compared with the hepatitis B group, the HBsAg-negative group had a higher proportion of patients with an Eastern Cooperative Oncology Group Performance Status score of 0 at initial diagnosis (17.69%) and a lower proportion of patients with early-to-medium Barcelona Clinic Liver Cancer stage (stages A and B) (30.26% vs 51.60%,P<0.001); the number of patients with stages C and D in the HBsAg-negative group was 1.83 times that in the hepatitis B group (P<0.001). The HBsAg-negative group had a significantly lower median survival time (15.22 months) than all patients and the hepatitis B group (P=0.024、0.031). Compared with all patients and the hepatitis B group, the HBsAg negative group had significantly lower 1- and 3-year survival rates (1-year survival rate: 56.0% vs 61.7% and 66.2%,χ2=4.93,P=0.026; 3-year survival rate: 24.0% vs 45.2% and 44.1%,χ2=6.867,P=0.009). Conclusion HBsAg-negative HBV-related HCC is commonly seen in patients aged >60 years with positive anti-HBs, anti-HBe, and anti-HBc. The population aged >60 years with HBV infection should be the high-risk population for HCC, and it is recommended to perform HCC screening every 6 months to increase the early diagnostic rate of HBsAg-negative HBV- related HCC.

hepatitis B virus； hepatitis B surface antigens； carcinoma, hepatocellular； disease attributes

10.3969/j.issn.1001-5256.2017.04.015

2016-11-24；

2016-12-21。

全軍醫(yī)學(xué)科技“十二五”科研重點(diǎn)項(xiàng)目(BWS11J074)；國家自然基金課題(81272330)

馬燕(1988-)，女，主要從事肝臟腫瘤治療方面的研究。

楊永平，電子信箱：yongpingyang@hotmail.com。

R512.62； R735.7

A

1001-5256(2017)04-0674-05