Antitumor Effect of Resveratrol: Mechanism and Research Progress
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摘要: 白藜芦醇是一种天然的多酚类化合物,广泛存在于葡萄、苹果、蓝莓、李子和花生等多种植物中,因其具有抗氧化、抗炎、抗病毒、神经保护、心脏保护、免疫调节和抗肿瘤等多种生物学功能被广泛研究。本综述分析白藜芦醇的多效抗肿瘤作用,包括抑制肿瘤细胞增殖与转移、促进肿瘤细胞自噬、改善肿瘤微环境、降低肿瘤细胞耐药性、诱导表观遗传修饰等,并对其在结直肠癌、乳腺癌、肺癌、宫颈癌、前列腺癌、口腔癌等肿瘤中的研究进展进行了总结。凭借其广泛的抗肿瘤活性,白藜芦醇有望成为潜在的肿瘤预防和治疗药物。Abstract: Resveratrol, a natural polyphenolic compound widely found in a variety of plants such as grapes, apples, blueberries, plums and peanuts, has been widely studied for its multiple biological functions such as its antioxidant, anti-inflammatory, antiviral, neuroprotective, cardioprotective, immunomodulatory and antitumor effects. This review aims to analyze the pleiotropic antitumor effects of resveratrol, including inhibition of tumor cell proliferation and metastasis, promotion of tumor cell autophagy, improvement of the tumor microenvironment, reduction of tumor cell resistance, and induction of epigenetic modifications. The research progress of resveratrol in colorectal, breast, lung, cervical, prostate, and oral cancers is also summarized. With its wide range of anti-tumor activities, resveratrol is expected to be a potential drug for tumor prevention and treatment.
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Keywords:
- Resveratrol /
- Polyphenolic compounds /
- Antitumor effects /
- Tumor prevention /
- Tumor therapy
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宫颈脱落细胞学诞生于20世纪40年代,为降低宫颈癌发病率作出了巨大贡献。随着对该检查技术认识的不断深入,假阴性问题越来越受到关注,加之我国在细胞学领域起步晚,细胞学医师和技师均严重不足,我国大部分地区细胞学判读无法满足宫颈癌筛查的需求。因此,提高制片质量和阅片水平,进而实现计算机辅助阅片或自动阅片成为细胞学领域追求的目标。近年来,借助人工智能技术,计算机辅助阅片助力宫颈癌筛查的研究越来越深入,且应用更加广泛[1-4],2014年版TBS (the Bethesda system)明确规定,计算机辅助阅片系统可用于宫颈脱落细胞学,并对其临床应用进行了规定[5]。2017年12月,北京协和医院开始使用美国食品药品监督管理局(Food and Drug Administration, FDA)认证的ThinPrep玻片扫描分析影像系统(ThinPrep Imaging System, TIS)进行临床阅片,本研究通过将TIS辅助阅片与人工阅片进行对比分析,探讨TIS辅助阅片在宫颈细胞学中的应用价值,为未来研发更先进的自动化阅片工具提供循证医学证据。
1. 材料与方法
1.1 样本来源
本研究为回顾性分析。宫颈液基细胞学(liquid-based cytology, LBC)样本来自于中国医学科学院北京协和医院妇产科行机会性筛查的门诊患者,比较2016年12月至2017年5月LBC样本的人工阅片结果和2017年12月至2018年5月LBC样本的TIS辅助阅片结果。人工阅片纳入标准:临床取样满意(LBC鳞状上皮细胞数量≥5000个);TIS辅助阅片纳入标准:临床取样满意且TIS辅助阅片成功。对细胞学异常患者进行组织学随访,随访数据来自北京协和医院病理科,随访时间截至2019年5月。
本研究已通过北京协和医院伦理审查委员会批准(审批号:S-K1604),并豁免患者知情同意。
1.2 仪器
LBC制片仪(ThinPrep 2000)由美国Hologic公司生产;高危型人乳头瘤病毒(high risk-human papillomavirus, Hr-HPV)检测仪(Cobas 4800)为美国罗氏公司产品;TIS由美国Hologic公司生产,软件版本号为3.2,分别通过美国FDA、国家药品监督管理局(National Medical Products Administration, NMPA)的认证,为二类医疗器械。
1.3 LBC阅片及判读标准
1.3.1 TIS辅助阅片
系统自动扫描玻片,使用智能化光学细胞选取算法识别每张玻片最可疑的22个目标视野(field of view, FOV),将相应视野的坐标值存储入数据库,自动化显微镜根据坐标值定位的22个FOV呈现给医生判读。若22个FOV均正常,则该玻片可判读为正常结果;若医生发现有异常细胞,需要阅读整张玻片给出判读结果。
1.3.2 人工阅片
人工阅片由两名有经验的细胞学医生共同完成。LBC玻片制片完成后,按照传统阅片流程将玻片放置光学显微镜下进行阅片,每张玻片阅片时间不少于3 min。
1.3.3 LBC判读标准
LBC判读标准采用2014年国际癌症协会推荐的新TBS报告系统[5]。判读结果包括:(1)未见上皮内病变细胞或恶性细胞(negative for intraepithelial lesion or malignancy, NILM);(2)非典型鳞状上皮细胞(atypical squamous cell, ASC),包括不能明确意义的非典型鳞状上皮细胞(atypical squamous cells of undetermined significance, ASC-US)和不除外高度鳞状上皮内病变的非典型鳞状上皮细胞(atypical squamous cell cannot exclude high-grade squamous intraepithelial lesion,ASC-H);(3)低度鳞状上皮内病变(low-grade squamous intraepithelial lesion, LSIL);(4) 高度鳞状上皮内病变(high-grade squamous intraepithelial lesion, HSIL);(5)鳞状细胞癌(squamous-cell carcinoma, SCC);(6)不典型腺细胞(atypical glandular cells,AGC);(7)腺癌(adenocarcinoma, AC)。除NILM外均归为细胞学异常,分为鳞状上皮细胞异常(ASC-US、ASC-H、LSIL、HSIL、SCC)和腺细胞异常(AGC和AC)。
以鳞状上皮细胞异常患者的Hr-HPV阳性率和ASC/SIL用于评价细胞学阅片质控,ASC/SIL=(ASC-US+ASC-H)/(LSIL+HSIL)。
1.4 宫颈组织学病理诊断
细胞学异常患者行宫颈组织学活检,组织学病理诊断结果均由病理科医师给出。按照组织病理学结果分为正常、凹空细胞/宫颈上皮内瘤变Ⅰ级(cervical intraepithelial neoplasm grade Ⅰ, CIN Ⅰ)、CIN Ⅱ、CIN Ⅲ、SCC、不典型子宫内膜增生(endometrial intraepithelial neoplasia,EIN)、原位腺癌(adenocarcinoma in situ,AIS)和AC。本研究设定组织学异常标准为凹空细胞/ CIN Ⅰ(因细胞学判读为HPV感染引起的凹空细胞病例可定为LSIL,故将病理诊断为凹空细胞的病例与CIN Ⅰ划分为同一病理级别)、CIN Ⅱ、CIN Ⅲ、SCC、EIN、AIS、AC。为与组织学的诊断术语相对应,TBS报告系统中LSIL对应于组织学诊断凹空细胞/CIN Ⅰ,细胞学HSIL相对应的组织学诊断为CIN Ⅱ/ Ⅲ。
1.5 统计学处理
采用SPSS 25.0软件进行统计学分析。细胞学及组织病理学结果等计数资料以频数或百分数表示,组间比较采用卡方检验。以P<0.05为差异具有统计学意义。
2. 结果
2.1 TIS辅助阅片与人工阅片结果比较
TIS辅助阅片共计16 564例,细胞学阳性总检出率为15.21%;人工阅片共计17 407例,细胞学阳性总检出率为9.58%,TIS辅助阅片检出率增长了58.77%,差异具有统计学意义(P<0.001)。其中ASC-US、ASC-H、LSIL和HSIL检出率分别提高了2.77%、0.28%、2.08%和0.35%,AGC和AC检出率均提高了0.08%,差异均具有统计学意义(P均<0.05),见表 1。
表 1 两种阅片方式细胞学异常检出结果比较[n(%)]阅片方法 总检出 ASC-US ASC-H LSIL HSIL SCC AGC AC TIS辅助阅片(n=16 564) 2520(15.21) 1396(8.43) 68(0.41) 813(4.91) 184(1.11) 6(0.04) 34(0.21) 19(0.11) 人工阅片(n=17 407) 1668(9.58) 986(5.66) 22(0.13) 493(2.83) 132(0.76) 7(0.04) 22(0.13) 6(0.03) χ2 249.029 99.414 25.934 98.956 11.446 0.035 5.033 7.431 P值 <0.001 <0.001 <0.001 <0.001 0.001 0.851 0.025 0.006 TIS:ThinPrep玻片扫描分析影像系统;ASC-US:不能明确意义的非典型鳞状上皮细胞;ASC-H:不除外高度鳞状上皮内病变的非典型鳞状上皮细胞;LSIL:低度鳞状上皮内病变;HSIL:高度鳞状上皮内病变;SCC:鳞状细胞癌;AGC:不典型腺细胞;AC:腺癌 2.2 细胞学与组织学结果比较
截至2019年5月,共1008例细胞学异常患者追溯到组织学随访结果,其中人工阅片383例,TIS辅助阅片625例。结果显示,LBC判读为ASC-US的患者中,TIS辅助阅片组织学诊断为CIN Ⅰ的比例高于人工阅片(51.58%比47.06%), 组织学诊断为CIN Ⅱ/ Ⅲ的比例低于人工阅片(15.09% 比21.85%)。
LBC判读为SCC的患者中,TIS辅助阅片和人工阅片对应组织学SCC的符合率均为100%。TIS辅助阅片腺细胞异常患者53例,是人工阅片(28例)的1.89倍。TIS辅助阅片AGC检出率为0.21%,其中22例追溯到组织学结果:1例AIS(4.55%),1例EIN(4.55%)、7例子宫内膜癌(31.82%),AGC随访患病率为40.91%;人工阅片的AGC检出率为0.13%,11例追溯到组织学结果:1例AIS(9.09%),3例子宫内膜癌(27.27%),AGC随访患病率为36.36%。TIS辅助阅片细胞学判读为AC的患者19例,检出率为0.11%,15例追溯到组织学结果:2例宫颈腺癌(13.33%),8例子宫内膜癌(53.33%),4例卵巢癌(26.67%),1例结肠癌转移(6.67%),组织学符合率为100%;人工阅片细胞学为AC的患者6例,检出率为0.03%,5例追溯到组织学结果:3例子宫内膜癌(60.00%),2例透明细胞癌(输卵管来源),组织学符合率100%。TIS辅助阅片经组织学证实为AC的数量是人工阅片的2.3倍(37例比16例),见表 2,3。
表 2 两种阅片方式细胞学与组织学结果比较[n(%)]细胞学结果 阅片方式 组织学结果 阴性 凹空细胞/CIN Ⅰ CIN Ⅱ/Ⅲ SCC EIN AIS AC ASC-US TIS辅助阅片(n=285) 94(32.98) 147(51.58) 43(15.09) 0(0) 0(0) 0(0) 1(3.51) 人工阅片(n=119) 35(29.41) 56(47.06) 26(21.85) 1(0.84) 0(0) 0(0) 1(0.84) LSIL TIS辅助阅片(n=214) 19(17.29) 133(62.15) 22(20.56) 0(0) 0(0) 0(0) 0(0) 人工阅片(n=156) 32(20.51) 85(54.49) 38(24.36) 1(0.64) 0(0) 0(0) 0(0) ASC-H TIS辅助阅片(n=22) 5(22.73) 9(40.91) 8(36.36) 0(0) 0(0) 0(0) 0(0) 人工阅片(n=12) 2(16.67) 5(41.67) 4(33.33) 1(8.33) 0(0) 0(0) 0(0) HSIL TIS辅助阅片(n=63) 5(7.94) 7(11.11) 48(76.19) 3(4.76) 0(0) 0(0) 0(0) 人工阅片(n=76) 6(7.89) 14(18.42) 50(65.79) 6(7.89) 0(0) 0(0) 0(0) SCC TIS辅助阅片(n=4) 0(0) 0(0) 0(0) 4(100) 0(0) 0(0) 0(0) 人工阅片(n=4) 0(0) 0(0) 0(0) 4(100) 0(0) 0(0) 0(0) AGC TIS辅助阅片(n=22) 8(36.36) 3(13.64) 1(4.55) 1(4.55) 1(4.55) 1(4.55) 7(31.82) 人工阅片(n=11) 6(54.55) 1(9.09) 0(0) 0(0) 0(0) 1(9.09) 3(27.27) AC TIS辅助阅片(n=15) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 15(100) 人工阅片(n=5) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 5(100) CIN:宫颈上皮内瘤变;EIN:不典型子宫内膜增生;AIS:原位腺癌;TIS、ASC-US、LSIL、ASC-H、HSIL、SCC、AGC、AC:同表 1 表 3 两种阅片方式异常腺细胞的组织来源比较[n(%)]异常腺细胞 阅片方式 组织来源 阳性符合 子宫颈 子宫内膜 输卵管 卵巢 转移性直肠癌 AGC TIS辅助阅片(n=22) 1(4.55) 8(36.36) 0(0) 0(0) 0(0) 9(40.91) 人工阅片(n=11) 1(9.09) 3(27.27) 0(0) 0(0) 0(0) 4(36.36) AC TIS辅助阅片(n=15) 2(13.33) 8(53.33) 0(0) 4(26.67) 1(6.67) 15(100) 人工阅片(n=5) 0(0) 3(60.00) 2(40.00) 0(0) 0(0) 5(100) 合计 TIS辅助阅片(n=37) 3(8.1) 16(43.24) 0(0) 4(10.81) 1(2.7) 24(64.86) 人工阅片(n=16) 1(6.25) 6(37.5) 2(12.5) 0(0) 0(0) 9(56.25) TIS、AGC、AC:同表 1 2.3 鳞状上皮细胞异常患者的Hr-HPV检测结果及ASC/SIL比值
TIS辅助阅片16 564例,LBC判读结果阳性患者为2520例,其中2333例鳞状上皮细胞异常患者可随访到Hr-HPV检查结果。人工阅片17 407例,LBC结果阳性患者为1668例,其中1026例鳞状上皮细胞异常患者可随访到Hr-HPV检查结果。TIS辅助阅片和人工阅片ASC-US、ASC-H、LSIL、HSIL、SCC的Hr-HPV阳性率均无显著性差异(P均>0.05),见表 4。TIS辅助阅片和人工阅片的ASC/SIL比值亦无统计学差异(1.47比1.61,P=0.152)。
表 4 鳞状上皮细胞异常患者Hr-HPV阳性率[%(n/N)]阅片方式 ASC-US ASC-H LSIL HSIL SCC TIS辅助阅片(N=2333) 87.00(1144/1315) 92.06(58/63) 91.99(712/774) 99.34(150/151) 100(30/30) 人工阅片(N=1026) 89.57(567/633) 100(17/17) 93.71(283/302) 96.97(64/66) 100(8/8) χ2 2.656 1.439 0.922 1.889 0.935 P值 0.103 0.579 0.337 0.220 0.576 Hr-HPV:高危型人乳头瘤病毒;TIS、ASC-US、ASC-H、LSIL、HSIL、SCC、AGC、AC:同表 1 2.4 两种阅片方式工作效率比较
TIS辅助阅片平均每张用时1.5~2 min,人工阅片平均每张用时3 min,TIS辅助阅片时间减少了33%~50%,工作效率显著提升。
3. 讨论
本研究通过比较宫颈LBC标本的两种阅片方式,结果发现除SCC外,TIS辅助阅片对不同级别异常细胞学检出率均明显高于人工阅片,阳性总检出率提升58.77%(15.21% 比9.58%)。细胞学结果与组织学结果对比分析发现,TIS辅助阅片与人工阅片的组织学符合率无显著性差异。
细胞学阳性报告率是实验室判读质控标准之一,本研究中TIS辅助阅片HSIL、LSIL、ASC-US的报告率分别为1.11%、4.91%、8.43%,均高于2006年美国病理学家协会(College of American Pathologists, CAP)公布的细胞学阳性报告率的中位数[HSIL(0.6%)、LSIL(3%)、ASC-US(4.9%)],说明使用TIS后,异常细胞的识别能力显著增强。ASC-US是宫颈异常细胞学中判读率最高的术语,是指鳞状上皮细胞发生了形态改变,在改变程度和数量方面均不足以判读为上皮内病变或癌,具有很大程度的不确定性。ASC-US的判读主要与判读标准的掌握、制片质控、取材等因素有关。本研究发现,TIS辅助阅片与人工阅片相比,LBC判读为ASC-US的患者其组织学病理诊断为CIN Ⅱ/Ⅲ的比率由21.85%降至15.09%,LBC判读为LSIL的患者其组织学病理诊断为CIN Ⅱ/ Ⅲ的比率由24.36%降至20.56%,说明细胞学判读的准确性有所改善,更贴近国内外细胞学实验室公认的基准范围[6-11]。从另一个角度亦反映,TIS辅助阅片对细胞学判读的趋势和准确性把握更接近国际公认的细胞学质控要求。
本研究通过分析发现,TIS辅助阅片检出异常腺细胞的数量是人工阅片的1.89倍(53例比28例),其中组织学证实为AC的数量是人工阅片的2.3倍(37例比16例),TIS辅助阅片AGC检出率高于人工阅片(0.21%比0.13%),提高了0.08%,且检出率符合CAP 2006年调查的基本范围(0.1%~0.2%)[11]。Harbhajanka等[12]报道的TIS辅助阅片AGC检出率为0.61%。Zheng等[13]报道的国内临检机构AGC报告率为0.1%,并分析报告率低的主要原因为中国病理医师对腺细胞的判读能力需提高。笔者认为腺细胞的识别需要制片质控,包括制片流程、染液等多环节达标,镜下单个平铺细胞、成片、成团的细胞结构染色清晰,是提高细胞学技师和医师阅片水平的第一步,其次才是在实践与理论之间进行探讨与总结。而制作TIS玻片的所有耗材、试剂、制片步骤均按照规定的实验操作步骤完成,制片的稳定性更有保证。既往我国AGC的报告率普遍偏低,一方面原因在于腺细胞在宫颈脱落细胞中确实不易获取;此外,腺细胞的判读一直是宫颈脱落细胞学的难点,我国宫颈细胞学发展起步晚,病理医师细胞学判读能力仍有待加强。本研究发现,TIS辅助阅片筛查出的子宫内膜癌数量明显高于人工阅片(8例比3例),在所有AC病例中,子宫内膜癌所占比例最高(36.36%),可能与TIS制片背景清晰,能够识别有细微差别的单个细胞及细胞胞核深染浓密的细胞团(图 1),进而提高了异常子宫内膜细胞的识别能力有关。
图 1 TIS制片(巴氏染色,×400)A. 成簇HSIL细胞团;B.单个散在HSIL细胞;C. AGC中性粒细胞袋;D.子宫内膜腺癌细胞
TIS、HSIL、AGC:同表 1ASC-US多见于提示有Hr-HPV感染的细胞学改变但未达到宫颈病变的标准,具有一定程度的不确定性,因此ASC/SIL和Hr-HPV阳性率可作为阅片者解释不确定性的有效反馈,通过数据从客观角度评价细胞学阅片质控。本研究数据显示,TIS辅助阅片与人工阅片异常鳞状上皮细胞的Hr-HPV阳性率和ASC/SIL比值均无差异,说明TIS辅助阅片与人工阅片按照TBS报告系统对细胞学评价标准把控稳定。北京协和医院对于绝大多数门诊患者采用Hr-HPV及细胞学联合筛查宫颈癌,因此所有玻片在人机双重筛查基础上,同时有Hr-HPV的验证,增强了细胞学的敏感性。假设以Hr-HPV作为初筛,TIS辅助阅片可以看作是第二次筛查,对于可疑玻片、与Hr-HPV检测结果不一致的玻片,或临床发现有盆腔包块、宫颈病变史及不规则阴道流血情况的玻片,均需在上述二次筛查基础上再行全玻片快速人工筛查[14-15]。粗略统计,本院80%以上的玻片至少经过3次筛查,在多次复诊同一玻片的基础上,TIS辅助阅片无一例HSIL漏诊,这也是本实验室阳性检出率能够达到15%左右的原因之一。传统人工阅片需3 min/张,TIS辅助阅片仅需1.5~2 min/张,阅片时间减少了33%~50%,不仅为多次反复阅片提供了可能,且使阅片者有更多时间研读阅片技术、积累更多经验。
然而,TIS仍有需要改进之处,譬如少部分玻片无法被判读,原因主要在于TIS是通过分析核染色程度区分胞核与胞浆及核浆比等数据信息,若胞浆染色过深,如萎缩性阴道炎或线索细胞等原因,导致胞核与胞浆区分困难,TIS则报告“玻片不能被分析”;若玻片中存有气泡、定位标识不清或盖玻片与载玻片不平行等,TIS也会报告“判读失败”。此类情况从侧面反映出规范化制片、提高液基制片质量是计算机辅助阅片的基础。
此外,本研究亦存在一定局限性。由于实验室日常工作量较大,故未采用同一批次样本,而是采用不同年份同一时期的样本进行对比分析,结果可能存在一定偏倚。
综上所述,TIS辅助阅片可提升子宫颈癌前病变筛查效率和检出率,协助实验室全面提升宫颈细胞学质控,相信随着计算机玻片扫描系统的更新、阅片水平的提升,计算机自动阅片临床应用将更加广泛和深入。
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