重视直肠癌的术前精准评估

徐惠绵 王鹏亮

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重视直肠癌的术前精准评估

徐惠绵 王鹏亮

徐惠绵 二级教授，博士生导师，国务院特殊津贴专家，现任中国医科大学附属第一医院肿瘤中心主任。中华医学会肿瘤学分会第十届侯任主委兼胃肠肿瘤学组组长、中国抗癌协会胃癌专业委员会侯任主委、中国医科大学胃肠肿瘤首席专家。曾获第十届中国医师奖、辽宁省政府优秀专家、中央保健委员会会诊专家、首届辽宁名医等荣誉称号。从医三十余年，在胃癌、结直肠癌诊断及外科治疗专业有较深的造诣。先后主持“863”国家高技术研究发展计划项目1项、国家自然科学基金6项、省部级科研项目11项。在《Annals of Surgery》《Stem cells》《Oncogene》《Annals of Oncology》《Cancer》等著名杂志发表SCI收录论文93篇，国内核心期刊论文161篇，累计影响因子300。主编胃癌专著2部。“胃癌三早与现代外科治疗研究”和“胃癌及癌前病变分子病理学机制研究” 分别荣获2001年、2006年国家科技进步二等奖；“胃癌转移规律及亚临床转移诊治研究”获2016年中国抗癌协会科技进步一等奖。

以往对于直肠癌患者术前评估主要关注的是手术方式的选择以及能否达到根治性切除。而近年来随着新辅助治疗及多学科诊疗模式等新技术在直肠癌临床实践中的应用，精准术前评估对患者也不仅限于手术方式选择、预后评估，更重要的是指导个体化综合治疗方案和流程的选择，使患者生存获益及生活质量提高。因此，精准的术前评估对于直肠癌患者显得尤为重要。本文旨在对直肠癌术前的精准评估做一概述，供临床医生借鉴。

直肠肿瘤； 术前评估； 新辅助治疗； 精准医学

近年来，随着人民生活质量的提高以及饮食结构的改变，我国结直肠癌的发病率逐年上升；全国癌症数据显示：2015年我国新发生结直肠癌病例约37.6万人，死亡病例约19.1万人，发病率及死亡率在所有肿瘤中均居第五位［1］。同欧美相比，我国直肠癌的比例较高；约占全部结直肠癌患者的半数以上［2］。

随着术前新辅助放化疗的应用、直肠癌外科技术手段的进步以及多学科协作（multidisciplinary team，MDT）诊疗模式的开展，使得直肠癌患者的治疗方式多样化个体化，治疗效果得到明显的提升，特别是保肛率的提高以及局部复发率的降低［3］。因此，对直肠癌患者进行术前精准评估，选择个体化治疗方案和流程，是进一步提高疗效的关键。

一、术前T分期的评估

手术前对于直肠癌T分期的评估是决定后续治疗的重要依据。根据直肠癌NCCN治疗指南：对于术前临床分期为肿瘤浸润突破肠壁固有肌层或达到浆膜下层及以上的患者（cT3-4b），应当先行术前放化疗或单纯放疗［4］。目前对于术前T分期的诊断，最常用的影像学检查方法为直肠核磁共振成像（magnetic resonance imaging，MRI）或直肠内镜超声（rectal endoscopic ultrasound，EUS）。EUS可显示正常肠壁不同的解剖层次交替形成三条强回声带以及两条低回声带，根据肿瘤侵犯所形成的回声中断来判断肿瘤的浸润深度。EUS对于T1-2期直肠癌诊断的准确度较高，且优于MRI［5］。但存在操作者的技术差异，肠道准备情况欠佳，气体较多及粪渣等都会影响EUS诊断的准确性。且有10～20%的T2期的直肠癌由于肿瘤周围的炎症反应而被高估，10%的T3期患者被低估［6］。此外，当肠腔狭窄内镜无法通过也会限制EUS的使用。

MRI 具有较高的软组织分辨率，可以在不同的断面上进行成像，因而可以较为清晰地显示直肠各层的解剖层次。尽管MRI 在T1-2期肿瘤的诊断的准确度上较EUS低，但由于MRI对局部解剖结构显示的更清晰，对T3-4期直肠癌则更具有优势［7］。北美放射学会利用高分辨率的MRI，将T3期肿瘤进一步分为cT3a：肿瘤突破肌层＜5 mm，cT3b：5～10 mm，cT3c ：＞10 mm［8］。尽管这一分类并没有体现在新版的TNM分期中，但业内认为对预后评估更准确。文献报道T3a期直肠癌的5年肿瘤相关生存率为85%，而T3b-3c期则仅为54%，强调T3a期同T3b-3c期肿瘤应区别对待［9］。尽管高分辨率MRI对于判断肿瘤浸润肌层（T3）的误差在0.5 mm之内，但对于T2期与T3a期的鉴别仍然不理想［10］，而对于T2期与T3a期的鉴别恰恰是术前诊断的难点及重点。对于T4期MRI诊断的准确性可达90%以上，并能够准确的评价肿瘤与直肠周围器官的关系［11-12］。

二、术前N分期的评估

区域淋巴结的转移是影响直肠癌预后的重要危险因素，如术前判断存在区域淋巴结转移的患者需要行新辅助放化疗。但目前，MRI，EUS，CT在内的多种影像学手段对于淋巴结转移的诊断均不够理想［13］。因此，对于N分期的判断是直肠癌术前评估的重点与难点。影像学诊断淋巴结转移主要是依据淋巴结的大小、形态、密度等特征。目前常以5 mm作为MRI检查淋巴结是否转移的临界值，但约有15～30%的阳性淋巴结直径＜5 mm［14］。亦有文献报道当淋巴结直径≥4 mm，淋巴结的边缘不规则以及低信号等，有助于提高阳性淋巴结诊断的准确率［15］。此外弥散加权成像技术（diffusion weighted imaging，DWI），以及应用淋巴结特异性的对比剂，如超小顺磁氧化铁颗粒及钆磷维司，亦有助于提高MRI阳性淋巴结的诊断率［16-18］。EUS诊断阳性淋巴结的灵敏度及特异度均较MRI低。近年来有学者提出，在超声内镜引导下，通过细针穿刺活检［19-20］，可以提高阳性淋巴结诊断的准确率，但该检查属有创操作，存在并发症的风险，并且受到多种因素的影响，其临床应用价值有待进一步验证。

近年来，放射组学技术发展迅速，使影像学从传统的图像时代深入到大数据时代。从影像检查图像中高通量的提取大量的影像学特征，通过数学方法对其进行定量转换后形成数字影像模式，利用特定的参数预测淋巴结转移概率。我国学者利用放射组学技术，预测结直肠癌淋巴结转移的概率，使其准确性得以提高［21］。期待放射组学技术对提高直肠癌术前精准N分期，具有更大的发展空间。

三、术前环周切缘及直肠周围血管浸润的评估

直肠癌环周切缘（ circumferential resection margin，CRM）是指直肠肿瘤与直肠系膜筋膜（mesorectal fascia，MRF）间的最短距离。CRM是影响预后的独立因素，主要与局部复发密切相关［22-23］。因此CRM的判定对直肠癌治疗策略的选择具有重要意义，并可避免部分患者接受过度治疗［24］。病理CRM阳性的判定为显微镜下CRM小于等于1 mm。来自欧洲的MERCURY实验证明高分辨率的MRI对CRM的预测准确率可达到94%［25］。一项荟萃分析显示：MRI对诊断CRM的灵敏度为77%，而特异度达到94%［26］。但是MRI对于中下段直肠癌诊断的准确率较低。有研究证明EUS可以辅助MRI更好的判断中下段直肠癌的CRM［27］。

直肠周围血管浸润是指病理检查发现直肠壁固有肌层外血管被肿瘤浸润及壁外的静脉浸润（extramural venous invasion，EMVI）。EMVI是预测直肠癌预后及远处转移的重要危险因素［28-29］。目前认为MRI是术前评价EVMI最为有效的检查手段。通过高分辨率MRI建立了EMVI评分标准，其预测敏感度及特异度分别为62%，88%［29］。此外EMVI尚可用于判断肿瘤对新辅助放疗的疗效。因此对于cT3且MRI-EMVI阳性的病例，可作为采取新辅助放化疗的依据之一［30］。提高MRI对于EMVI诊断的准确性，也是未来影像学需关注和深入研究的。

四、术前肝转移的评估

肝脏是结直肠癌远处转移最为常见的部位，约有60～70%结直肠癌发生肝转移，其中25%左右的患者出现同时性肝转移［31-32］。未接受肝转移灶切除的的患者5年生存率几乎为0，而接受肝转移灶切除的患者5年生存率可达到30～50%［33］。对于直肠癌患者，肝转移的定性定量诊断对决定治疗方式和流程至关重要。一项荟萃分析比较了超声、CT、 MRI、PET/CT在诊断结直肠癌肝转移的准确度，结果发现在检测的准确度上MRI均优于其余几种检查［34］。PET/CT在评估结直肠癌肝转移方面具有一定的优势。但是对肝转移小于1 cm的病灶，PET/CT存在假阴性的结果［35］。而MRI对诊断＜1 cm的病灶时则较敏感和特异。若使用特异性的对比剂及DWI-MRI技术，其诊断更为精准［36］。因此NCCN指南推荐肝脏MRI作为结直肠癌肝转移的一线检查手段，PET/CT作为二线检查手段。

五、术前肿瘤标志物的评估

1.癌胚抗原（carcinoembryonic antigen，CEA）是目前最为常用的肿瘤标志物。对结直肠癌早期发现，术后肿瘤复发，转移具有良好的监测作用，CEA是目前指南唯一推荐的用于结直肠癌监测的肿瘤标志物。第八版TNM分期将CEA 的重要性提到一个更高的位置。约有70～90%的结肠癌患者会出现血清中CEA的升高［37］。且与肿瘤分期相关，亦为预后不良的危险因素［38-40］。尚有助于对新辅助治疗的疗效评价，即手术前后血清CEA升高值变化不大的病例，预示不易达到病理上的完全缓解［41-42］。目前，对于CEA的争议主要集中在CEA阈值的设定，阈值过高会使一部分患者被漏诊，过低则可能会使一部分患者接受过度治疗。新近一项荟萃分析显示［43］：不同阈值的敏感度及特异度均不同，在每1 000例患者中，选取10 ug/L作为阈值相比于选取5 ug/L作为阈值，减少了78例假阳性病例，而仅漏诊一例。因此选取10 ug/L作为阈值更加合理。

2.循环肿瘤细胞/DNA的术前评估

循环肿瘤细胞（circulating tumor cell，CTC）是指由肿瘤原发灶或转移灶释放入循环系统中的肿瘤细胞，并且具有肿瘤特异性抗原或其基因特征［44］。既往研究证实CTC是评估结直肠癌患者预后的独立危险因素，并且对术后的复发具有一定的预测作用［45］。一项荟萃分析显示：CTC可以早期预测结直肠癌化疗的有效性［46］。还可用于预测局部进展期直肠癌对于新辅助放化疗的反应［47］。

循环肿瘤DNA （circulating tumor DNA，ctDNA）是指凋亡或坏死的肿瘤细胞进入循环系统中释放的肿瘤DNA片段［48］。对于难以获得组织标本进行基因检测的患者可以通过对ctDNA进行检测来获取肿瘤相关的基因特征。对于术前患者，ctDNA检测可预估局限性癌或可能出现血行转移的潜在风险。对于接受化疗或靶向治疗的患者，ctDNA的检测可以帮助了解患者的基因突变情况，对化疗及靶向治疗具有重要的指导意义［49-51］。

六、新辅助治疗后的再评估

对于局部进展期直肠癌患者，接受新辅助放化疗的主要目的在于减小肿瘤体积，降低分期，提高保肛率、减少术后复发。接受新辅助治疗后再分期对于选择手术方式及个体化治疗模式至关重要。再分期评价所采用的影像学检查手段通常与初始评估的检查方法相一致。近年来随着MRI技术的发展，一些功能成像技术，例如DWI-MRI，可用于对新辅助治疗后直肠癌的分期的重新评价［52-53］。

对于新辅助治疗的患者，肿瘤退缩评分（tumor regression score，TRG）是疗效评估的重点。TRG主要是依据肿瘤对新辅助治疗后的病理学反应进行分级。一项荟萃分析结果显示，获得pCR的患者其五年无病生存率为83.3%，并且证明pCR是预后较好的独立预测因素［54］。Habr-Gama等［55］对71例达到临床完全缓解的患者未进行手术治疗，而采用等待——观望的策略（wait and see）。结果显示其5年总体生存率为100%，无病生存率达到82%。这为部分达到临床完全缓解的病例提供了新的治疗思路，其优点是免去了手术治疗的风险，尤其是对于无法保肛的患者获益最大。因此，对于术前判断患者是否达到pCR十分重要，目前文献报道PET/CT有助于预测直肠癌对于新辅助治疗的病理反应和缓解程度，但仍有待于更深入的研究和验证［56-58］。

七、低位直肠癌术前是否保肛的评估

我国直肠癌患者中约有70%为中低位直肠癌［59］，对于这部分患者在根治手术的前提下，应尽可能保留肛门，提高患者术后生活质量。低位直肠癌能否保肛取决于肿瘤下缘距齿状线的距离、浸润深度、淋巴结转移情况，肿瘤与肛门括约肌、肛提肌的关系、组织学分型等因素。既往提出的保肛手术适应证为：（1）高、中分化腺癌，未浸透肌层。肿瘤环周＜1/2周，肠管周围无肿大淋巴结，距齿状线1 cm以上；（2） 高中分化腺癌，浸透肌层，环周＞1/2周，距齿状线2～3 cm；（3）低分化或粘液腺癌，未浸透肌层，环周＜1/2周，距齿状线3～5 cm［60］。利用MRI评估肿瘤浸润情况，发现肿瘤侵及周围脏器、括约肌或肛提肌时，保肛手术则难以实现。Nougaret等［61］利用MRI对肿瘤与括约肌及肛提肌关系进行评价，提出了不同的分级标准，为手术决策提供了依据。亦有国内学者利用CT模拟盆腔来预测直肠癌手术方式，取得了较为满意的效果［62］。此外，CRM也是能否保肛的重要因素，应当确保CRM阴性的情况下行保肛手术。远端切缘距离也是评估能否保肛的重要依据之一。目前公认的远端切缘距离为2 cm［4］，可达到根治的效果获得长期生存，并可以保留较为满意的括约肌功能。新近一项荟萃分析显示远端切缘＞1 cm同≤1 cm在局部复发率上无差别［63］。说明传统的2 cm安全距离正逐渐接受挑战，而新提出的更加“冒险”的切缘距离是否真正具有临床意义尚需要大规模的临床试验加以验证。

术前除判断影响根治性切除的因素外，对于直肠肛管功能的评价亦是十分重要的。新辅助放化疗可使肿瘤缩小，提高患者的保肛率，但有文献表明这会对患者术后排便功能造成一定的影响［64-65］。因此，术前应在审慎对患者的括约肌功能评价的基础上，决定是否实施保肛手术。

综上，直肠癌的术前精准评估，对于直肠癌患者个体化治疗模式和流程的选择极为重要。目前淋巴结状态是直肠癌术前评估中的重点及难点，无论是直接手术或接受新辅助治疗，影像学对其预测能力均不够理想。期待放射组学或分子影像学进一步深入的研究。尽管等待——观望的治疗策略目前的结果较为乐观，但是其真正应用于临床实践，仍然需要大样本的临床研究对其进行验证。保肛手术应坚持在根治性切除的前提下，注重患者括约肌功能的保留，这样才会给保肛患者带来真正的获益。

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Emphasize on rectal cancer preoperative precise assessment

Xu Huimian, Wang Pengliang.
Department of Surgical Oncology, the First Affliated Hospital of China Medical University, Shenyang 110001, China

Xu Huimian, Email: xuhuimian@126.com

In recent years, as some new technology applied in the clinical practice of rectal cancer,such as neoadjuvant therapy, multidisciplinary team (MDT) and so on, the infuence of accurate preoperative assessment for patients is not only associated with operation selection and prognosis assessment, but also related with reasonable choice of personalized comprehensive treatment plan and process. Furthermore, it also can provide survival beneft and improve the quality of life for patients. Therefore, the precision preoperative assessment is critical for patients with rectal cancer. The purpose of this study is to given an overview to precision preoperative assessment of rectal cancer and provide reference for clinical oncologists.

Rectal neoplasms; Preoperative assessment; Neoadjuvant treatment; Precision medicine

2017-06-20）

（本文编辑：刘正）

10.3877/cma.j.issn.2095-3224.2017.05.001

国家自然科学基金项目（No.81372550）

110001 沈阳，中国医科大学附属第一医院肿瘤外科

徐惠绵，Email：xuhuimian@126.com

徐惠绵, 王鹏亮.重视直肠癌的术前精准评估[J/CD].中华结直肠疾病电子杂志, 2017, 6(5): 354-359.