​发病率与死亡率

据估计,2013年美国直肠癌新发病例数和死亡病例数约为:[1]

​新发病例数:40,340(仅直肠癌)。

死亡病例数:50,830(合并结肠癌与直肠癌)。

​流行病学研究多同时研究结肠癌和直肠癌(即结直肠癌),故很难分别描述结肠癌和直肠癌的流行病学特征。

​流行病学

结直肠癌(CRC)位列全球最常见恶性肿瘤第三位。2000年,世界范围内新发癌症中有9.4%为结直肠癌,诊断病例数为945,000例,死亡病例数为492,000例,占全球所有癌症死亡病例数的7.9%[2]。男性与女性的结直肠癌发病率基本相当。美国的所有种族人群中,非裔美国人的散发结直肠癌发病率和死亡率均居首位[3][4]

美国直肠癌大多为腺癌[5]。类癌、淋巴瘤、神经内分泌肿瘤等罕见肿瘤在结直肠癌中不足3%[5]

​胃肠道间质瘤亦可发生于结肠。(更多信息请参见PDQ总结 胃肠道间质瘤的治疗。)

​解剖学

直肠位于骨盆内,自肛门齿状线移行区粘膜延伸至乙状结肠腹膜返折处;硬质乙状结肠镜测量显示,至肛门缘处,直肠长度约为250px-375px[6]。直肠肿瘤的位置常用肿瘤下缘距肛缘、齿状线或肛管直肠环的距离表示。测量结果与使用的内镜种类(硬质乙状结肠镜或纤维乙状结肠镜)或肛门指检相关[7]。肿瘤距离肛门括约肌的距离决定了是否可行肛门括约肌保留术。骨盆的骨性结构限制了直肠手术操作,导致阴性切缘可能性降低,局部复发可能性增加[6]

危险因素

​遗传性危险因素

某些已知的单基因病患者罹患直肠癌的风险增高,相关的单基因病患者占结直肠癌病例的10%-15%左右。(更多信息请参见PDQ总结: 结直肠癌的遗传学​一节)遗传性结直肠癌综合征和相关的基因包括:[7][8][9]

​非息肉性疾病

遗传性非息肉病性结直肠癌(HNPCC)或Lynch综合征:错配修复(MMR)基因。

​息肉性疾病

​家族性腺瘤性息肉病(FAP):APC基因。

​Turcot综合征:APC基因,MMR基因。

轻表型家族性腺瘤性息肉病(AFAP):APC基因。

​增生性息肉综合征:BRAF和KRAS2基因。

错构瘤性疾病

​Peutz-Jeghers综合征:STK11/LKB1基因。

幼年性息肉病综合征:SMAD4/DPC4和BMPR1A基因。

​Cowden综合征:PTEN基因。

​Ruvalcaba-Myher-Smith综合征:PTEN基因。

遗传性混合性息肉病综合征。

​由MMR基因(包括hMSH2,hMLH1,hPMS1,hPMS2或hMSH6)缺陷引起的HNPCC是最常见的遗传性结直肠癌类型,约占所有结直肠癌的3%-5%[8]。大多数有遗传背景的病例与hMSH2(位于染色体2p)和hMLH1(位于染色体3p)基因相关。患病家系中,15%-60%的家庭成员中有hMSH2或hMLH1的突变,突变发生率和家族史特点有关[10]。德系犹太人患APC基因(I1307K)突变的结直肠癌的风险较高,约占德系犹太人群的6%-7%[11]

​其他危险因素

其他增加直肠癌风险的因素包括:

​结直肠癌或结直肠腺瘤病史。

​一级亲属中有结直肠癌或结直肠腺瘤病史[12]

​卵巢癌、子宫内膜癌或乳腺癌病史[13][14]

这些高危人群仅占所有结直肠癌病例的23%,因此,仅仅对这些人群进行筛查和早期癌症检测将漏诊大部分结直肠癌病例[15]。(更多信息请参见PDQ总结: 结直肠癌的筛查结直肠癌的预防。)

临床表现与症状

​直肠癌的症状和结肠癌类似,包括:[16]

​消化道出血。

​排便习惯改变。

​腹痛。

​肠梗阻。

​体重下降。

食欲改变。

乏力。

除了梗阻性症状,直肠癌的所有症状均和疾病的分期无关,亦无诊断特性[17]。体格检查可能发现可触及的直肠肿块、退指可见鲜血。存在转移性疾病时可有淋巴结肿大、肝大或肺部体征[7]。实验室检查可发现缺铁性贫血、电解质异常或肝功能异常。

临床评估与分期

准确的分期可提供的关键信息包括直肠原发肿瘤的位置、大小和转移灶的大小、数量和位置等。在病程初期,准确分期可以帮助决定手术方式和新辅助化疗方案,以尽可能实现切缘干净。对于原发性直肠癌,盆腔影像学可以显示肿瘤侵犯的深度、距肛门括约肌的距离、环周(径向)切缘阴性的可能性和局部区域性淋巴结、周围器官的侵犯情况[18]。初始临床评估和分期方法包括:[7][18][19][20][21][22][23]

肛门指检和(或)直肠阴道检查,硬式前列腺镜检查可以帮助评估是否实施保肛手术[7][18][19]

全面结肠镜检查,排除肠道其他部位肿瘤[7]

行全身计算机断层扫描(CT),排除转移性疾病[7]

腹腔和盆腔的磁共振成像(MRI)评估肿瘤浸润深度和实现环周(径向)切缘阴性的可能性,同时确认是否有局部淋巴结转移和远处转移[18]

硬式或软式直肠腔内超声(ERUS)评估梗阻性病灶的浸润深度,检查是否有局部淋巴结转移[19][21]

使用正电子发射断层扫描(PET)评估远处转移情况[18]

测量血清癌胚抗原(CEA)水平,评估预后和治疗效果[22][23]

对于直肠癌(T)分期,一些研究认为ERUS的准确性在80%至95%,CT为65%至75%,MRI则为75%至85%。ERUS对转移淋巴结的评估准确性约为70%至75%,CT为55%至65%,MRI则为60%至70%[19]。对84项研究进行的一项荟萃分析指出,在转移淋巴结的评估中,ERUS、CT和MRI三种影像手段并未优于其他手段[24]。硬式ERUS在T和区域淋巴结(N)分期上的准确性与软式ERUS相似,但遇到技术上的困难时,硬式ERUS可能无法准确评估T、N分期。此时需要考虑进一步使用MRI或软式ERUS[21][25]

对直肠癌患者来说,环周切缘(CRM)是重要的病理分期参数,测量单位为毫米,定义为腹膜后或者脏层腹膜距肿瘤最深浸润部位的最近距离[26]

美国癌症联合委员会和美国国家癌症研究所资助的研究小组基于回顾性研究数据,建议结直肠癌患者至少活检12枚淋巴结,以确认淋巴结的受累情况[7][26][27][28]。[ 证据等级:3iiiA]这一建议认为,受检淋巴结数量既反映术中肠系膜淋巴血管的受累情况,也对病理标本中淋巴结检出情况进行了评估。回顾性研究显示,结直肠癌手术清扫淋巴结数量和治疗结局相关[29][30][31][32]。若怀疑疾病进展或复发,则需要进一步分期评估。MRI对评估局部复发时的骶尾部受累很有帮助[18]

治疗

由于直肠癌局部复发风险高,总体预后差,其治疗与结肠癌存在一定不同。差异体现在手术方式、放疗和化疗方案方面。直肠癌手术除了要明确治疗目的(根治还是姑息),还要考虑肛门括约肌、泌尿功能和性功能的维持和保护等治疗问题[25][33]。直肠癌的治疗需要多种模式联合治疗,以及多学科肿瘤专家的共同参与,如胃肠病学、肿瘤药物学、肿瘤外科学、肿瘤放射学和放射学的专业知识。

直肠癌的外科治疗手段各异,选择时应当考虑肿瘤的位置、分期、是否存在高危因素(即手术切缘阳性、淋巴血管浸润、神经浸润和组织学分化程度较差)等,手术方法包括:

对T1期肿瘤行选择性息肉切除术。

对某些临床分期为T1/T2N0期的直肠癌行选择性经肛门局部切除术(LE)和经肛门内镜显微手术(TEM)。

直肠低位前切除术(LAR)由保留自主神经(ANP)的全直肠系膜切除术(TME)组成。

对于无法保留肛门括约肌的患者,行经腹会阴联合直肠癌切除术(APR)伴全直肠系膜切除术(TME),保留永久性结肠造口。

对于能够彻底切除、切缘干净且组织学特征良好的恶变息肉,可以采用息肉切除术[35][36]。中上段进展期直肠癌患者首选LAR及肠吻合术。对于可根治的局部进展期直肠癌,采用ANP和TME技术的LAR优于APR[25][33]

II期或III期直肠癌患者可以接受术后治疗,但目前更倾向于使用术前新辅助放化疗[37]。[证据等级:1iA]新辅助放化疗的益处包括:缩小肿瘤体积、降期、增加可切除性、提高保肛率和局部控制率等[37]。术前放化疗的病理完全缓解率可达10%-25%[38][39][40][41][42][43][44][45]。但是和单纯手术相比,术前放疗的并发症风险增加,手术联合辅助化疗已经足以治愈一些局部复发风险较低的直肠癌患者[46][47][48][49]。(更多信息请参见: 治疗选择概述。)

预后因素

直肠癌患者的预后与下述因素相关:[7][25][26][29][30][31][32][50][51][52]

是否存在淋巴结受累,阳性淋巴结的数量[7][29][30][31][32]

粘连或浸润毗邻器官[26]

是否存在远处转移[7][26]

是否存在高危病理学特征,包括手术切缘阳性、脉管瘤栓、神经浸润和组织学分化较差等[50][51][53]

是否存在肠穿孔或肠梗阻[7][52]

CRM,或肿瘤对肠壁的浸润深度[7][25][54]

但一些多中心前瞻性研究只证实了疾病分期(原发肿瘤、局部淋巴结和远处转移)与预后相关。

大量研究评估了许多其他临床、病理和组织分子与预后的关系,但目前缺乏多中心前瞻性临床试验的证实[55][56][57][58][59][60][61]。比如,一项以人群为基础的研究调查了607例诊断时年龄小于等于50岁的结直肠癌患者。研究显示,遗传性非息肉病性直肠癌相关的MSI-H和患者的生存率改善独立相关,是独立于肿瘤分期的预后因素[62]。并且有研究报道,基因表达谱可以用于预测直肠腺癌对于术前放化疗的反应,并且可以用于评估II期和III期直肠癌患者接受以5-氟尿嘧啶为基础的新辅助化疗的预后[63][64]。一些研究观察了人种和民族差异对于辅助治疗后直肠癌患者总生存率(OS)的影响。一项研究显示,黑人的OS短于白人,这一生存率差异可能与肿瘤位置、手术类型和合并症情况等因素相关[65]

随访

直肠癌术后监测计划的主要目的包括:[66]

对直肠癌患者的常规、定期检查可以早期发现和处理复发性疾病[66][67][68][69][70]。两项临床研究中发现强化随访组的生存率有统计学显著获益。对这两项研究和另外四项研究行荟萃分析,结果显示接受强化随访的患者生存率有统计学显著改善[66][71][72]。美国和欧洲肿瘤协会制定的治疗指南关于初步治愈性治疗后的结直肠癌患者的监测建议不同,目前无最佳监测方案[73][74]。关于应如何选择患者的随访评估方案,需要设计精良的大型前瞻性多中心随机研究以达成循证共识。

CEA是一种血清糖蛋白,常用于直肠癌患者的治疗和随访评估。对这一肿瘤标记物的使用进行文献综述,显示如下结果:[66]

由于血清CEA测定的敏感性低、特异性低,其对于直肠癌筛查的价值不高。

术后CEA测定仅限用于需要继续干预的患者,包括:II期或III期直肠癌患者(诊断后每2-3个月检测一次,至少2年)。将行肝转移灶切除的直肠癌患者。

一项荷兰TME回顾性研究发现,大多数结肠癌患者术前血清CEA水平正常,但复发患者的血清CEA至少升高50%。作者建议,不能因直肠癌患者术前血清CEA水平正常,就放弃对患者进行术后CEA水平监测[75][76]

相关总结

其他与直肠癌相关的信息请参加下列PDQ总结:

儿童罕见肿瘤的治疗(儿童结直肠癌)。

结直肠癌的遗传学​。

结直肠癌的预防​。

结直肠癌的筛查​。

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