胸段食管鳞癌颈淋巴转移诊治进展*

王海军 综述， 韩泳涛 审校

646000 四川 泸州，西南医科大学(王海军，韩泳涛)；610041成都，四川省肿瘤医院·研究所，四川省癌症防治中心，电子科技大学医学院 胸外科(韩泳涛)



•综述•

胸段食管鳞癌颈淋巴转移诊治进展*

王海军 综述， 韩泳涛△审校

646000 四川 泸州，西南医科大学(王海军，韩泳涛)；610041成都，四川省肿瘤医院·研究所，四川省癌症防治中心，电子科技大学医学院 胸外科(韩泳涛)

食管癌恶性程度高、预后差。淋巴结转移及阳性淋巴结数量是影响患者预后的重要原因之一，尤其颈淋巴结和喉返神经旁淋巴结是一直研究争议的热点。虽然颈胸腹三野淋巴结清扫术较胸腹两野淋巴结清扫术可以延长患者生存时间并减少复发，但是，该种术式在使患者生存获益的同时也带来了术后高并发症。颈淋巴结是否存在转移直接影响着淋巴结清扫范围，虽然可以通过多种方法诊断颈淋巴结有无转移，但是敏感性及特异性低。喉返神经旁淋巴结被认为是食管癌的前哨淋巴结，用于预测颈淋巴结是否存在转移，然而准确率不超过50%。本文将对目前食管癌颈淋巴转移诊治现状进行综述。

食管癌； 淋巴结清扫； 颈淋巴结； 超声； 前哨淋巴结

食管癌是引起全球肿瘤相关死亡的重要原因之一，其恶性程度高，预后差。食管鳞状细胞癌是中国及日本等亚洲国家的主要病理类型，发病率占所有病理类型的90%以上，主要发生于胸段食管。肿瘤切除+根治性淋巴结清扫目前仍是可切除鳞癌患者的首选方案，5年生存率约为15%～25%。术后复发和转移是导致患者高死亡率的主要原因，而颈淋巴结转移和复发是影响患者预后的重要因素[1-3]。虽然在胸腹二野淋巴结清扫术(two-field lymphadenectomy,2-FL)基础上扩大淋巴结清扫范围即颈胸腹三野淋巴结清扫术(three-field lymphadenectomy,3-FL)可以提高患者的生存率并降低复发率，但是与2-FL相比，3-FL术后吻合口瘘、喉返神经损伤等并发症发生率随之增加[4-5]。因此，为避免由于扩大化手术对3-FL非获益人群带来的各种负面效应，筛选出3-FL的获益人群非常重要。目前，大多数食管胸段鳞癌患者选择2-FL或3-FL的主要参照标准之一是术前颈淋巴结状态，术前检查怀疑或病理证实颈淋巴结转移时选择3-FL，反之则选择2-FL[4,6]。由此可知，术前准确预测颈淋巴结是否存在转移十分关键。尽管超声(ultrasonography)、CT(computed tomography)及PET-CT(positron emission tomography-CT)及MRI(magnetic resonance imaging)等无创检查和超声内镜(endoscopic ultrasound,EUS)及内镜引导下细针穿刺活检(endoscopic ultrasonography-guided fine needle aspiration,EUS-FNA)等有创方法都已被用于术前鉴别颈淋巴结良恶性，但是对于较小转移淋巴结及微转移淋巴结诊断能力有限[7-10]。胸内喉返神经旁淋巴结曾被部分学者作为前哨淋巴结预测食管癌颈淋巴结是否存在转移，但由于食管癌淋巴引流方式复杂多样、存在跳跃转移等特点限制了喉返神经旁淋巴结的预测作用。因此，胸内喉返神经旁淋巴结是否可以成为食管鳞癌的前哨淋巴结目前仍没有定论[11-13]。鉴于以上现状，本文将从食管癌三野淋巴结清扫研究现状、食管癌颈淋巴结转移诊断现状和食管癌前哨淋巴结研究现状三方面对食管胸段鳞癌颈淋巴转移相关热点问题进行综述(注：文中所提及喉返神经旁淋巴结均指胸内喉返神经旁淋巴结)

1 食管胸段鳞癌三野淋巴结清扫研究现状

复发和转移是导致食管鳞癌术后患者死亡的主要原因[14]。颈淋巴结有无转移是影响患者预后的重要因素之一。已报道的食管癌颈淋巴结转移率高达20%～60%[14-19]。因此，为降低术后复发率并延长患者生存时间，有必要扩大淋巴结清扫范围行颈淋巴结清扫。目前食管胸段鳞癌淋巴结清扫术式主要包括胸腹二野淋巴结清扫术(2-FL)和颈胸腹三野淋巴结清扫术(3-FL)，3-FL在2-FL基础上进一步清扫双颈部淋巴结。虽然3-FL较2-FL有降低术后颈淋巴结复发甚至提高生存率的优点，但同时也存在创伤大、并发症高等缺点。综上所述，选择3-FL的获益人群十分重要，也是当代精准治疗理念的要求。

1.1 三野淋巴结清扫术与两野清扫术的预后比较

相关研究报道，食管鳞癌患者3-FL术后5年总生存率为41.9%～73.2%[4,5,17,20-21]，2-FL 术后5年总生存率为33.7%～48.7%[22-24]。Kato等[22]早期的随机对照研究将150例胸段食管癌患者随机分组后分别接受3-FL和2-FL手术，其中鳞癌患者138例，术后总的5年生存率3-FL组和2-FL组分别为48.7%和 33.7%(P<0.01)。Kato等[25]后期报道胸段食管癌患者3-FL与2-FL术后局部复发率分别为17% 和 38%[25]。Akiyama等[23]比较了717例食管胸段鳞癌患者分别接受3-FL与2-FL 术的预后情况，术后总的5年生存率3-FL组与2-FL 组分别为55.0% 与 38.3%(P=0.0013)。Nishihira等[24]后来进行的前瞻性研究共纳入62例食管胸段鳞癌患者，随机分配到3-FL组(32例)和2-FL组(30例)，3-FL组与2-FL组术后5年生存率和复发率分别为66.2% vs.48.0% 与19.9% vs. 24.1%，虽然3-FL组较2-FL组更有提高生存率并降低复发率的趋势，但是均未达到统计学差异。Ma等[6]最近报道的一项meta分析包括超过7 000例食管癌患者，结果显示3-FL组较2-FL组具有明显的生存优势(3年生存率：RR=1.44,95%CI:1.19～1.75,P<0.01；5年生存率：RR=1.37,95%CI:1.18～1.59,P<0.01)。另一项meta分析也得出相似的结论[26]。虽然也有少数研究认为3-FL较2-FL并未显示出明显优势[27-28]。但从总体看，3-FL较2-FL在食管胸段鳞癌患者的优势已逐渐形成共识。并发症方面，食管胸段鳞癌患者3-FL术后死亡率为1.2%～6.4%，肺部并发症1.5%～31.3%，吻合口瘘1.5%～38.6%，喉返神经损伤2.6%～28% ；2-FL术后死亡率为6%～10.7%，肺部并发症0%～13.9%，吻合口瘘6.4%～29.1%，喉返神经损伤0～23.1%[4-5,17,20-21]。虽然3-FL比2-FL并发症发生率高，但随着医学的发展，尤其是对患者围手术期管理水平的提高、微创技术和机器人手术等新技术的逐渐开展及推广，手术对患者的创伤越来越小，术后各种并发症也较传统开放手术明显降低[4]。

1.2 三野淋巴结清扫的选择标准

虽然3-FL较2-FL可使食管胸段鳞癌患者获益，但术后并发症发生率高。是否3-FL适合所有食管胸段鳞癌患者一直存在争议，而筛选出3-FL获益人群至关重要。由于胸上段食管在解剖学上最靠近颈部，并且食管胸上段鳞癌患者比中下段患者发生颈淋巴结转移风险更高[16,29-30]。因此，许多研究认为3-FL适用于食管胸上段鳞癌患者[6,18,31-32]。Fujita等[31]比较了128例食管胸段鳞癌患者中3-FL组(63例)与2-FL组(65例)的预后情况，肿瘤分布包括上段11例、中段97例、下段38例。3-FL组与2-FL组术后5年生存率分别为40%和36%(P>0.05)，术后死于复发的比例为3-FL组33%和2-FL组51%(P<0.05)。生存分析结果显示对于中上段肿瘤伴淋巴结阳性患者，3-FL组较2-FL组具明显生存优势(P<0.05)，对于下段或淋巴结阴性患者两组间无明显生存差异。Udagawa等[18]评价了906例胸段食管癌患者行3-FL术的预后情况，他们认为3-FL是食管中上段鳞癌患者的标准淋巴结清扫方案。Ma等[6]和Ye等[26]的meta分析也显示3-FL的获益人群主要为食管胸中上段鳞癌患者，尤其是同时伴有淋巴结转移者。Tachimori等[32]最近报道了3 827例食管鳞癌患者3-FL术后的情况，包括上段983例、中段2 215例、下段629例，上、中、下段肿瘤患者颈淋巴结转移率依次为33.4%、22.8%和17.6%，术后5年生存率分别为42.3%、40.5%和30%，他们最后认为食管上段鳞癌患者必须行颈淋巴结清扫，对于中段患者也推荐行3-FL。此外，也有少数研究报道对于食管胸下段鳞癌伴中上纵隔淋巴结转移患者，甚至对于肿瘤侵及粘膜下层(T1b期)和淋巴结阴性患者也应选择3-FL[21,33-34]。目前对于胸上段食管鳞癌患者常规行颈淋巴结清扫术已为大多数学者所接受，对中下段患者术前伴颈淋巴结转移患者也应选择3-FL，但对于术前常规检查颈淋巴结阴性的食管中下段鳞癌患者，是否有必要行预防性颈淋巴结清扫术仍存在争议。

2 食管癌颈淋巴结转移诊断现状

食管癌患者颈部淋巴结是否存在转移直接决定术中淋巴结清扫术式。因此，术前准确评价颈淋巴结有无转移至关重要[7]。由于术前查体诊断准确率低，多种无创检查方法(如超声、MRI、CT、PET-CT)和有创检查方法(如EUS和EUS-FNA)已被广泛用于术前诊断食管癌颈淋巴结良恶性[8,35]。但是综合考虑准确性、方便性、经济性及安全性等因素，超声目前仍是术前筛选食管癌颈淋巴结转移的首选无创检查。

2.1 超声

超声学上淋巴结转移的诊断依据主要参考淋巴结大小、边界及内部回声、内部血流分布和淋巴门表现等[36]。目前超声诊断食管癌颈淋巴结转移主要依据淋巴结大小和边界及内部回声。Yoshinaka等[37]根据边界及内部回声表现，将食管癌颈淋巴结分为3种类型，第1型：边界回声不清，内部回声均匀；第2型：边界回声清，内部弱回声；第3型：边界回声清楚，边缘不光滑，内部回声不均匀，一般认为第2、3型恶性可能性大，尤其第3型诊断敏感性、特异性和准确性分别高达92.3%、96.3%和95.7%。Natsugoe等[38]报道该标准的敏感性、特异性及准确性分别为74.5%、94.1% 和87.6%。然而，淋巴结边界及内部回声判断主观性强，与检查者经验明显相关，因此，根据淋巴结大小选择量化指标更为可靠。超声下淋巴结直径及长短径之比已被广泛作为鉴别良恶性标准，但是缺乏统一的阳性分界值。Tohnosu等[9]早期报道了58例胸段食管癌患者经超声诊断颈淋巴结转移情况，当淋巴结阳性分界值定为超声测量长径大于1cm且短径/长径大于0.5时，诊断敏感性、特异性及准确率分别为78.4%、93.3% 和90.4%。Tachimori等[10]分析了209例胸段食管癌患者术前颈淋巴结转移情况，包括鳞癌192例，结果显示超声测量下阳性淋巴结的分界值定为短径≥5mm且短径/长径≥0.5时，诊断敏感性及准确性分别为78.9% 和94.0%。Leng等[7]最近发表的meta分析评价了超声诊断食管癌颈淋巴结转移的情况，纳入了22项研究共计3 513例食管癌患者，分析结果显示当超声测量下阳性颈淋巴结大小分界值为5mm及>5mm时，敏感性分别为84% (67%～93%) 与93% (90%～95%)，特异性分别为94% (76%～98%) 与 98% (89%～100%)。但由于超声测量食管癌患者直径小于5mm的淋巴结中，病理诊断阳性率高达36%～42%[39]，因此，单独将超声下淋巴结大小或边界及内部回声表现作为阳性标准并不是最佳选择，应该综合淋巴结大小和形态学表现建立最佳诊断标准。日本食管疾病协会推荐的超声下阳性淋巴结标准为：1.边界清楚；2.内部回声不均匀；3.短径/长径大于0.5；4.长径大于5mm，同时满足以上标准时，诊断敏感性、特异性、准确率、假阳性率和假阴性率分别为71.4%、100%、87.7%、10.5%和0%[40]。Cwik 等[41]近期报道了超声诊断83例食管胸段鳞癌患者颈淋巴结转移的情况，根据上述标准，超声诊断的敏感性、特异性、阳性及阴性预测值分别为100%、96%、81% 和100%。总体来看，虽然超声诊断颈淋巴结转移的准确性较高，但是与检查者经验、检查设备等因素密切相关，目前缺乏统一标准。尽管多普勒频谱分析技术(Doppler spectral analysis)和超声弹性成像技术(elastography)等检查方法也被用于诊断颈淋巴结转移，但仍处在研究初期[42-43]。

2.2 MRI和PET/MR

常规MRI诊断淋巴结转移的敏感性、特异性及准确性分别为25%～62 %, 67%～88 % 和56%～77 %[44]。PET/MR是一种在MRI和PET基础上发展起来的新兴检测技术，诊断食管癌淋巴结转移的准确性为83.3%[45]。综上可见，MRI和PET/MR诊断准确性并未较其他无创检查明显提高，尤其是PET/MR费用昂贵，目前较少用于术前诊断食管癌淋巴结转移。虽然随着高分辨率MRI、超顺磁性氧化铁(SPIO)MRI及弥散加权成像技术等新技术的出现，MRI诊断食管癌淋巴结转移敏感性可达81%～100%，特异性达90%以上[46-48]，但目前仍处于临床研究阶段。

2.3 CT和PET/CT

已报道的CT诊断食管癌颈淋巴结转移的敏感性为30%～75.9 %，特异性为34.0 %～93%[8,49-51],主要由于CT对直径大小正常的转移淋巴结分辨率低；此外，炎症及结核等原因引起的肿大淋巴结均导致CT诊断的假阳性率增加[52]。目前PET/CT诊断食管癌淋巴结转移的敏感性为49%～57%，特异性为81.1 %～87%[8,50-51]。可见PET/CT诊断准确性并未较CT明显提高，分析可能原因为：(1)PET/CT空间分辨率低，对于转移的小淋巴结诊断能力有限[53-54]；(2)原发肿瘤对FDG吸收与肿瘤周围淋巴结对FDG的吸收相互影响PET/CT的准确鉴别[55]；(3)仅有镜下转移的淋巴结对FDG吸收少且体积无明显长大， PET-CT对其诊断准确率低[56]。综上可知，CT诊断食管癌颈淋巴结转移准确性低，PET/CT虽然对于诊断原发肿瘤及远处转移有较高准确性，但鉴别淋巴结转移良恶性的敏感性及特异性较低。

2.4 EUS和EUS-FNA

EUS作为一种有创检查手段，其诊断食管癌淋巴结转移的敏感性为42%～100%，特异性为70%～91%[8,48,50,57]。尤其随着高分辨率内镜的出现，EUS诊断淋巴结转移准确率明显提高[57]。术前在EUS引导基础上对发现的可疑淋巴结行细针穿刺活检，可以进一步提高EUS诊断准确率。目前报道的EUS-FNA诊断食管癌淋巴结转移的敏感性、特异性及准确性分别达93%、100%和98%[54,58-59]。尽管EUS和EUS-FNA对于术前鉴别食管癌淋巴结良恶性十分有用，但两者作为有创操作，对术者能力要求高，并有穿孔风险。此外，EUS穿透深度约为5cm，两者主要用于诊断食管肿瘤周围的较大可疑淋巴结，对于远处转移淋巴结诊断能力低[54,60]。考虑到有创性及使用范围有限等特点，EUS和EUS-FNA虽然诊断准确性高，但并不是术前鉴别食管癌颈淋巴结良恶性的首选方法。

3 食管癌前哨淋巴结研究现状

食管胸段鳞癌患者术前有无颈部淋巴结转移直接决定是否行颈淋巴结清扫。上述各种检查方法虽然对较大淋巴结诊断准确性较高，但对较小转移淋巴结，尤其是仅有微转移灶的淋巴结诊断准确率低。由于解剖学上纵隔喉返神经旁淋巴结处于颈胸交界区，是胸内最高淋巴结，并通过淋巴导管与颈淋巴结直接交通[61]；此外，食管癌患者喉返神经旁淋巴结转移率最高，与预后密切相关[29,62]。因此，一些学者尝试将喉返神经旁淋巴结作为食管癌的“前哨淋巴结”预测颈淋巴结有无转移，进而指导是否需要行颈淋巴结清扫[11-13,19,63]。Tabira等[12]早期报道了86例食管胸段鳞癌患者R0切除术后喉返神经旁淋巴结转移情况，喉返神经旁淋巴结阳性与阴性患者颈淋巴结转移率分别为43.5%(10/23)，和11.1%(7/63)(P=0.001)，喉返神经旁淋巴结预测颈淋巴结转移的敏感性、特异性、阳性预测值及阴性预测值分别为58.8%、81.2%、43.5%和88.8%，多变量分析显示喉返神经旁淋巴结转移与颈淋巴结转移明显相关(OR=4.5,95%CI=1.3～15.9,P=0.02)。Ueda等[13]后期分析了71例胸段食管癌患者喉返神经旁淋巴结与颈淋巴结转移的情况，喉返神经旁淋巴结阳性与阴性患者颈淋巴结总转移率分别为40.9%和10.2%(P=0.007)，多变量logistic回归分析显示喉返神经旁淋巴结转移与中下段食管癌患者颈淋巴结转移明显相关(P=0.03)。作者进一步比较了41例术中根据喉返神经旁淋巴结冰冻结果决定是否选择颈淋巴结清扫患者的预后情况，当喉返神经旁淋巴结冰冻结果为阳性时选择颈淋巴结清扫，阴性时放弃颈淋巴结清扫，10例因为术中喉返神经旁淋巴结冰冻阳性而接受了颈淋巴结清扫的患者中2例患者经术后病理证实存在颈淋巴结转移。随访结果显示术中根据喉返神经旁淋巴结冰冻结果选择性颈清组患者与常规颈清组患者术后颈淋巴结复发率分别2.6%(1/39)和6.7%(2/30)(P=0.5757)，3年生存率分别为83.3%和57.2%(P<0.05)。Taniyama等[11]和Li等[19]近期研究也显示纵隔内喉返神经旁淋巴结可以作为食管癌颈淋巴结有无转移的预测因子。综上分析，喉返神经旁淋巴结虽然在一定程度上可以预测颈淋巴结转移，但准确率较低。此外，上述均为小样本回顾性研究，证据级别低。因此，喉返神经旁淋巴结能否作为食管癌的前哨淋巴结仍需进一步研究证实。

4 结 语

总之，目前对于上段食管癌及颈部淋巴结阳性患者，三野淋巴结清扫的优势已经逐渐得到认同,但是术后并发症高，因此，对于中下段肿瘤及颈淋巴结阴性患者是否该预防性颈淋巴结清扫目前存在争议。作者认为应该结合颈部超声及肿瘤位置，同时根据患者自身各方面特点选择精准化颈淋巴结清扫。术前颈部淋巴结转移的诊断手段虽然众多，鉴于安全经济及高敏感性和特异性等优点，颈部超声仍然是首选方法，综合淋巴结大小和形态学表现建立阳性诊断标准是较为合理的选择。关于前哨淋巴结的问题，从目前文献来看，喉返神经旁淋巴结与颈淋巴结阳性及阴性一致率都不高。此外，食管癌的淋巴引流系统非常复杂，存在“跳跃转移”特性，常规的检测方法对于淋巴结转移，尤其是对微转移的诊断准确率低。因此，喉返神经旁淋巴结能否作为食管癌的前哨淋巴结仍然存在较大争议。以上问题有待于进一步前瞻性大样本随机对照研究来解决。

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ResearchAdvancesintheDiagnosisandTreatmentoftheCervicalLymphNodeMetastasisofEsophagealCancer*

Wang Haijun1, Han Yongtao1,2△

(1.TheSouthwestMedicalUniversity,Luzhou646000,Sichuan,China; 2.TheDepartmentofThoracicSurgery,SichuanCancerHospital&Intitute,SichuanCancerCenter,SchoolofMedicine,UniversityofElectronicScienceandTechnologyofChina,Chengdu610041,Sichuan,China)

Esophageal cancer is a highly malignant tumor with a poor prognosis. Lymph node involvement and the number of positive nodes , especially the cervical and recurrent laryngeal nerve nodes, are independent prognostic predictors after esophagectomy . Three-field lymphadenectomy (3-FL) may prevent recurrence and prolong survival for esophagus carcinoma when compared with two-field lymphadenectomy (2-FL),whereas it is also a highly invasive procedure that can lead to severe complications .The status of cervical lymph nodes is one of the most important factors to identify whether 3-FL should be performed. Unfortunately,current clinically used approaches demonstrated a lower sensitivity and specificity in identifying cervical lymph node metastasis. Recurrent laryngeal nerve nodes also have been regarded as the sentinel nodes to predict cervical node metastasis with an accuracy of less than 50% . We will review the current diagnosis and treatment progress of cervical lymph node metastasis of esophageal cancer.

Esophageal Cancer； Lymphadenectomy； Cervical Lymph Node; Ultrasonography； Sentinel Node

2017- 02- 24 [

] 2017- 04- 06

*国家科技支撑计划项目(编号：2015BAI12B08)

△韩泳涛，E-mail:hanyongt@aliyun.com

R735.1；R730.41；R730.56

A

10.3969/j.issn.1674- 0904.2017.03.013

Wang HJ, Han YT.Research advances in the diagnosis and treatment of the cervical lymph node metastasis of esophageal cancer [J].J Cancer Control Treat, 2017,30(3):219-225.[王海军, 韩泳涛.胸段食管鳞癌颈淋巴转移诊治进展 [J].肿瘤预防与治疗，2017,30(3):219-225.]