Abstract
目的
总结分析左侧肺鳞癌和腺癌4L组淋巴结转移的临床病理学特征及4L组淋巴结转移的危险因素。
方法
回顾性纳入2008年1月~2020年4月在解放军总医院第一医学中心胸外科行左侧肺癌切除+4L组淋巴结清扫的患者134例，依据病理学类型不同分为肺鳞癌组（60例）及肺腺癌组（74例），分析两组间围术期临床病理学特征差异，用logistic回归探讨4L组淋巴结转移的危险因素。
结果
所有患者4L组淋巴结转移率16.4%（22/134），两组患者在年龄、性别、吸烟史、新辅助化疗、肿瘤大小、肿瘤位置及类型、脏层胸膜侵犯、Ki-67指数、4L组淋巴结转移及病理分期（Ⅱ期）有统计学差异，肺鳞癌患者4L组淋巴结转移率明显低于肺腺癌。单因素分析显示病理类型（鳞癌/腺癌）、肺膜侵犯、脉管癌栓、肿瘤标志物阳性、第5组淋巴结转移、第6组淋巴结转移、第7组淋巴结转移、第8组淋巴结转移、第9组淋巴结转移及第10组淋巴结转移是4L组淋巴结转移的高危因素，多因素分析发现，病理类型（鳞癌/腺癌）（OR=0.120，P=0.025）、第5组淋巴结转移（OR=18.784，P=0.007）及第10组淋巴结转移（OR=5.233，P=0.044）为4L组淋巴结转移的独立危险因素。
结论
左侧肺癌出现4L组淋巴结转移并不少见，肺腺癌更易出现，在评估周围结构损伤风险较低，且4L组淋巴结转移可能性较大后应当予以清扫。
Keywords: 左侧肺癌, 4L组淋巴结, 转移, 危险因素
Abstract
Objective
To analyze the clinicopathological characteristics and risk factors of 4L lymph node metastasis in left non-small cell lung cancer.
Methods
We retrospectively analyzed the data of 134 patients undergoing surgical resection of left non-small cell lung cancer and 4L lymph node dissection, including 60 patients with squamous cell carcinoma (SCC) and 74 with lung adenocarcinoma (ADC). The clinicopathological characteristics of the patients were analyzed, and logistic regression analysis was used to identify the predictors of station 4L metastasis.
Results
Of these patients, 16.4% (22/134) presented with station 4L metastasis. The patients with SCC and ADC showed significant differences in age, gender, smoking history, neoadjuvant chemotherapy, tumor size, tumor location and type, visceral pleural invasion, Ki-67 index, 4L metastasis and pathological TNM stage (stage Ⅱ). The rate of station 4L metastasis was significantly lower in SCC group than in ADC group. Univariate analysis revealed that pathological types (SCC or ADC), visceral pleural invasion, lymphovascular invasion, tumor markerabnormality, and station 5 to 10 metastasis were all high-risk factors for station 4L metastasis. Multivariate analysis suggested that the pathological type (OR=0.120, P=0.025), station 5 metastasis (OR=18.784, P=0.007) and station 10 metastasis (OR=5.233, P=0.044) were independent risk factors for 4L metastasis in patients with left non-small cell lung cancer.
Conclusion
In patients with left non-small cell lung cancer, station 4L metastasis is not rare and is more likely to occur in patients with lung adenocarcinoma. Dissection of the 4L lymph nodes should be performed in cases with low risk of damages of the adjacent tissues and high risk of station 4L metastasis.
Keywords: left lung cancer, station 4L lymph node, metastasis, risk factors
肺癌是世界上最常见的恶性肿瘤，发病率和致死率牢牢占据第一并仍呈逐年上升趋势，淋巴结转移是肺癌最常见和最主要的转移途径，其转移率在30%到40%不等[1]。肺叶切除联合系统性淋巴结清扫术一直是可切除非小细胞肺癌的标准术式[2-3]，淋巴结清扫对于肺癌的精准分期、预后分析及系统治疗有着极其重要的作用[4]，并能在一定程度上降低局部复发率、提高患者远期生存率。目前对淋巴结清扫范围仍存在一些争议[2, 5-6]，4L组淋巴结由于其独特的位置及毗邻关系，在实际临床工作中清扫率并不高，多数胸科中心将左侧5、6、7、9、10、11组淋巴结作为常规清扫对象，而4L组淋巴结受限于认识、临床经验及手术技巧的缘故常常被忽略。近年来几项研究总结左侧肺癌4L组淋巴结转移的特征并再次突出清扫的重要性[7-13]，但国内外尚无研究从不同病理类型的角度分析4L组淋巴结转移状况的报道。本研究回顾性分析134例左侧肺鳞癌及腺癌患者4L组淋巴结清扫的临床资料，总结二者之间不同的临床病理学特征，分析4L组淋巴结转移的危险因素，探索左侧肺癌行4L组淋巴结清扫的临床价值，希望能给后续研究提供思路，现报道如下。
1. 资料和方法
1.1. 一般资料
回顾性分析2008年1月至2020年4月在解放军总医院第一医学中心胸外科行左侧肺癌手术患者的相关资料，纳入标准：（1）术中行肺叶切除（包括左全肺）+系统性淋巴结（包括4L组）清扫；（2）术后病理类型为鳞癌及腺癌，排除标准：（1）术后病理为原位癌、微浸润性癌、转移癌及其他类型肿瘤；（2）未达到国际肺癌研究协会（IASLC）建议的淋巴结清扫要求：清扫站数小于3组，未包括第7组淋巴结；（3）影像学提示直径小于2cm的纯磨玻璃结节（pGGO）或磨玻璃成分大于75%的混合GGO mGGO）；（4）亚肺叶切除，包括肺段切除及局部切除；（5）术前评估有远处转移不适合手术者。
1.2. 术前评估
患者术前均接受常规化验检查，包括肿瘤标志物、血气分析、心电图、心脏超声、肺功能、头颅CT/MRI、胸部CT、腹部超声、颈部淋巴结超声、全身骨扫描，部分患者还行全身正电子发射-计算机断层显像（PET/CT），评估后均无手术禁忌症。
1.3. 手术方法
常规全身麻醉，采用双腔气管插管，右侧卧位，右侧单肺通气。切口位于第4或第5肋间，开胸或胸腔镜手术（VATS），解剖性肺叶切除、袖式切除或全肺切除，系统性淋巴结清扫。4L组淋巴结的清扫要点：在迷走神经主干与主动脉弓下缘交汇处，暴露左喉返神经起始，牵拉左肺动脉干，显露动脉韧带后方、主动脉弓下方、肺动脉干上方及左侧气管下段左侧区域，即为4L组淋巴结所在。尽量整块切除淋巴结及其周围脂肪组织，避免用力牵拉、夹持神经，注意能量器械的运用。
1.4. 观察指标
收集患者一般情况（包括年龄、性别、吸烟史、肿瘤家族史等）、围术期指标（术式、淋巴结清扫情况、肿瘤位置和大小）、术后并发症情况及组织病理结果。病理均由我院病理科两位经验丰富的病理医师评估。淋巴结清扫依据IASLC新版淋巴结分布图进行区分[14]，其中组织病理学结果按照IASLC第八版肺癌TNM（Tumor, Node, Metastasis）分期标准进行分期[15]，腺癌根据2015年WHO肺腺癌分类进行分析[16]。
1.5. 统计学分析
采用SPSS20.0统计学软件，对所有数据进行正态性和方差齐性检验，正态分布的计量资料用均数±标准差表示，两组间资料比较采用独立样本t检验，非正态分布的计量资料采用M（QR)表示，组间比较采用非参数检验。计数资料用率和百分比表示，组间比较用χ2检验。应用logistic回归模型对4L组淋巴结转移及其影响因素进行单因素分析后得出有统计学差异的因素并进一步行多因素分析。P < 0.05时认为差异有统计学意义。
2. 结果
最终纳入134例研究对象，其中男性95例（70.9%），女性39例（29.1%）；年龄37~82岁，平均年龄（60.43±8.57）岁。根据病理类型不同分为肺鳞癌（SCC）组（n=60）与肺腺癌（ADC）组（n=74）。
2.1. SCC组和ADC组的一般资料比较
两组患者在年龄、性别、吸烟史、新辅助化疗方面均有统计学差异，SCC组年龄普遍大于ADC组；性别方面SCC组男性占比91.7%，ADC组男性占比54.1%，远低于SCC组；SCC组患者吸烟史占比73.3%，远高于ADC组的44.6%；有11.7%的SCC患者选择术前新辅助化疗，远高于ADC组。但两组患者在术前合并症及家族肺癌病史上并无统计学差异（表 1）。
1.
SCC组和ADC组的一般资料
Baseline characteristics of patients with pulmonary squamous cell carcinoma (SCC) and adenocarcinoma (ADC)
| Variables | SCC (n=60) | ADC (n=74) | P |
| Age (year) | 62.80±7.34 | 58.51±9.05 | 0.003 |
| Gender/case | < 0.001 | ||
| Male n (%) | 55 (91.7%) | 40 (54.1%) | |
| Female | 5 (8.3%) | 34 (45.9%) | |
| Smoking | 0.001 | ||
| Yes | 44 (73.3%) | 33 (44.6%) | |
| No | 16 (26.7%) | 41 (55.4%) | |
| Comorbidities | 0.890 | ||
| Yes | 22 (36.7%) | 28 (37.8%) | |
| No | 38 (63.3%) | 46 (62.2%) | |
| Neoadjuvant chemotherapy | 7 (11.7%) | 1 (1.4%) | 0.013 |
| Family history of lung cancer | 3 (5%) | 4 (5.4%) | 0.917 |
2.2. SCC组和ADC组的肿瘤特征及手术情况比较
两组患者在肿瘤大小、肿瘤位置及类型和术中出血量上有统计学差异，SCC患者肿瘤直径较大，更多表现为中央型占位，这使得肿瘤的分布在左上叶及左下叶较为平均，且均为实性结节，而ADC患者多表现为周围型占位，主要分布在左肺上叶，且有16.2%（12/74）的结节为mGGO。SCC患者术中出血量多于ADC患者，这可能与SCC患者较多为中央型占位、手术难度更高有关。两组患者在手术方式（肺叶切除/全肺切除、VATS/开胸）、淋巴结清扫（站数及数目）及术后并发症（包括声嘶）方面并无统计学差异（表 2）。
2.
SCC组和ADC组的肿瘤特征及手术情况
Surgical outcomes and tumor characteristics in patients in SCC and ADC groups
| Variables | SCC | ADC | P |
| Tumor diameter (mm) | 43.69±17.49 | 30.58±15.77 | < 0.001 |
| Tumor location | |||
| Left upper lobe | 35 (55.6%) | 55 (74.3%) | 0.051 |
| Left lower lobe | 28 (44.4%) | 19 (25.7%) | 0.012 |
| Anatomical type | < 0.001 | ||
| Central | 30 (50%) | 13 (17.6%) | |
| Peripheral | 30 (50%) | 61 (82.4%) | |
| CT characteristics | 0.001 | ||
| Solid | 60 | 62 | |
| Mixed-GGO | 0 | 12 | |
| Surgical procedure | |||
| Pneumonectomy | 18 (30%) | 16 (21.6%) | 0.270 |
| Lobectomy | 42 (70%) | 58 (78.4%) | 0.270 |
| VATS | 16 (26.7%) | 27 (36.5%) | 0.228 |
| Open thoracotomy | 44 (73.3%) | 47 (63.5%) | 0.228 |
| Blood loss (mL) | 195±210.47 | 123.78±93.80 | 0.017 |
| Lymph node dissection | |||
| Sampling stations | 5.52±1.20 | 5.42±1.41 | 0.671 |
| Sampling numbers | 16.22±8.03 | 14.43±6.71 | 0.163 |
| Postoperative complications | 13 (21.7%) | 10 (13.5%) | 0.215 |
| Hoarseness | 4 (6.7%) | 3 (4.1%) | 0.501 |
| Death within 30 d | 0 | 1 (1.4%) | 0.368 |
2.3. SCC组和ADC组的病理结果比较
所有患者4L组淋巴结转移为16.4%（22/134），仅次于第10组的转移率24.6%（33/134），高于第5组的转移率12.7%（17/134）、第11组的转移率10.4%（14/134）、第7组的转移率8.2%（11/134）、第6组的转移率2.2%（3/134）、第9组的转移率2.2%（3/134）、第12组的转移率1.5%（2/134）及第8组的转移率0.7%（1/134）。两组患者在脏层胸膜侵犯、Ki-67指数、4L组淋巴结转移及病理分期（Ⅱ期）有统计学差异，SCC患者较少出现脏层胸膜侵犯，但Ki-67指数明显高于ADC患者，4L组淋巴结转移率明显低于ADC患者，而病理分期Ⅱ期明显多于ADC组。两组患者在脉管癌栓、无淋巴结转移、N1淋巴结转移、N2淋巴结转移、第5组转移、第6组转移、第7组转移、第8组转移、第9组转移、第10组转移、第11组转移、第12组转移及病理分期（Ⅰ期、Ⅲ期、Ⅳ期）等方面并无统计学差异。如若剔除4L组淋巴结转移的计算，有4例患者将从pN2降为pN1，有2例患者将从pN2降为pN0（表 3）。
3.
SCC组和ADC组的病理结果
Pathological results of patients in SCC and ADC groups
| Variables | SCC | ADC | P |
| Visceral pleural invasion | 18 (30%) | 38 (51.4%) | 0.013 |
| Lymphovascular invasion | 2 (3.3%) | 6 (8.1%) | 0.240 |
| Ki-67 index (%) | 55.42±21.80 | 35.20±27.05 | < 0.001 |
| pN stage | |||
| N0 | 35 (58.3%) | 45 (60.8%) | 0.896 |
| N1 | 19 (31.7%) | 24 (32.4%) | 0.925 |
| N2 | 11 (18.3%) | 23 (31.1%) | 0.093 |
| 4L metastasis | 5 (8.3%) | 17 (23%) | 0.023 |
| Station 5 metastasis | 6/42 (14.3%) | 11/55 (20%) | 0.402 |
| Station 6 metastasis | 1/13 (7.7%) | 3/16 (18.75%) | 0.421 |
| Station 7 metastasis | 5/60 (8.3%) | 6/74 (8.1%) | 0.962 |
| Station 8 metastasis | 1/7 (14.3%) | 0/11 (0) | 0.365 |
| Station 9 metastasis | 3/51 (5.9%) | 0/52 (0) | 0.116 |
| Station 10 metastasis | 16/60 (26.7%) | 18/74 (24.3%) | 0.758 |
| Station 11 metastasis | 6/43 (14%) | 9/50 (18%) | 0.694 |
| Station 12 metastasis | 1/2 (50%) | 1/7 (14.3%) | 0.881 |
| pTNM stage | |||
| Ⅰ | 22 (36.6%) | 37 (50%) | 0.123 |
| Ⅱ | 20 (33.3%) | 12 (16.2%) | 0.021 |
| Ⅲ | 17 (28.3%) | 25 (33.8%) | 0.500 |
| Ⅳ | 1 (1.7%) | 0 | 0.267 |
2.4. 4L组淋巴结转移的影响因素
单因素logistic回归分析4L组淋巴结转移的危险因素提示：病理类型（鳞癌/腺癌）、肺膜侵犯、脉管癌栓、肿瘤标志物（癌胚抗原CEA、细胞角蛋白19片段CYFRA21-1、鳞状细胞癌抗原）阳性、第5组转移、第6组转移、第7组转移、第8组转移、第9组转移及第10组转移是4L组淋巴结转移的高危因素，见表 4。进一步多因素logistic回归分析发现，病理类型（鳞癌/腺癌）、第5组转移及第10组转移为4L组淋巴结转移的独立危险因素（表 5）。
4.
单因素分析4L组淋巴结转移的影响因素
Univariate analysis of correlation between clinicopathological factors and station 4L metastasis
| Variable | OR | 95%CI | P |
| Gender | 1.482 | 0.506-4.344 | 0.471 |
| Age (≤60 yrs/> 60 yrs) | 0.483 | 0.190-1.222 | 0.120 |
| Smoking history | 1.083 | 0.428-2.742 | 0.866 |
| Neoadjuvant chemotherapy | 0.714 | 0.083-6.114 | 0.758 |
| Histology (SCC/ADC) | 0.305 | 0.105-0.883 | 0.023 |
| Visceral pleural invasion | 4.800 | 1.740-13.242 | 0.001 |
| Lymphovascular invasion | 5.944 | 1.363-25.934 | 0.009 |
| Left upper lobe | 1.816 | 0.623-5.297 | 0.269 |
| Left lower lobe | 0.490 | 0.168-1.426 | 0.184 |
| Central neoplasm | 0.811 | 0.291-2.261 | 0.688 |
| Tumor marker abnormality | 4.037 | 1.332-12.238 | 0.010 |
| Tumor diameter (> 4 cm/≤4 cm) | 0.993 | 0.392-2.516 | 0.989 |
| Station 5 metastasis | 17.667 | 5.469-57.069 | < 0.001 |
| Station 6 metastasis | 17.526 | 1.731-177.434 | 0.001 |
| Station 7 metastasis | 8.025 | 2.192-29.384 | < 0.001 |
| Station 8 metastasis | 0.159 | 0.107-0.235 | 0.024 |
| Station 9 metastasis | 11.1 | 0.961-1283273 | 0.017 |
| Station 10 metastasis | 8.050 | 2.979-21.755 | < 0.001 |
| Station 11 metastasis | 1.316 | 0.339-5.111 | 0.691 |
| Station 12 metastasis | 0.833 | 0.772-0.899 | 0.528 |
| Cell differentiation | |||
| Well | 0.825 | 0.762-0.894 | 0.196 |
| Moderate | 0.331 | 0.105-1.042 | 0.050 |
| Poor | 2.072 | 0.818-5.250 | 0.120 |
| Unknown | 2.240 | 0.707-7.092 | 0.162 |
5.
多因素分析4L组淋巴结转移的影响因素
Multivariate analysis of correlation between clinicopathological factors and station 4L metastasis
| Variable | OR | 95%CI | P |
| OR: Odds ratio; CI: Confidence interval. | |||
| Histology (SCC/ADC) | 0.120 | 0.019-0.765 | 0.025 |
| Visceral pleural invasion | 2.290 | 0.458-11.441 | 0.313 |
| Lymphovascular invasion | 8.605 | 0.621-113.714 | 0.102 |
| Tumor marker abnormality | 3.664 | 0.620-21.666 | 0.152 |
| Station 5 metastasis | 18.784 | 2.212-159.506 | 0.007 |
| Station 6 metastasis | 0.035 | 0.000-6.459 | 0.208 |
| Station 7 metastasis | 11.942 | 0.725-196.707 | 0.083 |
| Station 8 metastasis | - | - | 0.999 |
| Station 9 metastasis | - | - | 1 |
| Station 10 metastasis | 5.233 | 1.046-26.182 | 0.044 |
3. 讨论
近年来放化疗、靶向治疗及免疫治疗的快速发展，肺癌的治疗手段多样化，预后也在一定程度上得到改善，但其病死率仍旧占据癌症病死率第一，主要原因就是多数肺癌患者在就诊时已发生淋巴结转移，尤其是纵隔淋巴结转移。而对于可切除非小细胞肺癌的淋巴结清扫范围，学术界仍有一些分歧。包括NCCN指南[2]、IASLC[15]、ESMO指南[17]及ESTS指南[18]在内的国外几大权威机构，均建议彻底的纵隔淋巴结清扫应至少包括隆突下淋巴结在内的3站，但对左侧肺癌清扫4L组淋巴结并未做常规推荐。而4L组淋巴结是淋巴回流的重要中转站之一，其重要性并未像右侧4R组淋巴结被提到该有的高度。前言提及国内几大胸科中心关于左肺癌4L组淋巴结转移特征及其对预后的影响研究，相关国外杂志述评仍对此态度不一[19-21]。
4L组淋巴结有着特殊的解剖结构，其与主动脉弓、胸导管和左喉返神经的毗邻关系使得清扫它有着一定的挑战性，即便是在手术量大、经验丰富的胸科中心，相当一部分胸外科医生也会忽略它的清扫[22-23]，因为这毫无疑问会减少损伤主动脉弓、左喉返神经及相邻结构所导致的相应并发症[23-24]。然而，Wang等[7]、Zhao等[8]、Fang等[9]及Yang等[10]的研究中，左侧肺癌4L组淋巴结的转移率分别为20.9%（29/139）、14.6%（67/460）、11.9%（48/405）及11.8%（46/391）。我们的研究中有16.4%（22/134）患者出现4L组淋巴结转移，与其它研究结果类似，可见4L组淋巴结转移率并不低[7-10, 25-26]。进一步分析，如若剔除4L组淋巴结转移的计算，有4例患者将从pN2降为pN1，有2例患者将从pN2降为pN0，这将显著影响这6位患者最终的pTNM分期及后续治疗方案的制定和预后的判断。从生存率的角度分析，Fang等[9]的研究认为4L组淋巴结阳性的患者有着更差的远期预后，而Wang等[7]的研究显示清扫4L组淋巴结与不清扫4L组淋巴结的5年无病生存率（DFS）和全因死亡率（OS）分别为（54.8% vs 42.7%，P=0.0376）和（58.9% vs 47.2%，P=0.02），Zhao等[8]的研究显示5年DFS和OS分别为（52.6% vs 46.7%，P=0.022）和（65.8% vs 56.3%，P=0.006），Yang等[10]的研究显示5年OS为（72.9% vs 62.3%，P=0.002）。由此可见4L组淋巴结的清扫对生存率有改善[7-8, 10, 25]。获益的原因我们考虑主要有两方面：首先，系统性清扫带来更少的肿瘤细胞残留，即治疗效果；再者，系统性清扫带来更准确的分期，患者能从后续辅助治疗（放化疗、靶向治疗及免疫治疗）中获益。
在此基础上，我们的研究还有新发现：左肺鳞癌和腺癌两组患者在肺门淋巴结转移率（10、11、12）、纵隔淋巴结转移率（5、6、7、8、9）并未显示出统计学差异，但4L组淋巴结的转移率却有着明显差异（8.3% vs 23%，P=0.023），这在国内外研究中尚属首次发现，我们推测这与腺癌容易早期出现淋巴结转移和血行转移有关[27]。肺鳞癌与腺癌患者的一般临床资料、手术情况及病理学特征，与流行病学调查及既往研究显示的特征一致[28]。
在4L组淋巴结转移的影响因素探索方面，有研究显示肿瘤直径[8, 13]、左上叶占位[13]、术前临床N2分期[8]、第5组淋巴结转移[9, 12]、第7组淋巴结转移[12]、第8组淋巴结转移[12]及第10组淋巴结转移[7-8, 12]是其独立危险因素，并建议若肿瘤直径大于3 cm，术前评估怀疑淋巴结转移，应行包括4L组淋巴结在内的系统性清扫。本研究显示病理学类型、第5组淋巴结转移及第10组淋巴结转移是4L组淋巴结转移的独立危险因素，与前述研究结果一致，第5组和第10组淋巴结作为独立危险因素屡次出现在不同的研究中，我们推测这两组淋巴结与4L组淋巴结存在过渡区（主肺动脉窗和气管支气管角），这也能解释部分研究显示左上叶肺癌更易出现4L组淋巴结转移[10, 13, 29]。
清扫4L组淋巴结未成为共识，主要原因还是其独特的解剖位置和清扫可能引起的并发症。本研究中术后并发症（声音嘶哑、心律失常、乳糜胸等）发生率为17.2%（23/134），声音嘶哑发生率为5.2%（7/134），与既往研究报道并发症率类似[12]，在可接受范围内，多数胸外科医生关注的术后声音嘶哑问题与清扫第5组淋巴结也存在较大关联。因此担心可能出现的并发症并不是清扫4L组淋巴结的障碍，对它的认识、清扫技能及其给左侧肺癌患者带来的生存获益，才是我们应该认真审慎的。
我们的研究，存在以下几点局限性：首先，这是一篇单中心回顾性研究，难免存在选择偏移和样本量较少等因素对结果的干扰，也未做倾向性评分平衡组间的变量差异及偏移；再者，缺少患者的随访资料，使得4L组淋巴结清扫对生存率的改善与否存疑，还需进一步完善随访结果。希望后期能有多中心的随机对照试验，来进一步评估4L组淋巴结的清扫价值。
综上所述，左侧肺癌出现4L组淋巴结转移并不少见，肺腺癌更易出现，在评估周围结构损伤风险较低，且4L组淋巴结转移可能性较大后应当予以清扫。
Biography
申磊磊，在读博士研究生，主治医师，E-mail: drshenats@163.com
Contributor Information
申 磊磊 (Leilei SHEN), Email: drshenats@163.com.
梁 朝阳 (Chaoyang LIANG), Email: chaoyangliang301@sina.com.
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