Abstract
目的
探讨合并尘肺的非小细胞肺癌患者的手术安全性。
方法
本研究收集了从2019年8月–2021年5月在四川大学华西第四医院就诊的165例非小细胞肺癌患者的临床资料，其中21例患者合并尘肺，为尘肺组，剩余144例患者为普通组。两组均行肺癌根治术。比较分析两组患者围手术期的临床资料，包括术前、术中、术后指标。
结果
两组患者均无围手术期死亡。尘肺组男性患者比例以及有吸烟史患者比例高于普通组（P<0.05）；尘肺组患者体质量指数、肺通气功能、弥散功能低于普通组（P<0.05）。尘肺组中位手术时间和中位术中出血量与普通组比较差异无统计学意义；尘肺组Ⅱ期/Ⅲ期肿瘤比例、术后并发症发生率、中位术后拔管天数和中位术后住院天数均高/长于普通组（P<0.05）；尘肺组淋巴结钙化、胸膜致密粘连发生率和更改手术方式发生率（从胸腔镜手术转换为开放手术或胸腔镜辅助）也较普通组更高（P<0.05）。单因素分析显示年龄、吸烟史、尘肺、肺功能受损、淋巴结钙化、胸膜致密粘连、术中出血量是非小细胞肺癌患者发生术后并发症的危险因素（P<0.05），进一步多因素回归分析显示吸烟史（OR=1.37，P<0.05）、淋巴结钙化（OR=2.36，P<0.05）和肺功能受损（OR=5.21，P<0.05）是发生术后并发症的独立危险因素。
结论
尘肺患者行肺癌根治手术围手术期风险相对更高，应引起术者及护理人员重视。
Keywords: 尘肺, 非小细胞肺癌, 围手术期, 术后并发症
Abstract
Objective
To explore the surgical safety of patients with comorbid non-small cell lung cancer (NSCLC) and pneumoconiosis.
Methods
In this study, the clinical data of 165 NSCLC patients treated at West China Fourth Hospital, Sichuan University from August 2019 to May 2021 were collected. Among them, 21 patients with comorbid pneumoconiosis were included in the pneumoconiosis group, and the remaining 144 patients were included in the general group. Radical resection for lung cancer was performed in both groups. The perioperative clinical data, including preoperative, intraoperative and postoperative indicators, of the two groups were compared and analyzed.
Results
There was no perioperative death in either group. The proportions of male patients and patients with smoking history in the pneumoconiosis group were significantly higher than those in the general group (P<0.05). The body mass index (BMI), pulmonary ventilation function and diffusion function in the pneumoconiosis group were significantly lower than those in the general group (P<0.05). There was no significant difference in the median operative time and the median volume of intraoperative blood loss between the pneumoconiosis group and the general group. In the pneumoconiosis group, the proportion of advanced tumors (stage Ⅱ/Ⅲ), incidence of postoperative complications, median duration of postoperative intubation, and postoperative length of hospital stay were higher/longer than those of the normal group (P<0.05). Compared with the general group, the incidences of lymph node calcification, dense pleural adhesion and surgical method alteration (switching from thoracoscopic surgery to open surgery or video-assisted thoracoscopy) were also significantly higher in the pneumoconiosis group (P<0.05). Univariate analysis showed that age, smoking history, pneumoconiosis, pulmonary ventilation dysfunction, lymph node calcification, dense pleural adhesion and the volume of intraoperative blood loss were the risk factors for postoperative complications. Further multivariate regression analysis demonstrated that smoking history (OR=1.37, P<0.05), lymph node calcification (OR=2.36, P<0.05) and pulmonary ventilation dysfunction (OR=5.21, P<0.05) were independent risk factors for postoperative complications.
Conclusion
NSCLC patients with comorbid pneumoconiosis face relatively greater risks during the perioperative period when they undergo radical resection for lung cancer. Therefore, the close attention of surgeons and the nursing staff should be raised accordingly.
Keywords: Pneumoconiosis, Non-small cell lung cancer, Perioperative period, Postoperative complications
尘肺病是在职业活动中长期吸入生产性粉尘并在肺内潴留而引起肺组织不可逆弥漫性纤维化为主的全身性疾病[1]。发展中国家空气污染、职业暴露等因素相对突出，尘肺病等间质性肺疾病发生率显著高于发达国家[2]。我国尘肺病患者总数及新增患者数在全球均排第一，并且还在呈现不断增长的态势[3]。肺癌作为世界以及我国致死率最高的恶性肿瘤，每年发病率不断升高[4-5]，其中85%的病理类型是非小细胞肺癌[6]。基于这样的流行病学背景，尘肺合并肺癌患者在我国数量巨大。有部分尘肺患者初次确诊肺癌时，肿瘤本身具备手术根治性切除指征，但患者身体状况相对较差，肺功能有不同程度受损，严重者存在低氧和二氧化碳潴留，使得其围手术期安全性成为胸外科医生头痛的难题。尘肺患者多于职业病专科医院就诊，目前国内外关于尘肺患者合并肺癌手术安全性的研究报道甚少。我院作为国家卫生健康委员会直属以职业病防治等为特色的综合医院，尘肺就诊患者相对较多。本研究收集了2019年8月–2021年5月在我科住院行肺癌根治术的21例尘肺患者的临床资料，与同期普通肺癌患者进行比较，对合并尘肺的肺癌患者围手术期安全性进行了初步探索，并分析术后并发症发生的危险因素。现报道如下。
1. 资料与方法
1.1. 患者选择
回顾性收集2019年8月–2021年5月在我科住院行肺癌根治术的165例患者的临床资料，均为非小细胞肺癌患者。男性51例，女性115例。年龄40～83岁，根据有无尘肺疾病分为尘肺组（n=21）和普通组（n=144）。尘肺组入组标准为：①有多年职业暴露病史，胸部影像学表现符合《职业病尘肺诊断》（GBZ 70-2015），经职业病科诊断为尘肺；②不合并其他全身性疾病，如高血压、冠心病、慢性阻塞性肺疾病（chronic obstructive pulmonary disease, COPD）等；③术前评估肿瘤可R0切除；④术中冰冻和术后病理均证实为非小细胞肺癌。排除标准为：①肺通气功能障碍：根据英国胸科协会（British Thoracic Society, BTS）与美国胸内科医生协会（American College of Chest Physician, ACCP）推荐：肺叶切除需术前第一秒用力呼气容积（forced expiratory volume in 1 second, FEV1）>1.5 L。普通组入组标准：除不合并尘肺外，其余和尘肺组标标准一致；普通组排除标准和尘肺组一致；期间4例Ⅲ期尘肺合并肺癌患者，FEV1≤1.5 L，未行手术；②局部晚期肿瘤，术前评估无法R0手术切除。普通组患者均无职业暴露史，无尘肺病以及其他疾病（高血压、冠心病、COPD等）。两组患者均在电视胸腔镜下进行肺癌根治术。本研究经四川大学华西第四医院医学伦理委员会批准（批件号 HXSY-EC-2022007）。
1.2. 数据收集
通过电子病历系统收集患者的围手术期临床资料，包括：①术前指标：患者年龄、性别、体质量指数（body mass index, BMI）、吸烟史、肺功能。肺功能指标主要包括：肺活量（vital capacity, VC），肺总量（total lung capacity, TLC），FEV1，用力肺活量（forced vital capacity, FVC），单次呼吸的一氧化碳的扩散能力（carbon monoxide diffusing capacity in a single breath, DLCOSB）；②术中指标：手术方式（胸腔镜、胸腔镜中转开胸或扩大切口）、术中出血量、胸膜致密粘连情况、淋巴结钙化情况、手术时间；③术后指标：肿瘤分期、术后胸腔引流管留置时间、术后并发症发生（并发症主要为重度漏气、肺部感染、切口感染）以及术后住院时间。
1.3. 统计学方法
计量资料以
表示，其中符合正态分布的计量资料采用独立样本t检验，不符合正态分布的计量资料采用Mann-Whitney U检验。计数资料以频数和百分比（%）表示，比较采用χ2检验，当不满足χ2检验标准时采用Fisher确切概率法。分析术后发生并发症的危险因素时采用Cox回归分析。P<0.05为差异有统计学意义。
2. 结果
2.1. 术前资料
结果见表1。尘肺组和普通组患者年龄差异无统计学意义。尘肺组男性患者比例以及有吸烟史患者比例高于普通组（P<0.01），尘肺组BMI低于普通组（P<0.05）；两组患者肺功能比较尘肺组肺通气功能以及肺弥散功能（FEV1、FVC、DLCOSB）较普通组差（P<0.05），两组患者的肺容量（VC、TLC）无明显差异（P>0.05）。
表 1. Patients’ basic information and lung function.
患者基本资料以及肺功能
| Characteristic | Pneumoconiosis group (n=21) | General group (n=144) | P |
| VC: Vital capacity; TLC: Total lung capacity; FEV1: Forced expiratory volume in 1 second; FVC: Forced vital capacity; DLCOSB: Carbon monoxide diffusing capacity in a single breath. | |||
| Age/yr., median (P25,
P75) |
54 (52, 56) | 56.5 (45.5, 61.5) | 0.88 |
| (Male/female)/case | 21/0 | 91/53 | <0.01 |
| Smoking history/case (%) | 15 (71.43) | 78 (54.17) | <0.01 |
BMI/(kg/m2),
|
20.11±2.36 | 21.55±2.06 | 0.02 |
VC/L,
|
2.38±1.55 | 3.05±1.21 | 0.82 |
TLC/L,
|
5.85±0.64 | 5.99±0.79 | 0.75 |
FEV1/L,
|
1.28±0.80 | 1.98±0.41 | 0.04 |
FVC/L,
|
1.67±0.65 | 2.20±1.35 | <0.01 |
| DLCOSB/(mL/[min·
mmHg]), 
|
4.32±1.98 | 5.59±1.60 | 0.02 |
2.2. 两组术中以及术后资料
结果见表2。两组患者术后并发症（主要为重度漏气、肺部感染、切口感染）发生率、手术方式更改发生率、淋巴结钙化发生率、胸膜致密粘连发生率、Ⅱ期和Ⅲ期肿瘤比例（Ⅱ期/Ⅲ期）、术后拔管天数和术后住院天数的差异有统计学意义（P<0.05），尘肺组更高/长；在手术时间和术中出血方面两组差异无统计学意义。
表 2. Intraoperative and postoperative conditions of patients in the two groups.
两组患者术中及术后情况
| Intraoperative and post-
operative conditions |
Pneumoconiosis
group (n=21) |
General group (n=144) | P |
| *Postoperative complications included severe air leak, lung infection, and surgical site infection. # Median (P25, P75). | |||
| Complication*/case (%) | 12 (57.14) | 15 (10.42) | 0.012 |
| Surgical method alteration/case (%) | 10 (47.62) | 16 (11.11) | 0.010 |
| Lymph-nodes calcified/case (%) | 12 (57.14) | 27 (18.75) | 0.010 |
| Dense pleural adhesion/case (%) | 6 (28.57) | 13 (9.03) | 0.020 |
| Operative time#/min | 141 (140, 226) | 126 (125, 198) | 0.590 |
| Intraoperative blood loss volume#/mL
|
200 (100, 400) | 100 (50, 200) | 0.110 |
| Postoperative intubation time#/d | 6 (5, 7) | 5 (4, 5) | 0.040 |
| Postoperative hospital stay#/d | 10 (9, 11) | 7 (6, 9) | <0.010 |
| Tumor stage/case (%) | |||
| Ⅰ | 4 (19.05) | 55 (38.19) | 0.040 |
| Ⅱ/Ⅲ | 17 (80.95) | 89 (61.81) | 0.010 |
2.3. 术后并发症发生危险因素的单因素分析
分析性别、年龄（中年组≤60岁和老年组>60岁）、BMI（患者BMI的中位数为21.2 kg/m2，将患者分为BMI≥21.2 kg/m2组和BMI<21.2 kg/m2组）、吸烟史、尘肺、肿瘤分期、肺通气功能障碍、手术方式更改、淋巴结钙化、胸膜致密粘连、术中出血量是否为术后并发症发生的危险因素。单因素分析结果如表3所示。年龄、吸烟史、尘肺、肺通气功能障碍、淋巴结钙化、胸膜致密粘连、术中出血量是患者术后发生并发症的危险因素（P<0.05）。
表 3. Univariate analysis of postoperative complications.
术后并发症的单因素分析
| Characteristic | Postoperative complications | P | |
| No (n=138) | Yes (n=27) | ||
| Gender/case | 0.670 | ||
| Male | 95 | 17 | |
| Fmale | 43 | 10 | |
| Age/case | 0.030 | ||
| ≤60 yr. | 88 | 12 | |
| >60 yr. | 50 | 15 | |
| BMI/case | 0.550 | ||
| ≥21.2 kg/m2 | 71 | 12 | |
| <21.2 kg/m 2 | 67 | 15 | |
| Smoking history/case | 0.020 | ||
| Yes | 64 | 19 | |
| No | 74 | 8 | |
| Pneumoconiosis/case | 0.020 | ||
| Yes | 10 | 11 | |
| No | 128 | 16 | |
| Tumor stage/case | 0.650 | ||
| Ⅱ/Ⅲ | 88 | 18 | |
| Ⅰ | 50 | 9 | |
| Pulmonary ventilation
dysfunction/case |
0.010 | ||
| Yes | 37 | 19 | |
| No | 101 | 8 | |
| Surgical method replacement/case | 0.160 | ||
| Yes | 18 | 8 | |
| No | 120 | 19 | |
| Lymph-nodes calcified/case | <0.010 | ||
| Yes | 21 | 18 | |
| No | 117 | 9 | |
| Dense pleural adhesion/case | <0.050 | ||
| Yes | 13 | 6 | |
| No | 125 | 21 | |
| Intraoperative blood loss
volume/mL, median (P25, P75) |
100 (50, 100) | 200 (90, 450) | 0.015 |
2.4. 术后并发症发生危险因素的多因素回归分析
将单因素分析中差异有统计学意义的指标纳入多因素分析进行逐步回归，结果如表4所示。吸烟史、淋巴结钙化和肺通气功能障碍是术后发生并发症的独立危险因素。有吸烟史患者术后发生并发症的风险为无吸烟史患者的1.37倍，淋巴结钙化的患者术后发生并发症的风险是非淋巴结钙化患者的2.36倍，肺通气功能障碍患者发生术后并发症的风险是肺功能正常患者的5.21倍。
表 4. Multivariate analysis of postoperative complications(n =165) .
术后并发症的多因素分析（n=165）
| Characteristic | B | SE | Wald | OR | P | 95% CI |
| B: Partial regression coefficient; SE: Standard error; CI: Confidence interval; OR: Odds ratio. | ||||||
| Smoking history | 0.90 | 0.32 | 7.90 | 1.37 | <0.001 | 1.07-10.74 |
| Lymph node calcification | 3.12 | 0.67 | 21.42 | 2.36 | <0.001 | 1.76-27.76 |
| Pulmonary ventilation
dysfunction |
1.34 | 0.36 | 13.85 | 5.21 | <0.001 | 2.22-30.67 |
3. 讨论
目前2020版美国国立综合癌症网络（National Comprehensive Cancer Network, NCCN）指南对于患尘肺的非小细胞肺癌患者的手术适应症以及治疗方案并没有确切的意见。本研究收集了我科近2年手术治疗的非小细胞肺癌患者的临床资料，包括尘肺患者和普通患者，比较两组患者不同的临床特点，分析尘肺对手术的影响，并探寻术后并发症的危险因素。
从术前基本资料可以看出，尘肺组患者存在致术后并发症发生的危险因素。首先，尘肺组男性患者比例以及吸烟史比例明显高于普通组。煤矿工作人员以男性为主[7]，2018年全国第六次国家卫生服务调查我国成年人男性吸烟比例明显高于女性[8]。吸烟导致多种肺部疾病，吸烟患者肺部手术术后有更高的并发症发生率[9]。其次，尘肺组BMI明显低于普通组。BMI反映患者营养状况，MATSUOKA等[10]发现肺癌患者BMI越低，围手术期会出现更多并发症，5年生存率明显更低。另外，尘肺组肺功能较普通组低。两组患者肺功能的比较，发现尘肺组患者肺功能受损主要表现在肺通气指标和弥散指标降低。BLACKLEY等[11]提出尘肺患者肺部改变以肺纤维化为主，多表现为阻塞性通气障碍，通气功能下降，肺弥散功能亦受影响明显，而肺容积相对正常或轻微下降。肺功能较差（特别是FEV1、FVC较低）的肺癌患者往往术后出现并发症相对较多，住院时间更长[12]。综上，尘肺合并肺癌患者存在多种危险因素，围手术期会有更高的风险。
胸腔镜下肺癌根治术是目前非小细胞肺癌主要的手术方式，手术切口小，创伤小、并发症少，长期疗效与开放手术相当[13-14]。本研究观察到尘肺组患者手术中更改手术方式、扩大切口的比例高于普通组。尘肺患者常常出现胸膜腔致密粘连和肺部淋巴结纤维化，致密粘连的胸膜腔导致腔镜操作没有空间。纤维化后的淋巴结嵌顿在支气管、血管之间，牵拉周围组织结构，又称其为门钉淋巴结。这些情况致使胸腔镜手术存在较大的风险，而术中及时更改手术方式后，两组患者均顺利完成手术，平均手术时间、术中出血量无明显差异，手术风险并未明显增加。
两组患者术后情况，主要比较了肿瘤分期、并发症发生率、住院天数以及留置胸腔引流管天数等临床资料。尘肺组Ⅱ期和Ⅲ期肿瘤患者所占比例较高，尘肺患者因经济困难，多数没有常规体检，未能在早期发现肿瘤。更重要的是，普通CT在分辨尘肺与肺癌方面存在一定的困难，这可能降低了肺癌的诊断率，目前推荐高分辨CT乃至磁共振成像来提高尘肺肺癌的诊断率[15]。尘肺组患者并发症发生率明显高于普通组，术后并发症以重度漏气为主，其余为肺部感染和伤口感染。查阅文献以及结合临床经验，我们认为尘肺患者BMI较低，吸烟史比例高，肺通气以及弥散功能较差，都会增加肺癌患者术后并发症发生[16]；其次尘肺患者更常出现胸膜致密粘连和淋巴结纤维化，术中清扫钙化淋巴结、游离粘连胸膜可能损伤肺组织以致术后长期漏气。尘肺组术后肺部漏气比例高，留置胸腔引流管天数以及住院天数必然更多。针对这些并发症采取一些应对措施，术中使用LigaSure游离淋巴结以及粘连的肺组织尽量减少术后漏气的发生[17]，对于术后持续漏气的患者可使用胸腔内灌注粘连剂等方法；肺部感染则加强痰液引流，根据细菌药敏结果调整抗菌药物；伤口感染则局部换药时充分清理分泌物，必要时二期缝合。所有术后患者最终均痊愈出院，无1例患者死于术后并发症。
对患者术后并发症危险因素的单因素分析结果显示，年龄、吸烟史、尘肺、肺通气功能障碍、淋巴结钙化、胸膜致密粘连和术中出血量是术后并发症发生的危险因素，多因素回归分析发现吸烟史、淋巴结钙化和肺通气功能障碍是术后并发症发生的独立危险因素。东京医科大学肿瘤中心一项从2008年到2012年的研究发现，肺功能受损是肺癌术后并发症发生的独立危险因素[18-20]。多因素分析中尘肺并不是术后并发症发生的独立危险因素，原因可能是尘肺作为危险因素受其他因素的影响，但肺纤维化、炎症渗出是尘肺主要的病理改变，淋巴结钙化也是尘肺患者较常见的表现，这些肺部改变导致肺功能特别是肺通气功能受损，并且手术难度以及风险增加。肺通气功能障碍、淋巴结钙化这些独立危险因素与尘肺密切相关，由此可见尘肺对肺癌术后并发症发生影响较大。如何减少尘肺患者术后并发症，减轻围手术期患者身体上的痛苦和经济上的负担，是我们下一步需要解决的问题。除了戒烟，改善术前肺功能是关键。近些年术前肺康复治疗得到越来越广泛的关注和重视，目前很多研究提出的术前肺康复，包括：吸气肌训练、呼吸再训练和气道廓清技术，能显著改善肺功能，且能减少肺部手术术后并发症[21-23]。
综上，合并尘肺的非小细胞肺癌患者手术难度大，围手术期风险高，并发症相对多。但术前准确的评估、严格把控适应症，术中由具有丰富经验的胸外科手术医生根据情况选择合适的手术方式，这些措施使尘肺合并肺癌患者手术安全性得到保障。
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