内镜治疗早期贲门癌、拉网筛查食管癌、头颈部癌合并食管癌的相关研究

发布时间：2018-08-15 17:20

【摘要】：第一部分内镜下黏膜切除术与内镜黏膜下剥离术在治疗食管胃交界早期病变(Siewert Ⅱ型)的回顾性研究前言：随着内镜治疗技术的发展,内镜下治疗食管胃交界的早期病变已成为了一种选择。据了解,到目前为止尚无文献报道内镜下黏膜切除术(EMR)和内镜黏膜下剥离术(ESD)在治疗食管胃交界早期病变的单中心临床对照研究。为此,我们进行了一项回顾性研究,目的就是分析比较EMR与ESD在治疗食管胃交界早期病变方面的可行性、安全性和有效性。材料和方法：本项研究包括130例接受内镜治疗的食管胃交界早期病变患者,其中52例接受EMR、78例接受ESD。内镜操作时间、并发症、整块切除率、完整切除率和复发率是这项研究的主要指标。结果： EMR组和ESD组在年龄、性别构成、病变大小、病理分型、内镜分型和肿瘤浸润深度方面并没有明显的统计学差异(P0.05)。ESD组较EMR组手术操作时间更长(64.4±33.9 min vs 22.1±8.0 min;P0.05)。ESD组较EMR组更易发生并发症(16.7% vs 3.8%；P0.05),并发症包括出血(7.7% vs 3.8%),穿孔(5.1%vs 0%)和术后狭窄(5.1% vs 0%)。ESD组较EMR组有更高的整块切除率和完整切除率(98.7%和92.3% vs 23.1%和23.1%；P0.05)。ESD组较EMR组复发率较低(0% vs 7.7%；P0.05)。结论：在治疗食管胃交界早期病变方面,ESD较EMR存在更高的技术难度,但是ESD在整块切除率和完整切除率方面明显高于EMR,同时ESD随访结果显示其复发率较低。因此,上述试验结果显示内镜黏膜下剥离术和内镜下黏膜切除术在治疗食管胃交界早期病变的明显不同,内镜黏膜下剥离术优于内镜下黏膜切除术,特别是对于病变直径超过14mm的病变。当然,如果内镜下黏膜切除术可以达到整块切除的标准,仍不失是治疗食管胃交界早期病变的一个选择。第二部分海绵拉网胶囊(CytospongeTM)联合p53免疫组织化学染色筛查早期食管癌及癌前病变中的应用前言：我国是食管鳞癌的最高发的国家之一,在食管癌的高发区已经开展了应用内镜下碘染色进行筛查的项目。鉴于在全部高危人群开展以内镜为主的筛查项目在成本、技术和风险上都存在一定的问题。因此,我们需要一种简单、成本低的方法作为初筛工具。为此,我们在食管癌高发区开展了海绵拉网胶囊(CytospongeTM)联合p53免疫组织化学染色筛查早期食管癌及癌前病变这项前瞻性队列研究,以判断其在筛查早期食管癌及癌前病变中的可行性、安全性和有效性。材料和方法：87例受试者年龄的中位数为58岁(24～70岁),包括52名男性受试者(59.8%)和35名女性受试者(40.2%)。所有受试者先进行拉网检查,填写调查问卷后,进行内镜检查或接受内镜下治疗。结果：根据活检或内镜治疗术后的病理诊断,本试验共包括28例正常食管、11例食管炎、12例轻度不典型增生(LGIN)、13例中度不典型增生(MGIN)、14例重度不典型增生(HGIN)和9例早期食管癌(EESCC)。以异型的鳞状细胞(Atypia)作为标志物,海绵拉网胶囊(CytospongeTM)筛查食管鳞状上皮轻度不典型增生(LGIN)、中度不典型增生(MGIN)的敏感度均低于10%,但在筛查食管重度不典型增生和早期食管鳞状细胞癌方面的敏感度可以达到约70%、特异度为93.8%。而以p53阳性的异型的鳞状细胞(p53+ Atypia)作为标志物,海绵拉网胶囊筛查筛查食管鳞状上皮重度不典型增生(HGIN)和早期食管鳞状细胞癌(EESCC)的敏感度仅为26.1%、特异度为98.4%。结论：海绵拉网胶囊(CytospongeTM)是一种简单、安全、易于接受的筛查工具,将其应用于筛查食管重度不典型增生和早期食管癌的敏感度可以达到约70%,但是以p53作为生物标志物以提高敏感度的预期没有达到。第三部分头颈部鳞状细胞癌伴发食管鳞状细胞癌的相关研究前言：头颈部鳞状细胞癌(HNSCC)患者,特别是发生在口腔、口咽及下咽者,经常会伴发食管鳞状细胞癌(ESCC).HNSCC伴发ESCC通常用“区域癌化”进行阐释。多原发肿瘤需要多种治疗措施相结合,但是对于异时多原发癌,对先发的肿瘤的治疗措施有可能会影响第二原发肿瘤的治疗。材料和方法：8例食管癌伴发早期下咽癌的患者接受了内镜黏膜下剥离术,其中有2例患者下咽部病变为双原发癌,即共10处病变。3例头颈部鳞癌患者因既往接受过放化疗或外科手术造成食管入口或颈段食管狭窄,导致普通内镜无法通过。这3例患者接受了经腹入路早期食管癌内镜下黏膜切除术。另外,我们收集了8例头颈部鳞癌伴发食管鳞癌患者的肿瘤组织标本、配对癌旁标本及血液标本进行二代基因检测。结果：8例食管癌伴发早期下咽癌的患者(共10处病变),下咽处病变均接受内镜黏膜下剥离术,所有病例均达到了整块切除,整块切除率为100%。在这组病例中,有2例病变侧切缘烧灼处存在重度不典型增生,因此8处病变符合完整切除,完整切除率为80%；所有病例均未发生并发症且随访期间无复发发生。3例头颈部鳞癌患者因既往接受过放化疗或外科手术造成食管入口或颈段食管管腔狭窄,导致普通内镜无法通过,此3例患者均成功接受了经腹入路早期食管癌内镜下黏膜切除术。在这组病例中,除1例发生术后食管狭窄,未发生其他并发症且随访期间未发现局部复发。8例头颈部鳞癌合并食管鳞癌标本基因检测的结果为：1、肿瘤组织的基因及其相应的外周血及血浆的基因显示出高度的一致性,同时血浆里游离的基因也显示出一定的突变位点,虽然同相对应的肿瘤组织比起来,这种突变位点要少一些,但是它却远远超过了相应外周血细胞的突变位点；2、5个突变位点(EGFR 8-p.E330*/13-p.P512L;ERBB212-p.L485/20-p.D821N;NRAS 5- p.K170N;PIK3CA 11-p.V580E,14- p.H701L;RB12- p.R46S/6- p.L199*)仅出现在同一个患者的头颈部鳞癌组织中,但未出现在食管癌组织中。结论：在治疗食管癌伴发早期下咽癌中,内镜黏膜下剥离术是一项既安全有效又侵入性较小的治疗措施。同时,对于既往因头颈部鳞癌接受治疗导致内镜不能对早期食管癌进行治疗的患者可以采用经腹入路早期食管癌内镜下黏膜切除术。通过对头颈部鳞癌伴发食管鳞癌基因检测研究发现,有可能利用个体血浆中脱落的DNA替代肿瘤组织本身进行基因位点突变检测,另外,食管癌与下咽癌在肿瘤基因突变位点上的存在差异,这可以帮助判断肿瘤是否为转移或双原发,同时指导下一步的精确的靶向治疗。
[Abstract]:Part I. Retrospective study of endoscopic mucosal resection and submucosal dissection in the treatment of early esophagogastric junction lesions (Siewert type II). Preface: With the development of endoscopic treatment technology, endoscopic treatment of early esophagogastric junction lesions has become a choice. It is understood that no literature has reported so far. We conducted a retrospective study to compare the feasibility, safety and efficacy of endoscopic submucosal dissection (ESD) and mucosal resection (EMR) in the treatment of early esophagogastric junction lesions. The study included 130 patients with early esophagogastric junction lesions treated with endoscopy, 52 with EMR, 78 with ESD. Endoscopic operation time, complications, block resection rate, complete resection rate and recurrence rate were the main indicators of this study. There was no significant difference between ESD group and EMR group (P 0.05). The operation time of ESD group was longer than that of EMR group (64.4+33.9 min vs 22.1+8.0 min; P 0.05). Complications in ESD group were more likely to occur (16.7% vs 3.8%; P 0.05), including bleeding (7.7% vs 3.8%), perforation (5.1% vs 0%) and postoperative stenosis (5.1% vs 0%). ESD group had a lower recurrence rate than EMR group (0% vs 7.7%; P 0.05). Conclusion: ESD has a higher technical difficulty than EMR in the treatment of early esophagogastric junction lesions, but ESD has a higher overall resection rate and complete resection rate than EMR. The ESD follow-up results also showed a low recurrence rate. Therefore, these results suggest that endoscopic submucosal dissection and endoscopic mucosal resection are significantly different in the treatment of early lesions at the esophagogastric junction. Endoscopic submucosal dissection is superior to endoscopic mucosal resection, especially for lesions larger than 14 mm in diameter. Endoscopic mucosal resection can reach the standard of block resection, but it is still a choice for the treatment of early esophagogastric junction lesions. Part II: Application of CytospongeTM combined with p53 immunohistochemical staining in screening early esophageal cancer and precancerous lesions. Foreword: China is one of the countries with the highest incidence of esophageal squamous cell carcinoma. Endoscopic iodine staining screening has been carried out in high-risk areas of esophageal cancer. In view of the cost, technical and risk problems of endoscopic-based screening in all high-risk groups, we need a simple, low-cost method as a primary screening tool. A prospective cohort study was conducted to determine the feasibility, safety and efficacy of CytospongeTM combined with p53 immunohistochemical staining in screening early esophageal cancer and precancerous lesions. Materials and Methods: The median age of 87 subjects was 58 years (24-70 years). Fifty-two male subjects (59.8%) and 35 female subjects (40.2%) were enrolled in the study. All subjects underwent screening, completed questionnaires, and underwent endoscopy or endoscopic treatment. Results: According to the pathological diagnosis after biopsy or endoscopic treatment, 28 normal esophagus, 11 esophagitis and 12 mild SARS were included in the study. Type I hyperplasia (LGIN), moderate atypical hyperplasia (MGIN) in 13 cases, severe atypical hyperplasia (HGIN) in 14 cases and early esophageal carcinoma (EESCC) in 9 cases. The sensitivity of CytospongeTM to detect mild atypical hyperplasia (LGIN) and moderate atypical hyperplasia (MGIN) in esophageal squamous epithelium was lower than 10% with atypia as a marker. The sensitivity and specificity for screening severe atypical hyperplasia and early esophageal squamous cell carcinoma were 70% and 93.8% respectively, while p53 positive atypical squamous cells (p53 + Atypia) were used as markers for screening severe atypical hyperplasia (HGIN) and early esophageal squamous cell carcinoma (EESC). Conclusion: CytospongeTM is a simple, safe and easy-to-accept screening tool. The sensitivity of CytospongeTM in screening for severe atypical esophageal hyperplasia and early esophageal cancer can reach about 70%, but it is not expected to increase the sensitivity by using p53 as a biomarker. Part III. Preface: Head and neck squamous cell carcinoma (HNSCC) patients, especially in the oral cavity, oropharynx and hypopharynx, often accompanied by esophageal squamous cell carcinoma (ESCC). HNSCC accompanied by ESCC is usually explained by "regional carcinogenesis". Multiple primary tumors need more. Materials and Methods: Eight patients with esophageal carcinoma complicated with early hypopharyngeal carcinoma underwent endoscopic submucosal dissection. Among them, 2 patients with hypopharyngeal lesions were double primary carcinoma, i.e. 10 lesions. Three patients underwent endoscopic mucosal resection via abdominal approach for early esophageal cancer. In addition, tumor specimens from 8 patients with head and neck squamous cell carcinoma complicated with esophageal squamous cell carcinoma were collected. Results: Eight patients with esophageal carcinoma complicated with early hypopharyngeal carcinoma (10 lesions) underwent endoscopic submucosal dissection. All patients achieved total resection, with a total resection rate of 100%. Because of atypical hyperplasia, 8 lesions accorded with complete resection, and the complete resection rate was 80%. All cases had no complications and no recurrence occurred during follow-up. Three patients with head and neck squamous cell carcinoma had stenosis of the esophageal entrance or cervical esophagus caused by previous radiotherapy, chemotherapy or surgery, which resulted in the failure of general endoscopy. Endoscopic mucosal resection of early esophageal carcinoma via abdominal approach was successfully performed. In this group of patients, no complications occurred except one case of postoperative esophageal stricture, and no local recurrence was found during the follow-up period. The results of gene detection in 8 cases of head and neck squamous cell carcinoma complicated with esophageal squamous cell carcinoma were as follows: 1. The plasma gene showed a high degree of consistency, and the plasma free gene also showed a certain mutation site, although compared with the corresponding tumor tissue, this mutation site is less, but it is far more than the corresponding peripheral blood cell mutation site; 2,5 mutation sites (EGFR 8-p.E330*/13-p.P512L; ERBB212; -p.L485/20-p.D821N; NRAS 5-p.K170N; PIK3CA 11-p.V580E, 14-p.H701L; RB12-p.R46S/6-p.L199*) only appeared in head and neck squamous cell carcinoma of the same patient, but did not appear in esophageal carcinoma. Conclusion: Endoscopic submucosal dissection is safe, effective and less invasive in the treatment of esophageal carcinoma with early hypopharyngeal carcinoma. Meanwhile, endoscopic mucosal resection of early esophageal cancer through abdominal approach may be used in patients who were previously unable to be treated by endoscopy for head and neck squamous cell carcinoma. In addition, there are differences between esophageal cancer and hypopharyngeal cancer in gene mutation sites, which can help to determine whether the tumor is metastatic or dual primary, and guide the next step of accurate targeted therapy.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735;R739.91

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