浅表食管癌诊断性内镜切除的技术可行性和肿瘤学安全性GIE201811.ppt

Technical feasibility and oncologic safety of diagnostic endoscopic resection for superficial esophageal cancer 浅表食管癌诊断性内镜切除的技术可行性和肿瘤学安全性,Abstract,Background and Aims: Active use of endoscopic resection (ER) for cM3-SM2 esophageal cancer may enable sufficient extent of esophageal resection and help determine the need for lymph node dissection based on histopathologic findings. However, ER preceding esophagectomy may have an adverse impact on outcomes. This study was designed to determine the technical feasibility and oncologic safety of diagnostic ER. 背景和目的：积极使用内镜切除(ER)治疗cM3-SM2型食管癌，可使食管切除的范围足够，并可根据组织病理学结果确定是否需要淋巴结清扫。然而，食管切除术前ER可能对预后有不良影响。本研究旨在探讨诊断性ER的技术可行性及肿瘤学安全性。,回顾食管癌TNM分期,第八版 TNM 分类,T 分期分为 Tis：高度不典型增生；T1：癌症侵犯黏膜固有层，粘膜肌层或粘膜下层，并被分为 T1a（癌症侵犯黏膜固有层或粘膜肌层）和 T1b（癌侵犯粘膜下层）；T2：癌侵犯固有肌层；T3：癌症侵犯外膜；T4：癌侵入局部结构并且被分类为 T4a：癌侵入相邻结构例如胸膜，心包膜，奇静脉，膈肌或腹膜，T4b：癌侵入主要相邻结构，例如主动脉，椎体或气管。 N 分类为 N0：无区域淋巴结转移; N1：涉及 12 个区域淋巴结转移; N2：涉及 3-6 个区域淋巴结转移；N3：涉及 7 个或以上区域淋巴结转移。M 分类为 M0：无远处转移；M1：远处转移,Methods: A single-institution retrospective cohort study was performed between July 2008 and June 2014. During this period, 135 consecutive patients with clinical T1a-M3N0M0, T1b-SM1N0M0, and T1b-SM2N0M0 primary esophageal cancer were referred to our division. Eight patients who underwent chemoradiotherapy as primary treatment were excluded because of inadequate pathologic findings. Based on oncologic and physical factors, we categorized the remaining 127 patients into 2 groups: primary esophagectomy (n = 54) and primary ER (n = 73). 方法:在2008年7月至2014年6月间进行单机构回顾性队列研究。在此期间，共有135例临床T1a-M3N0M0、T1b-SM1N0M0、T1b-SM2N0M0原发性食管癌患者转入我科。8例以放化疗为主治疗的患者因病理表现不佳被排除在外。根据肿瘤和物理因素，我们将其余127例患者分为两组:直接手术食管切除术(54例)和先行内镜下切除(73例)。,Results: In all 127 patients, the 3-year overall survival (OS) and disease-free survival (DFS) rates were 95.7% and 87.6%, respectively. No adverse event requiring surgical intervention was observed after ER. Diagnostic ER had no negative impact on surgical outcomes, DFS, and OS after esophagectomy. Fourteen patients (19.2%) of those who received primary ER underwent curative resection, whereas 11 (20.4%) who had pT1a disease, no lymphovascular invasion, and no pathologic lymph node metastasis underwent primary esophagectomy. 结果:127例患者的3年总生存率(OS)和无病生存率(DFS)分别为95.7%和87.6%。ER术后无不良事件需要手术治疗。诊断性ER对食管切除术后的手术结局、DFS、OS无不良影响。先行ER患者中有14例(19.2%)行根治性切除，而11例pT1aN0M0患者 (20.4%) 行直接食管切除术。,Conclusions: Diagnostic ER for cM3-SM2 esophageal cancer with or without subsequent esophagectomy was feasible and safe, not only from a surgical perspective but also an oncologic perspective. Approximately 20% of cM3-SM2N0M0 patients can potentially avoid undergoing additional treatment including esophagectomy using diagnostic ER. 结论:cM3-SM2食管癌无论有无后续食管切除术，无论是从手术角度还是从肿瘤学角度，诊断性ER都是可行和安全的。大约20%的cM3-SM2N0M0患者使用诊断性ER可以避免接受包括食管切除术在内的额外治疗。,Introduction,Although esophagectomy with 3-field lymph node dissection is the standard therapy for clinical T1a/T1b (cM3-cSM2)N0M0 esophageal cancer, it has high risk of postoperative mortality and morbidity because of its complexity. The procedure is associated with other long-term postoperative problems, such as aspiration pneumonia caused by dysphagia and malnutrition. 虽然T1a/T1b (cM3-cSM2)N0M0食管癌的标准治疗方法是食管切除术加3野淋巴结清扫，但其复杂性使其术后死亡率和发病率较高。该手术与其他长期的术后问题有关，如吞咽困难引起的吸入性肺炎和营养不良。,Endoscopic resection (ER) is the standard treatment for clinical T1a-M1/M2 N0M0 disease with cancerous involvement of no more than three fourths of the esophageal circumference; it is a safe, less-invasive procedure that preserves esophageal function. ER for pathologic T1a-M1 and T1a-M2 is sufficiently radical because pathologic lymph node metastasis is rarely observed. According to the Japanese Esophageal Society guidelines, ER may be indicated in patients with pathologic T1a-M3 and T1b-SM1 lesions not accompanied by clinical evidence of lymph node metastasis. 内镜切除(ER)是临床T1a-M1/M2 N0M0疾病的标准治疗方法，其癌变累及食管周长不超过四分之三;这是一种安全、低侵入性的保留食管功能的手术。 ER对于病理性T1a-M1和T1a-M2的病变具有足够的根治性，因为很少观察到病理性淋巴结转移。根据日本食管学会的指南，ER可能适用于病理T1a-M3和T1b-SM1不伴有淋巴结转移的临床征象的患者中。,However, performing unnecessary esophagectomy in patients with cT1a-M3/cT1b-SM1/cT1bSM2 disease is possible because tumor depth assessment accuracy is limited even after using magnifying endoscopy with narrow-band imaging (M-NBI), EUS, and esophagography. Moreover, because of technical advances, ER can be safely applied for cT1a-M3/cT1b-SM1/cT1b-SM2 disease and for involvement of more than three-fourths of the esophageal circumference. 然而，对于cT1a-M3/cT1b-SM1/cT1bSM2疾病患者进行不必要的食管切除术是可能的，因为即使使用放大内镜和窄带成像(M-NBI)、EUS和食管造影后，肿瘤深度评估的准确性也有限。此外，由于技术的进步，ER可安全地应用于cT1a-M3/cT1b-SM1/cT1b-SM2疾病，并可用于累及食管周长的四分之三以上的病变。,Therefore, active use of ER and its subsequent pathologic findings (also referred to as diagnostic ER) can help determine the appropriate esophageal resection extent when necessary, combined with radical lymph node dissection, provided that ER preceding esophagectomy does not have any negative impact on outcomes. This study was designed to determine technical feasibility and oncologic safety of diagnostic ER for clinical T1a-M3, T1b-SM1, and T1b-SM2 esophageal cancer. 因此，如果在食管切除术前先行ER对预后没有任何负面影响的话，积极使用ER及其后续病理发现(也称为诊断ER)可以在必要时帮助确定适当的食管切除范围，结合根治性淋巴结清扫。本研究旨在确定临床T1a-M3、T1b-SM1、T1b-SM2食管癌诊断性ER的技术可行性及肿瘤学安全性。,2018.07-2014.06 单中心,Among patients who underwent CRT/radiotherapy or those who received no additional treatment after ER, relapse in regional lymph nodes within 1 year after ER was considered as indicative of pre-existing lymph node metastasis. 在接受CRT/放疗或ER后未接受额外治疗的患者中，ER后1年内局部淋巴结复发被认为是原有淋巴结转移的指示。 Disease-free survival (DFS) and overall survival (OS) were also calculated from the primary treatment date. The presence of residual tumors was classified as R0, no residual tumor; R1, microscopic; and R2, macroscopic residual tumor. 无病生存(DFS)和总生存(OS)也从最初的治疗日期开始计算。残余瘤的存在分为R0，无残余瘤;R1,微观;R2，肉眼可见的残余肿瘤。,Methods,Pretreatment patient workup included laboratory investigations, upper GI endoscopy, esophagography, thoracoabdominal contrast-enhanced CT, and positron emission tomography. Esophageal cancer was diagnosed based on histopathologic examination of endoscopic biopsy specimens. Clinical cancer stage was determined according to International Union Against Cancer, seventh edition. 治疗前的检查包括实验室检查、胃肠道内镜检查、食管造影、胸腹造影增强CT和正电子发射断层扫描。通过内镜活检标本的病理组织学检查诊断食管癌。临床癌症分期根据国际抗癌联盟第七版确定。 Tumor invasion depth was determined by 6 experienced endoscopists based on both macroscopic findings and advanced imaging, including M-NBI according to the Japanese Esophageal Society classification, which is based on degree of microvascular irregularity observed by M-NBI. 肿瘤浸润深度由6名经验丰富的内镜医师根据宏观表现和高级影像确定，其中M-NBI根据日本食管学会分类，根据M-NBI观察到的微血管不规则程度。,On identifying type B1, B2, and B3 vessels in the tumor, the histologic tumor invasion depth was predicted as T1a-M1/M2, T1a-M3/T1b-SM1, and T1b-SM2 or greater, respectively.7,8 B1 is defined as type B vessels with a loop-like formation, B2 is defined as type B vessels without a loop-like formation that have a stretched and markedly elongated transformation, and B3 is defined as highly widened abnormal vessels.7 The avascular area was also defined as a low or no vascularity area surrounded by stretched irregular vessels. Large avascular areas were those 3 mm and were suggestive of T1b-SM2 or greater. 在鉴别肿瘤中B1、B2、B3型血管时，分别预测肿瘤的组织学侵袭深度为T1a-M1/M2、T1a-M3/T1b-SM1、T1b-SM2或以上。b1定义为B型血管有环状结构，B2定义为B型血管无环状结构，具有明显的伸长变形，B3定义为高度加宽的异常血管。无血管区也被定义为被不规则血管包围的低血管区或无血管区。大的无血管区域为3毫米，提示T1b-SM2或更高。,Kumagai等3基于手术切除标本的实体显微镜和组织病理对比研究，提出乳头内毛细血管环(intrapapillary capillary loops，IPCL )的形态变化对区分正常、异常黏膜以及判断食管癌的浸润深度有重要的意义。IPCL是由黏膜下引流静脉分出的树状血管所发出，正常为环形。IPCL常见的形态改变有交织、扩张、直径不规则和IPCL多形性等4种改变。根据IPCL形态改变的程度和局部黏膜碘染色的情况，可分为5级：（1）正常黏膜为碘染色阳性，ICPL形态正常；（2）炎症浸润为碘染色阳性，IPCL有扩张和/或延长；（3）轻度不典型增生则碘染色阴性，IPCL形态无明显改变或改变轻微；（4）重度不典型增生为碘染色阴性，IPCL在交织、扩张、直径不规则及多形性的4种形态改变中占2-3种以上；（5） 食管癌为碘染色阴性，IPCL可同时出现以上4种形态改变。Kumagai同时发现，m1期癌常只有IPCL的扩张，m2期癌的IPCL既有扩张又有延长，m3期癌多表现为IPCL变形和粗大肿瘤血管的混杂，sm期癌则只见到粗大的肿瘤血管，放大胃镜的这种分期与组织病理学的符合率达83.3%（60/72）。,Moreover, we also used chromoendoscopy in combination with M-NBI. The presence of pink-color sign in the Lugol-voiding lesions evaluated a few minutes after spraying with a Lugol dye solution was regarded as diagnosis of esophageal cancer.9 EUS was also used according to the endoscopists preference. Tumor depth was determined using EUS as follows: the second, third, fourth, and fifth layers in a 9-layered image corresponded to the superficial epithelium plus the interface echo, deep epithelium, lamina propria plus interface echo, muscularis mucosae minus interface echo, and submucosa, respectively. Initial endoscopic diagnosis regarding invasion depth was confirmed based on the agreement by expert endoscopists at the medical conference before therapy. 此外，我们还将染色体内镜与M-NBI结合使用。在Lugol染色液喷洒几分钟后，在Lugol-voiding病灶中发现粉红色标记，被认为是食道癌的诊断。也根据内窥镜医师的喜好使用EUS。采用EUS方法确定肿瘤深度:9层图像的第二层、第三层、第四层和第五层分别对应于浅表上皮+界面回声、深层上皮、固有层+界面回声、肌层粘膜减去界面回声和粘膜下层。在治疗前的医学会议上，经内镜专家同意，初步确定了侵入深度的内镜诊断。,In our hospital, combined thoracoscopiclaparoscopic esophagectomy with 3-field lymphadenectomy was primarily performed.15 Only 8 patients underwent thoracic procedures through a right thoracotomy because of their request or the presence of pleural adhesions. Five patients who underwent primary esophagectomy and had lymph node metastasis or pathologic T2 disease underwent postoperative chemotherapy or CRT. In addition, 3 patients who had positive resection margin after esophagectomy also underwent CRT. 在我院，以胸腔镜-腹腔镜联合食管切除术和三段式淋巴结切除术为主。仅8例患者因需要或存在胸膜粘连而行右侧胸廓切开术。5例食管切除术后出现淋巴结转移或病理T2疾病的患者术后接受化疗或CRT治疗。此外，3例食管切除术后切缘阳性的患者也行CRT治疗。,Oncologic follow-up,The discharged patients visited our outpatient clinic at least after 1 month, 3 months, and every 6 months until 5 years after treatment. In the outpatient clinic, routine physical examination and routine laboratory investigations for squamous cell carcinoma antigen, carcinoembryonic antigen, and carbohydrate antigen 19-9 were performed. Upper GI endoscopy was performed once a year after ER to detect local recurrence and metachronous multicentric or multiple cancers. In addition, thoracoabdominal CT was performed every 6 months to detect local recurrence and systemic metastasis at least for 5 years after esophagectomy. 出院患者至少在治疗后1个月、3个月、每6个月到门诊就诊一次，直到5年。门诊对鳞状细胞癌抗原、癌胚抗原、CA19-9进行常规体检及实验室检查。内镜检查一年一次，检查局部复发和异时多中心或多重癌症。此外，每6个月进行一次胸腹CT检查，以发现食管切除术后至少5年的局部复发和全身转移。,Diagnostic accuracy of preoperative staging of tumor depth,We evaluated positive predictive value (PPV) as an indicator of diagnostic accuracy of preoperatively estimated tumor depth. PPV for pathologic T1a-M3, T1b-SM1, and T1b-SM2 in patients with clinical findings of cT1a-M3, cT1b-SM1, and cT1b-SM2 was 70.9% (90/127 patients). PPV for pathologic T1a-M3 and T1b-SM1 was 55.2% (48/87 patients) and for pathologic T1b-SM2 was 42.5% (17/40 patients). PPV for pathologic T1b-SM2 or deeper in patients with a clinical diagnosis of T1b-SM2was 67.5% (27/40 patients). Fourteen patients (19.2%) of those who received primary ER underwent curative resection (defined as pT1a, no lymphovascular invasion, and complete resection), whereas 11 (20.4%) who had pT1a disease, no lymphovascular invasion, and no pathologic lymph node metastasis underwent primary esophagectomy. 我们评估阳性预测值(PPV)作为术前评估肿瘤深度诊断准确性的指标。cT1a-M3、cT1b-SM1、cT1b-SM2病理为T1a-M3、T1b-SM1、cT1b-SM2的患者，其诊断的PPV为70.9%(90/127例)。T1a-M3和T1b-SM1的PPV为55.2%(48/87例)，T1b-SM2为42.5%(17/40例)。T1b-SM2或以上患者的病理诊断为T1b-SM2的PPV为67.5%(27/40)。14例(19.2%)ER患者行根治性切除(定义为pT1a，无淋巴血管浸润，完全切除)，11例(20.4%)患者有pT1a疾病，无淋巴血管浸润，无病理淋巴结转移行食管切除术。,Risk factor for regional lymph node metastasis and recurrence Twenty patients experienced regional lymph node metastasis (n Z 17) or recurrence at regional lymph nodes (n Z 3). Risk factors were determined by using univariate and multivariate analyses. Only lymphatic invasion was found to be a risk factor (P Z .001; hazard ratio HR, 13.54; 95% confidence interval CI, 2.69-68.22). Tumor length was not a statistically significant risk factor (P Z .053; HR, 1.02; 95% CI, .99-1.05); however, the probability of regional lymph node metastasis and recurrence was increased for tumors approximately 5.0 cm in size by using a partial dependency plot (Fig. 3). 区域淋巴结转移和复发的危险因素: 20例患者经历区域淋巴结转移(n=17)或区域淋巴结复发(n=3)，采用单因素和多因素分析确定危险因素。只有淋巴管侵犯被发现是一个危险因素(pz.001;危害比HR， 13.54;95%置信区间CI， 2.69-68.22)。肿瘤长度不是统计学上显著的危险因素。然而，使用部分趋势图，肿瘤大小约5.0 cm，区域淋巴结转移和复发的概率增加(图3)。,According to univariate analyses, noncurative treatment was not a risk factor for death and recurrence; however, several factors, including ASA, performance status, Charlson comorbidity index score 3, lymphatic invasion, vessel invasion, pathologic lymph node metastasis, and tumor invasion depth greater than pT1b-SM2, were identified as significant risk factors. On multivariate analysis using a Cox regression model that included these factors, only vascular invasion and Charlson comorbidity index score 3 were identified as predictors of death. Moreover, ASA , Charlson comorbidity index score 3, and vascular invasion were also identified as predictors of recurrence. 根据单因素分析，非治愈治疗不是死亡和复发的危险因素;但ASA、体能状态、Charlson共病指数评分3、淋巴管浸润、血管浸润、病理淋巴结转移、肿瘤浸润深度大于pT1b-SM2等因素均为显著危险因素。在多因素Cox回归模型中，只有血管性侵犯和Charlson共病指数评分3是死亡的预测因子。此外，ASA、Charlson共病指数3、血管浸润也是复发的预测指标。,Discussion,The present study demonstrated the technical feasibility and oncologic safety of diagnostic ER for clinical T1a-M3, T1b-SM1, and T1b-SM2 esophageal cancer. To our knowledge, this is the first report demonstrating the potential advantages of diagnostic ER over primary esophagectomy for cM3-SM2 esophageal cancer. Few studies have investigated the use of diagnostic ER for minimizing invasive treatment. Fujiya et al. reported that diagnostic endoscopic submucosal dissection should be considered as a primary treatment for limited subset of patients with cT1b gastric cancer. 本研究论证了临床T1a-M3、T1b-SM1、T1b-SM2食管癌诊断性ER的技术可行性及肿瘤学安全性。据我们所知，这是第一个证明ER诊断对于临床M3-SM2食管癌比原来食管切除术有潜在优势的报道。很少有研究调查使用诊断性ER来减少侵入性的治疗。Fujiya等人报道，诊断性内镜下粘膜剥离术应该被认为是cT1b胃癌患者的一个主要治疗方法。,The Japan Clinical Oncology Group has conducted a phase II trial (JCOG0508) to evaluate the efficacy and safety of diagnostic ER + selective CRT for patients with cT1b-SM1 and cT1b-SM2 esophageal cancer. This is a representative study in Japan; however, patients with cT1aM3 tumor were not included in the study. Patients with cT1a-M3 disease and lymph vascular invasion are also at a risk of lymph node metastasis. Therefore, esophageal cancer prognosis must be investigated in these patients, as performed in the present study. This study has 3 major findings. 日本临床肿瘤学组进行了II期试验(JCOG0508)，以评估诊断性ER +选择性CRT对cT1b-SM1和cT1b-SM2食管癌患者的疗效和安全性。 这是日本的一个代表性研究;然而，cT1aM3肿瘤患者并未纳入研究。cT1a-M3疾病和淋巴管浸润患者也有淋巴结转移的危险。因此，这些患者的食管癌预后必须进行调查，正如本研究所做的。这项研究有三个主要发现。,First, our findings clearly suggested no adverse impact of diagnostic ER on short-term outcomes (including hospital stay, operative time, and adverse events) or long-term outcomes compared with those of primary esophagectomy. To our knowledge, no study has investigated the short- and long-term outcomes associated with the use of diagnostic ER to date. Diagnostic ER has potential negative impacts on short- and long-term outcomes, including the possibility of adverse events directly attributable to ER, risk of adverse events after esophagectomy after ER, the possible time lag of additional treatment when patients should undergo additional treatment based on the pathologic findings after ER, and potential increase in recurrence risk because of ER-induced changes in lymphatic flow. 首先，我们的发现明确表明，与原发性食管切除术相比，诊断性ER对短期预后(包括住院时间、手术时间、不良事件)或长期预后没有不良影响。据我们所知，目前还没有研究调查与使用诊断性ER相关的短期和长期结果。诊断性ER对短期和长期的结果有潜在的负面影响,包括直接归因于ER的可能的不良事件,ER之后食管切除术后不良事件的风险，ER病理结果提示患者需要其他治疗时造成的延误治疗，和因为ER诱发的淋巴流动的变化所致潜在的复发风险增加 。,However, in this study, ER was conducted with sufficiently low morbidity and seemed to not be inferior to the outcomes of a previous study. The incidence of postoperative adverse events of esophagectomy in this study was comparable with those in other studies irrespective of performance of diagnostic ER. There was no significant delay of treatment even if the patients underwent primary ER followed by additional treatment. No negative impact was observed on OS and DFS. 然而，在本研究中，ER的发病率很低，似乎并不比之前的研究差。本研究中食管切除术后不良事件的发生率与其他研究中不论有无诊断性ER的病例相当。即使患者进行了ER再进行额外治疗，治疗也没有明显延迟。没有观察到对OS和DFS的负面影响。,Second, this study showed that curative resection was achieved in approximately 20% of the patients with cT1a-M3, T1b-SM1, and T1b-SM2 by ER alone. It is not necessarily easy to precisely predict the invasion depth of esophageal cancer. EUS is the criterion standard for T-staging in the United States and other Western countries. The reported PPVs of mucosal and advanced cancers have previously been found to be 75.0% and 100.0%, respectively, but the true diagnostic accuracy may not be that high because many studies have analyzed only images with good quality and EUS was not superior because of the image quality. Moreover, EUS for esophageal lesion has a risk of aspiration during the procedure. Therefore, M-NBI is more commonly used than EUS in Japan. 其次，本研究表明，约20%的cT1a-M3、T1b-SM1、T1b-SM2患者仅通过ER就达到了治疗性切除。准确预测食管癌侵袭深度并非易事。EUS是美国等西方国家T分期的主要标准。黏膜和晚期癌症的阳性预测者以前分别被发现为75.0%和100.0%，但真正的诊断准确率可能没有那么高，因为很多研究都有只分析高质量的图像，而EUS的图像质量并不优越。此外，食管病变的EUS术中有误吸风险。因此，在日本，M-NBI比EUS更常用。,Recently, some studies have reported promising diagnostic accuracy for prediction of invasion depth. In contrast to these studies, the PPVs for cT1a-M3 or cT1b-SM1 and cT1b-SM2 or deeper were 55.2% and 67.5%, respectively, in this study, even when using M-NBI. Our results seem to be inferior to these previous studies. A possible explanation for this discrepancy is the difference in study populations. We only included patients with estimated invasion depths deeper than the muscularis mucosae (MM), whereas most patients in previous studies showed invasion of the epithelium/lamina propria mucosae (EP/LPM). The present study suggests that diagnostic ER should have clinical significance for lesions with esti