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Prognostic implications of mucosal and deep margin distances according to -status in oral tongue squamous cell carcinoma: A single-center retrospective study
根据 口腔舌鳞状细胞癌状态的粘膜和深缘距离的预后影响:一项单中心回顾性研究

Valentine Poissonnet MD | Bertille Segier MSc | Raphaël Lopez MD, PhD |
瓦伦丁·泊松内 MD |Bertille Segier 理学硕士 |Raphaël Lopez 医学博士,博士 |
Aurore Siegfried MD | Agnès Dupret-Bories MD, PhD | Jérôme Sarini MD |
奥罗尔·齐格弗里德 MD |Agnès Dupret-Bories 医学博士、博士 |杰罗姆·萨里尼 MD |
Vinciane Poulet MD | Franck Delanoë MD | Sébastien Vergez MD, PhD |
Vinciane Poulet 医学博士 |弗兰克·德拉诺 MD |Sébastien Vergez 医学博士、博士 |
Emilien Chabrillac MD
埃米利安·夏布里拉克(Emilien Chabrillac),医学博士

Department of Surgery, University Cancer Institute of Toulouse - Oncopole, Toulouse, France
图卢兹大学癌症研究所外科系 - Oncopole,图卢兹,法国
Department of Ear, Nose & Throat Surgery, Toulouse University Hospital - Larrey Hospital, Toulouse, France
图卢兹大学医院耳鼻喉外科 - 法国图卢兹拉里医院
Department of Biostatistics, Claudius Regaud Institute, University Cancer Institute of Toulouse - Oncopole, Toulouse, France
图卢兹大学癌症研究所克劳迪乌斯·雷戈研究所生物统计学系 - 法国图卢兹市Oncopole
Department of Maxillofacial Surgery, Toulouse University Hospital - Pierre Paul Riquet Hospital, Toulouse, France
图卢兹大学医院颌面外科 - 法国图卢兹皮埃尔·保罗·里凯医院
Department of Pathology, University Cancer Institute Oncopole and Toulouse University Hospital, Toulouse, France
法国图卢兹肿瘤大学癌症研究所和图卢兹大学医院病理学系

Correspondence 通信

Emilien Chabrillac, Department of Surgery, University Cancer Institute of Toulouse - Oncopole, 1 avenue Irène Joliot-Curie, 31100 Toulouse, France. Email: chabrillac.emilien@iuctoncopole.fr
Emilien Chabrillac,图卢兹大学癌症研究所外科 - Oncopole,1 avenue Irène Joliot-Curie,31100 Toulouse,France。电子邮件: chabrillac.emilien@iuctoncopole.fr
Section Editor: Benjamin Judson
栏目编辑:本杰明·贾德森

Abstract 抽象

Objective: To elucidate the prognostic implications of mucosal and deep margin distances in oral tongue squamous cell carcinoma (OTSCC), and to assess a different margin cut-off value in T1-T2 versus T3-T4 tumors.
目的:探讨口腔舌鳞状细胞癌(OTSCC)黏膜和深缘距离的预后意义,并评估T1-T2与T3-T4肿瘤的不同切缘临界值。

Methods: This single-center retrospective study included 223 patients who received surgery for a primary OTSCC between January 2017 and December 2021.
方法:这项单中心回顾性研究纳入了 2017 年 1 月至 2021 年 12 月期间接受原发性 OTSCC 手术的 223 例患者。

Results: Multivariable analysis showed that deep margin distance in T1-T2 tumors and in T3-T4 tumors was significantly associated with better RFS and OS. Mucosal and deep margin distances were globally clinically useful for 2-year RFS prediction of T1-T2 tumors, for which deep margins seemed to have more clinical utility than mucosal margins. The influence of margin distances on 2-year RFS seemed greater for T1-T2 tumors than T3-T4 tumors.
结果:多变量分析显示,T1-T2 肿瘤和 T3-T4 肿瘤的深切缘距离 与较好的 RFS 和 OS 显著相关。 黏膜和深切缘距离对 T1-T2 肿瘤的 2 年 RFS 预测具有全球临床意义,深切缘似乎比黏膜边缘更具临床效用。对于 T1-T2 肿瘤,边缘距离对 2 年 RFS 的影响似乎大于 T3-T4 肿瘤。

Conclusion: Mucosal and deep margin distances were associated with OS and RFS in OTSCC. Shorter deep margin distances may be aimed for in T1-T2 versus T3-T4 tumors.
结论:OTSCC黏膜和深缘距离与OS和RFS相关。与 T3-T4 肿瘤相比,T1-T2 的深切缘距离可能更短。

KEYWORDS 关键字

glossectomy, margin, recurrence, squamous cell carcinoma, tongue cancer
舌切除术、边缘、复发、鳞状细胞癌、舌癌

1 | INTRODUCTION 1 |介绍

Head and neck cancers are the sixth cancer worldwide, and among them oral cavity squamous cell carcinoma (SCC) is by far the most common cancer of head and neck, accounting for of all new cancers. The mainstay of their treatment is primary surgery. When excision margins are "close" or involved, current recommendation suggests re-resection or adjuvant treatment with radiotherapy (RT) or chemoradiotherapy (CRT). Surgical margins is one of the main prognostic factors for local control and survival in oral cavity cancers, and more specifically in tongue SCC. However, many other prognostic factors are involved, and the decision for adjuvant treatment relies on several factors, for example, -status, tumor differentiation, perineural invasion (PNI), and lymphovascular emboli (LVE).
头颈癌是全球第六大癌症, 其中口腔鳞状细胞癌(SCC)是迄今为止最常见的头颈癌, 占所有新发癌症的比重。 他们的主要治疗是初次手术。当切缘“接近”或受累时,目前的建议建议重新切除或用放疗 (RT) 或放化疗 (CRT) 辅助治疗。 手术切缘是口腔癌局部控制和生存的主要预后因素之一, 更具体地说是舌鳞状细胞癌。 然而,还涉及许多其他预后因素,辅助治疗的决定取决于几个因素,例如 状态、肿瘤分化、神经周围浸润 (PNI) 和淋巴血管栓塞 (LVE)。
While all oral cavity subsites are pooled in the 8th edition of the TNM staging system of the American Joint Committee on Cancer (AJCC), it is proven that all prognostic factors do not carry the same importance and incidence among oral cavity subsites. In the era of precision medicine, some of these subsites should be studied separately.
虽然所有口腔亚位点都汇总在美国癌症联合委员会 (AJCC) 第 8 版 TNM 分期系统中,但事实证明,所有预后因素在口腔亚位点中的重要性和发生率并不相同。 在精准医学时代,其中一些亚位点应该单独研究。
Practices vary among centers regarding macroscopic and microscopic surgical margin distances. Since it is difficult to find the best balance between oncological safety and morbidity of the surgery, the optimal surgical margin threshold in oral cavity SCC is still debated. The most recent meta-analysis tends to favor a threshold, however without distinguishing mucosal and deep margins, and regardless of tumor-related factors, for example, T-status, PNI, worst pattern of invasion.
关于宏观和微观手术切缘距离的实践因中心而异。 由于很难在肿瘤学安全性和手术发病率之间找到最佳平衡,因此口腔鳞状细胞癌的最佳手术切缘阈值仍存在争议。最近的荟萃分析倾向于设定 阈值,但不区分黏膜和深缘,也不考虑肿瘤相关因素,例如 T 状态、PNI、最差的浸润模式。
With regards to oral tongue SCC, a threshold has historically been considered as a "negative" margin and known to yield satisfactory oncologic outcomes, however with few studies differentiating T1-T2 and T3-T4 tumors. More recently, literature showed a trend toward suggesting narrower margin thresholds, up to regardless of T-status. large multicentric study by Otsuru et al. with robust methods analyzed receiver operating characteristic curves and suggested a mucosal margin threshold and a deep margin threshold for better local control in T1-T2 oral tongue SCC. Thus, we proposed a clinically applicable threshold inspired by the threshold from the literature review by Spence et al. and by rounding up the 3.1and thresholds of the Otsuru study, that is, for both mucosal and deep margins in T1-T2 tumors, and for both mucosal and deep margins in T3-T4 tumors.
关于口腔舌鳞状细胞癌, 阈值历来被认为是“阴性”边缘,并且已知会产生令人满意的肿瘤学结果,但很少有研究区分 T1-T2 和 T3-T4 肿瘤。 最近,文献显示, 无论 T 状态如何,都倾向于建议更窄的边际阈值。 Otsuru 等人的大型多中心研究采用稳健的方法分析了受试者的工作特征曲线,并提出了粘 膜边缘阈值和 深边缘阈值,以更好地控制 T1-T2 口腔舌鳞状细胞癌的局部控制。 因此,我们提出了一个临床适用的阈值,该阈值的 灵感来自 Spence 等人的文献综述, 并通过对 Otsuru 研究的 3.1 和 阈值进行四舍五入,即 T1-T2 肿瘤的粘膜和深缘,以及 T3-T4 肿瘤的粘膜和深缘。
To the best of our knowledge, only the study by Lee et al. compared early (T1-T2) and advanced (T3-T4) tongue SCC and hypothesized that a larger resection margin may be needed in more advanced T categories. In the era of precision medicine, more data are needed to determine the mucosal and deep surgical margin distances to aim for according to T-status.
据我们所知,只有 Lee 等人的研究比较了早期 (T1-T2) 和晚期 (T3-T4) 舌鳞状细胞癌,并假设更晚期的 T 类别可能需要更大的切除切缘。 在精准医疗时代,需要更多的数据来根据 T 状态确定要瞄准的粘膜和深部手术切缘距离。
The aim of this study was to comprehensively elucidate the prognostic implications of mucosal and deep margin distances in oral tongue SCC, as well as to assess a different margin cut-off value in versus T3-T4 tumors.
本研究的目的是全面阐明口腔舌鳞状细胞癌粘膜和深缘距离的预后意义,并评估 与 T3-T4 肿瘤的不同缘临界值。

2 | MATERIALS AND METHODS
2 |材料与方法

This single-center retrospective study was conducted in a comprehensive cancer center. Included patients received primary surgical treatment for a SCC arising from the oral tongue between January 2017 and December 2021. The study started 2 years after the last included patient was treated in order to theoretically have a minimum of 2 years of follow-up. Patients were operated in two different departments, however all pathological analyses were carried out in the same pathology department. Exclusion criteria were as follows: recurrent tumor, history of neck irradiation, history of another head and neck cancer in the past 5 years, distant metastasis at diagnosis. Specimens with fragmented tumor resection and/or multiple margins harvested ( margins or shorter dimension ) were also excluded as it may decrease the reliability of margins analysis given the complex threedimensional anatomy.
这项单中心回顾性研究是在综合癌症中心进行的。纳入的患者在 2017 年 1 月至 2021 年 12 月期间接受了口腔舌鳞状细胞癌的初级手术治疗。该研究在最后一名纳入的患者接受治疗 2 年后开始,理论上至少进行 2 年的随访。患者在两个不同的科室进行手术,但所有病理分析均在同一病理科室进行。排除标准如下:复发性肿瘤、颈部照射史、过去 5 年内另一种头颈癌病史、诊断时远处转移。具有碎片肿瘤切除和/或收获多个边缘( 边缘或更短尺寸 )的标本也被排除在外,因为考虑到复杂的三维解剖结构,这可能会降低边缘分析的可靠性。
Data were collected in the patients' electronic medical record by a senior investigator (VP). They included demographics, comorbidities, smoking status, alcohol abuse, cancer characteristics (location, local extension), treatment data (type of surgery, reconstruction, adjuvant treatment), pathological data (TNM staging according to AJCC 8th edition, superficial and deep excisional margins, pathological prognostic factors), and follow-up data (recurrence and survival).
数据由高级研究员 (VP) 在患者的电子病历中收集。它们包括人口统计学、合并症、吸烟状况、酗酒、癌症特征(位置、局部扩展)、治疗数据(手术类型、重建、辅助治疗)、病理数据(根据 AJCC 第 8 版的 TNM 分期、浅切缘和深切缘、病理预后因素)和随访数据(复发和生存)。
The primary treatment of resectable tongue SCC was the same in both departments, that is, wide local excision with of macroscopic superficial margins. Intraoperative margins for frozen section analysis were not routinely harvested at either site. In cases where the intraoperative examination of the specimen (ex vivo) by the surgeon showed insufficient margins, additional margins were harvested. In cases of close or involved resection margins on permanent section analysis, the decision to perform further resection was made on a case-by-case basis as recommended by the multidisciplinary meeting. Adjuvant RT or CRT was offered to T3 and patients as well as or patients with adverse pathological features (close or positive margins, PNI, LVE), in accordance with international guidelines.
两个科室对可切除舌鳞状细胞癌的主要治疗相同,即大范围局部切除, 肉眼下浅缘。冷冻切片分析的术中切缘在任一部位均未常规采集。如果外科医生对标本的术中检查(离体)显示余量不足,则收获额外的余量。在永久性切片分析中切除边缘接近或受累的情况下,根据多学科会议的建议,根据具体情况决定进行进一步切除。根据国际指南,向 T3 和 患者以及 /或 具有不良病理特征(切缘接近或阳性、PNI、LVE)的患者提供辅助 RT 或 CRT。
Specimen were fixed in formalin, dehydrated with an alcohol gradient, and embedded in paraffin. Fivemicrometer-thick sections were obtained with a microtome, stained with hematoxylin-eosin, and viewed under an optical microscope (Leica DM3000, Leica Microsystems, Inc., Wetzlar, Germany). Pathologists measured the resection margins in five directions (anterior, posterior, lateral, medial, deep), except in cases in which reliable measurement was impossible, for example, the anterior/ lateral margin in mandibulectomy specimens. Margins distances were calculated from the invasive component of the tumor. Only the presence of invasive SCC classified margins as "positive," as opposed to dysplasia and carcinoma in situ.
将标本固定在福尔马林中,用醇梯度脱水,并包埋在石蜡中。用切片机获得五微米厚的切片,用苏木精-伊红染色,并在光学显微镜下观察(Leica DM3000,Leica Microsystems,Inc.,Wetzlar,Germany)。病理学家在五个方向(前、后、外侧、内侧、深部)测量切除边缘,除非无法可靠测量,例如下颌切除术标本中的前/外侧边缘。从肿瘤的侵袭性成分计算边缘距离。只有浸润性鳞状细胞癌的存在将边缘归类为“阳性”,而不是异型增生和原位癌。
In accordance with the existing literature, a clinically applicable margin threshold was chosen for assessment of clinical relevance, that is, for both mucosal and deep margins in T1-T2 tumors and for both mucosal and deep margins in T3-T4 tumors.
根据现有文献, 选择临床适用的边缘阈值来评估临床相关性,即 T1-T2 肿瘤的粘膜和深缘以及 T3-T4 肿瘤的粘膜和深缘。
This study was conducted within a General Data Protection Regulation-compliant and secure system, in accordance with the French legal framework of MR-004 set up by the National Commission on Informatics and Liberty. This study was recorded in the Health Data Hub and received approval by the local research committee (reference: F20230315180652).
本研究是在符合《通用数据保护条例》的安全系统中进行的,该系统符合国家信息学和自由委员会建立的法国 MR-004 法律框架。这项研究被记录在健康数据中心,并获得了当地研究委员会的批准(参考:F20230315180652)。

2.1 | Statistical analysis
2.1 |统计分析

Continuous variables were summarized using median and range (min-max) and categorical variable with number and percentages. Missing data were described for all variables. Recurrence-free survival (RFS) was defined as the time between the date of surgery and the date of first recurrence or death. Patients still alive and without recurrence were censored at the date of last contact. Overall survival (OS) was defined as the time between the date of surgery and the date of death or censored at the date of last contact. Disease-specific survival (DSS) was defined as the time between the date of surgery and the date of cancer-related death. Patients still alive were censored at the date of last contact and patients who died of other causes were censored at their date of death. Local-recurrence-free survival was defined as the time between the date of surgery and the date of local recurrence. Patients still alive and without local recurrence were censored at their date of last contact, and those who had any other event (death or other type of recurrence) were censored at the date of occurrence of this other event. All survival rates were estimated by the Kaplan-Meier method with their confidence interval ( CI). Univariable and multivariable analyses were performed using the Logrank test and Cox proportional hazards model, respectively. Variable selection for multivariable analysis was based on clinical relevance and results of univariable analyses.
使用中位数和范围(最小值-最大值)和带有数量和百分比的分类变量对连续变量进行汇总。描述了所有变量的缺失数据。无复发生存期 (RFS) 定义为手术日期与首次复发或死亡日期之间的时间。仍然活着且没有复发的患者在最后一次接触之日被审查。总生存期 (OS) 定义为手术日期和死亡日期之间的时间,或在最后一次接触之日进行删失。疾病特异性生存期 (DSS) 定义为手术日期和癌症相关死亡日期之间的时间。仍然活着的患者在最后一次接触之日被审查,死于其他原因的患者在死亡之日被审查。局部无复发生存期定义为手术日期和局部复发日期之间的时间。仍然活着且没有局部复发的患者在最后一次接触之日被审查,而那些有任何其他事件(死亡或其他类型的复发)的患者在发生其他事件之日被审查。所有存活率均采用Kaplan-Meier方法及其 置信区 间(CI)估计。单变量和多变量分析分别使用 Logrank 检验和 Cox 比例风险模型进行。多变量分析的变量选择基于临床相关性和单变量分析的结果。
The clinical usefulness of margins (mucosal and deep) was assessed using decision curve analysis (DCA). This method calculates the net benefit for both margins on the RFS at 1 and 2 years and displays it graphically to compare to scenes where all patients recurred/died or none at 1 and 2 years.
使用决策曲线分析 (DCA) 评估边缘(粘膜和深部)的临床有用性。该方法计算 1 年和 2 年时 RFS 两个边缘的净收益,并以图形方式显示,以与所有患者在 1 年和 2 年复发/死亡或无复发/死亡的场景进行比较。
Statistical tests were two-sided and -value was considered significant. All statistical analyses were carried out using STATA version 18 software.
统计检验是双面的, -值 被认为是显著的。所有统计分析均使用STATA第18版软件进行。

3 | RESULTS 3 |结果

A total of 223 patients were included. Most of them were males , sex ratio ), with a median age at surgery of 62 years (21-94). They were active or former smokers in and of cases, respectively. Tobacco exposure exceeded 20 pack-years among of the active or former smokers. The prevalence of past and active alcohol abuse was and , respectively.
共纳入223例患者。他们中的大多数是男性 ,性别比例 ),手术时的中位年龄为62岁(21-94岁)。他们分别是活跃或曾经的吸烟者 。活跃或既往吸烟者的烟草暴露时间超过20包年 。既往酗酒和现役酗酒的患病率分别为
Oral tongue SCC were unilateral in of cases and bilateral in the remaining . Tumors involved the floor of the mouth, base of tongue, gingiva, tonsillar region/ pillars, and buccal mucosa in , and . A mandibulectomy was performed in of patients. A pull-through approach was required in of cases. Defect coverage was achieved with primary closure, pedicled or free flap in , and of cases, respectively. The neck treatment was as follows: bilateral neck dissection ( ), unilateral neck dissection ), sentinel lymph node biopsy ( ), or none ). Adjuvant treatment was carried out in of patients and consisted of RT alone ( ) or CRT ( ). When performed, RT was delivered to the tumor bed in all cases, and to the neck in of patients.
口腔舌鳞状细胞癌在病例中 为单侧,其余 病例为双侧。肿瘤累及口腔底部、舌根、牙龈、扁桃体区域/支柱和颊粘膜。 对患者进行了下颌骨切除术。 在一些情况下,需要采取直通式方法。缺损覆盖率分别通过一期闭合、带蒂或游离皮瓣实现 。颈部治疗如下:双侧颈部清扫术( )、单侧颈部清扫 术、前哨淋巴结活检( )、或无 )。对 患者进行辅助治疗,包括单独放疗 ( ) 或 CRT ( )。进行放疗时,在所有病例中,放疗都被输送到肿瘤床,并被输送到患者的颈部
Pathological outcomes are displayed in Table 1. When taking into account re-resections harvested intraoperatively, mucosal and deep margins were positive in and of definitive pathological examinations, respectively. Margin distances on histology are shown in Table 2.
病理结果见表1。当考虑到术中收获的重新切除时,粘膜和深缘分别在 确定性病理检查中呈 阳性。组织学的切缘距离如表2所示。
After a median follow-up of 37.5 months ( [34.3-42.8]), of patients had presented with a recurrence. The initial recurrence was local, regional, and/or distant metastasis in , and of cases, respectively. Among the of patients who died during the study period, of deaths were related to the disease. The 5 -year OS and RFS were ( [63.7-79.1]) and (95%CI [52.8-68.5]), respectively. The 3 -year DSS and LRFS were ( CI [79.490.0]) and ( CI [82.1-92.0]), respectively. Kaplan-Meier estimates of RFS according to surgical margin distance and T-status are shown in Figure 1.
中位随访37.5个月( [34.3-42.8])后, 患者出现复发。最初的复发分别是 局部、区域和/或远处转移。 在研究期间死亡的患者中, 死亡与疾病有关。5年OS和RFS分别为 63.7-79.1])和 (95%CI [52.8-68.5])。3年DSS和LRFS分别为 CI [79.490.0])和 CI [82.1-92.0])。图 1 显示了根据手术切缘距离和 T 状态对 RFS 的 Kaplan-Meier 估计。
Table 3 shows results of univariable analysis of OS and RFS. The following variables were significantly associated with OS and RFS: pathological T-status, N-status, PNI, and adjuvant RT. When adjusting for these four variables in multivariable analysis, the following variables were significantly associated with better OS: deep margin distance to the proposed threshold ( ) and mucosal margin distance as a continuous variable (HR ). A mucosal margin distance to the proposed threshold only showed a statistical trend for better .
表 3 显示了 OS 和 RFS 的单变量分析结果。以下变量与 OS 和 RFS 显著相关:病理 T 状态、N 状态、PNI 和辅助 RT。在多变量分析中调整这四个变量时,以下变量与较好的OS显著相关:到建议阈值的深边距 )和作为连续变量的粘膜边距(HR )。与建议阈值的粘膜边缘距离 仅显示出更好的 统计趋势。
TABLE 1 Pathological outcomes.
表1 病理结局。
Pathological data 病理数据 Patients,  病人
Differentiation
分化
Low 
Medium 中等
High 
Missing 失踪 2
Tumor size  肿瘤大小
and  
Missing 失踪 1
Depth of invasion
入侵 深度
and  
Missing 失踪 4
Bone invasion: Yes 骨侵袭:是
Perineural invasion 神经周围浸润
Presence  存在
Yes 是的
Missing 失踪 1
Quantity  数量
Numerous 众多
Rare 罕见