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Should sub-millimeter margins be deemed positive in oral cavity squamous cell carcinoma?
在口腔鳞状细胞癌中，亚毫米边缘是否应被视为阳性？

Chung-Jan Kang , Li-Yu Lee , Shu-Hang , Chien-Yu Lin , Kang-Hsing Fan , Wen-
姜忠简 ， 李 丽宇 ， 李淑航 ， 林 建宇 ， 范 康兴 ， 温Cheng Chen , Jin-Ching Lin , Yao-Te Tsai , Shu-Ru Lee , Chih-Yen Chien , Chun-Hung Hua ,
陈成 ， 林金晶 ， 蔡 耀特 ， 李 淑茹 ， 钱志彦 ， 华振雄 ，Cheng Ping Wang , Tsung-Ming Chen , Shyuang-Der Terng , Chi-Ying Tsai , Hung-
王成平 ， 陈宗明 ， Shyuang-der Terng ， 蔡 志英 ， 洪-Ming Wang , Chia-Hsun Hsieh , Chih-Hua Yeh , Chih-Hung Lin , Chung-Kan Tsao , Nai-
王明 ， 谢嘉勋 ， 叶志华 ， 林志雄 ， 曹 忠根 ， 乃-Ming Cheng , Tuan-Jen Fang , Shiang-Fu Huang , Li-Ang Lee , Ku-Hao Fang , Yu-
程明 ， 方端仁 ， 黄祥福 ， 李 丽昂 ， 方 渠浩 ， 余Chien Wang , Wan-Ni Lin , Li-Jen Hsin , Tzu-Chen Yen , Yu-Wen Wen , Chun-Ta Liao
王健 ， 林婉妮 ， Li-Jen Hsin ， Tzu-Chen Yen ， Yu-温 温 ， Chun-Ta Liao Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
长庚纪念医院和长庚大学耳鼻咽喉头颈外科，台湾桃园，中华民国 Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
长庚纪念医院和长庚大学病理科，台湾桃园，中华民国 Department of Diagnostic Radiology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
长庚纪念医院和长庚大学放射诊断科，台湾桃园，中华民国 Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
长庚纪念医院和长庚大学放射肿瘤科，台湾桃园，中华民国 Department of Radiation Oncology, New Taipei Municipal TuCheng Hospital, Taiwan, ROC
台湾新北市土城医院放射肿瘤科 Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan, ROC
中华民国台湾嘉义长庚纪念医院放射肿瘤科 Department of Radiation Oncology, Changhua Christian Hospital, Changhua, Taiwan, ROC
中华民国彰化市彰化市基督教医院放射肿瘤科 Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan, ROC
中华民国嘉义长庚纪念医院耳鼻咽喉头颈外科 Research Service Center for Health Information, Chang Gung University, Taoyuan Taiwan, ROC
长庚大学健康信息研究中心，台湾桃园 Department of Otolaryngology, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan, ROC
长庚大学医学院长庚纪念医院高雄医学中心耳鼻喉科，台湾 Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan, ROC
中华医科大学医院耳鼻喉科，台湾台中 Department of Otolaryngology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan, ROC
国立台湾大学医院医学院耳鼻喉科，台湾台北，中华民国 Department of Otolaryngology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, ROC
台北医学大学双和医院耳鼻喉科，台湾新北市 Department of Head and Neck Surgery, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, ROC
顾家乐基金会孙中山癌症中心头颈外科，台湾台北，中华民国 Department of Oral and Maxillofacial Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC
长庚大学长庚纪念医院口腔颌面外科，台湾桃园，中华民国 Department of Medical Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
长庚纪念医院和长庚大学肿瘤内科，台湾桃园，中华民国 Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
长庚纪念医院和长庚大学整形外科，台湾桃园，中华民国 Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
长庚纪念医院和长庚大学核医学与分子影像中心，台湾桃园，中华民国 Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
长庚大学医学院生物医学系， 台湾桃园， 中华民国 Division of Thoracic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
长庚纪念医院胸外科，台湾桃园，中华民国

A R T I C L E I N F O

Keywords: 关键字：

Oral cavity squamous cell carcinoma
口腔鳞状细胞癌
Resection margins 切除切缘
Positive margins 正边距
Cancer registry 癌症登记处
Clinical outcomes 临床结果

Abstract 抽象

A B S T R A C T Background: While several studies have indicated that a margin status of should be classified as a positive margin in oral cavity squamous cell carcinoma (OCSCC), there is a lack of extensive cohort studies comparing the clinical outcomes between patients with positive margins and margins .
A B S T R A C T 背景：虽然一些研究表明，在口腔鳞状细胞癌 （OCSCC） 中，切缘状态应 归类为阳性切缘，但缺乏广泛的队列研究比较切缘阳性患者之间的临床结果 。

Methods: Between 2011 and 2020, we identified 18,416 Taiwanese OCSCC patients who underwent tumor resection and neck dissection. Of these, 311 had margins and 1013 had positive margins. To compare patients with margins and those with positive margins, a propensity score (PS)-matched analysis ( 253 in each group) was conducted.
方法：2011-2020年，我们确定了18,416例台湾OCSCC患者接受了肿瘤切除和颈部清扫术。其中，311家有利润率 ，1013家有正利润率。为了比较有切缘 和有正切缘的患者，进行了倾向评分 （PS） 匹配分析（每组 253 名）。

Results: The group with margins displayed a notably higher prevalence of several variables: 1) tongue subsite, 2) younger age, 3) smaller depth of invasion), 4) early tumor stage, and 5) treatment with surgery alone. Patients with margins demonstrated significantly better disease-specific survival (DSS) and overall survival (OS) rates compared to those with positive margins ( versus versus , both
结果：有边缘 的组在几个变量上的患病率明显更高：1）舌亚位，2）年龄较小，3）浸润深度较小），4）早期肿瘤阶段，以及5）单独手术治疗。与切缘阳性的患者相比，有切缘 的患者表现出显着更好的疾病特异性生存期 （DSS） 和总生存率 （ vs vs ，两者

0.0001). Multivariable analysis further confirmed that positive margins were an independent predictor of worse 5 -year DSS (hazard ratio and . In the PS-matched cohort, the 5 -year outcomes for patients with margins compared to positive margins were as follows: DSS, versus , respectively ( ) and OS, versus , respectively ( ).
0.0001）。 多变量分析进一步证实，阳性切缘是 5 年 DSS 较差的独立预测因子（风险比 和 .在 PS 匹配队列中，切缘患者 与切缘阳性患者的 5 年结局如下：DSS 与 ，分别为 （ ） 和 OS， 分别为 （ ）。
Conclusions: OCSCC patients with a margin status exhibited distinct clinicopathological characteristics and a more favorable prognosis compared to those with positive resection margins.
结论：与切缘阳性患者相比，切缘状态 的OCSCC患者表现出明显的临床病理特征和更良好的预后。

Introduction 介绍

The primary approach to treating oral cavity squamous cell carcinoma (OCSCC) is surgical intervention, which may include neck dissection depending on the specifics of the case. After surgery, the patient may receive adjuvant chemoradiotherapy (CRT) or radiotherapy (RT), depending on the assessment of pathological risk factors (RFs) . One of the key RFs is surgical margin status, which is determined by pathologists but can be significantly influenced by the surgeon's actions. Notably, the advent of digital pathology has introduced decimal measurements, providing more precise information about resection margins [3]. In addition, the integration of artificial intelligence technology has facilitated the identification of skipped lesions, which could potentially change the classification of margin status from clear to close or positive [4]. Research consistently shows a strong association between positive or close margins and both local control and survival outcomes [5-12]. As a result, the National Comprehensive Cancer Network (NCCN) guidelines recommend that patients with OCSCC and positive resection margins should receive postoperative CRT instead of RT alone to improve locoregional control . While the NCCN guidelines define positive margins as the presence of malignant cells at the resection margin [1], other studies and guidelines consider positive margins to include invasive cancer within of the resection margin .
治疗口腔鳞状细胞癌 （OCSCC） 的主要方法是手术干预，根据病例的具体情况，可能包括颈部清扫术。手术后，患者可能会接受辅助放化疗 （CRT） 或放疗 （RT），具体取决于对病理危险因素 （RF） 的评估。其中一个关键的 RF 是手术切缘状态，它由病理学家确定，但可能会受到外科医生行为的显着影响。值得注意的是，数字病理学的出现引入了十进制测量，提供了有关切除边缘的更精确信息[3]。此外，人工智能技术的整合促进了对跳过病变的识别，这可能会将边缘状态的分类从清晰变为关闭或阳性[4]。研究一致显示，阳性或接近切缘与局部控制和生存结局之间存在很强的相关性[5-12]。因此，美国国家综合癌症网络 （NCCN） 指南建议 OCSCC 和切缘阳性的患者应接受术后 CRT 而不是单独放疗，以改善局部区域控制 。虽然NCCN指南将阳性切缘定义为切除边缘存在恶性细胞[1]，但其他研究和指南认为阳性切缘包括切缘内 的浸润性癌症 。
A recent meta-analysis of seven studies involving 2215 patients found that a margin distance of , which includes positive margins and margins of less than , was associated with a 2.96 -fold increase in local recurrence rate compared to margins of or greater [5]. However, some surgeons have expressed confidence in the adequacy of margins following wide resection and questioned the significance of postoperative margins of less than . In addition, it has been argued that re-excision with margins often does not uncover residual tumor and can cause secondary tissue damage. It is well established that the absence of residual cancer in a re-resection, even when performed immediately, is more likely attributable to challenges in localizing the residual disease rather than the possibility of no cancer remaining. Consequently, the true efficacy of re-resection as opposed to observational management in this context can only be accurately assessed through extended longitudinal patient monitoring. Furthermore, to elucidate the clinical and prognostic implications associated with positive surgical margins versus those less than , it is necessary to undertake a study encompassing a large cohort of patients, which would provide the statistical power necessary to draw meaningful conclusions.
最近一项meta分析纳入了7项研究，涉及2215例患者，发现与切缘率或 更大切缘相比，切缘距离为 （包括正切缘和切缘小于 ）与局部复发率增加2.96倍相关[5]。然而，一些外科医生对广泛切除后切缘的充分性表示有信心，并质疑术后切缘小于 .此外，有人认为，有 边缘的重新切除通常不会发现残留的肿瘤，并可能导致继发性组织损伤。众所周知，即使立即进行再切除，也没有残留的癌症，更可能是由于残留病灶定位的挑战，而不是没有癌症的可能性。因此，在这种情况下，与观察性治疗相比，再切除术的真正疗效只能通过扩展的纵向患者监测来准确评估。此外，为了阐明与手术切缘阳性与手术切缘小于手术切缘相关的临床和预后影响 ，有必要进行一项包含大量患者的研究，这将提供得出有意义的结论所需的统计功效。
Unfortunately, there is a significant dearth of comprehensive research that investigates the differences in outcomes between these two margin groups, as defined by the AJCC Staging Manual, Eighth Edition, specifically within the context of OCSCC. In order to delve into this subject, we undertook a nationwide investigation in Taiwan. Our study aimed to test two hypotheses: first, that OCSCC patients with positive margins and those with margins of less than would exhibit distinct clinicopathological characteristics, and second, that these two groups would display a minimum survival difference of at the 5 -year mark following propensity score (PS) matching.
不幸的是，根据 AJCC 分期手册第八版的定义，特别是在 OCSCC 的背景下，严重缺乏全面的研究来调查这两个边缘组之间结果的差异。为了深入研究这个主题，我们在台湾进行了全国性的调查。我们的研究旨在检验两个假设：首先，切缘阳性的 OCSCC 患者和切缘小于 OCSCC 的患者会表现出不同的临床病理特征，其次，这两组在倾向评分 （PS） 匹配 后 5 年标记处表现出最小生存差异。

Methods 方法

Data sources 数据源

The study was conducted using patient data from the Taiwanese Cancer Registry Database (TCRD) "long-form", which provides comprehensive coverage of over of patients diagnosed with OCSCC in Taiwan. However, a limitation of the TCRD is the absence of information on salvage therapy for patients who experienced disease relapse. To evaluate survival outcomes, additional data were obtained from the Taiwanese National Health Insurance Research Dataset (TNHIRD). The study adhered to the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines [16,17]. The research protocol was approved by the Chang Gung Memorial Hospital Ethics Committee under reference number 201801398B0A3. The requirement for informed patient consent was waived.
该研究使用来自台湾癌症登记数据库 （TCRD） “长表”的患者数据进行，该数据库全面覆盖 了台湾被诊断患有 OCSCC 的患者。然而，TCRD的一个局限性是缺乏关于疾病复发患者的挽救性治疗的信息。为了评估生存结果，从台湾国民健康保险研究数据集（TNHIRD）中获得了额外的数据。该研究遵循了肿瘤标志物预后研究报告建议（Reporting Recommendations for Tumor Marker Prognostic Studies， REMARK）指南[16,17]。该研究方案已获得长庚纪念医院伦理委员会的批准，参考编号为201801398B0A3。免除了患者知情同意的要求。

Patient selection 患者选择

The study focused on patients diagnosed with OCSCC between 2011 and 2020. The initial pool considered for inclusion consisted of 47,025 subjects, and their selection was based on the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes. The study flow chart (Figure 1) provides detailed information about the inclusion and exclusion criteria. Patients were excluded if their medical records indicated any of the following: 1) prior history of cancer, 2) non-surgical treatment as the initial approach, 3) unknown pathological stage, 4) unavailable data regarding tumor depth, surgical margins, and extranodal extension (ENE), 5) no information on pathological lymph node metastases, 6) lack of data on tumor differentiation, and 7) nodal yield of fewer than 10 nodes. After applying these exclusion criteria, the final study cohort consisted of 22,419 patients. Initially, the study participants were staged based on the criteria outlined in the AJCC Staging Manual, Seventh Edition (2010). However, an updated classification according to the AJCC Staging Manual, Eighth Edition (2018), was obtained by considering the depth of invasion (DOI) and ENE [18]. Out of the 22,419 patients included in the study, (6086/22419) were found to have disease, whereas (12330/22419) showed pNO disease. Additionally, of the patients did not undergo neck dissection, resulting in a pNx status. Among the 18,416 patients who underwent tumor excision and neck dissection, (1013/18416) had a positive margin. Furthermore, of the patients had a margin of less than (8064/18416) a margin greater than or equal to but less than , and a margin greater than or equal to . The main objective of the study was to compare outcomes between patients with positive margins and those with margins of less than . Furthermore, patients with margins between and , as well as margins greater than or equal to 5 , were included for comparison. The follow-up period was defined as the time from the day of surgery to either the patient's death or the end of the study (December 2021).
该研究的重点是 2011 年至 2020 年间被诊断患有 OCSCC 的患者。最初考虑纳入的受试者包括 47,025 名受试者，他们的选择基于国际肿瘤疾病分类第三版 （ICD-O-3） 代码。研究流程图（图1）提供了有关纳入和排除标准的详细信息。如果患者的病历表明存在以下任何一种情况，则患者被排除在外：1）既往癌症病史，2）非手术治疗作为初始方法，3）病理分期未知，4）关于肿瘤深度、手术切缘和结外延伸（ENE）的数据不可用，5）没有关于病理性淋巴结转移的信息，6）缺乏肿瘤分化数据，以及7）淋巴结产量少于10个淋巴结。在应用这些排除标准后，最终的研究队列由22,419名患者组成。最初，研究参与者是根据 AJCC 分期手册第七版（2010 年）中概述的标准进行分期的。然而，根据AJCC分期手册第八版（2018年），通过考虑侵袭深度（DOI）和ENE获得了更新的分类[18]。在纳入研究的 22,419 名患者中， （6086/22419） 被发现患有 疾病，而 （12330/22419） 显示 pNO 疾病。此外， 患者未接受颈部清扫术，导致 pNx 状态。在接受肿瘤切除和颈部清扫术的 18,416 例患者中， （1013/18416） 的切缘呈阳性。此外， 在患者中，切缘小于 （8064/18416），切缘大于或等于 但小于 ，切 缘大于或等于 。 该研究的主要目的是比较切缘阳性患者和切缘小 于的患者之间的结局。此外，纳入边缘介于 和 以及边缘大于或等于 5 的患者进行比较。随访期定义为从手术当天到患者死亡或研究结束（2021 年 12 月）的时间。

Data collection 数据采集

After obtaining the study variables from the 2019 release of the TCRD and the 2020 release of the TNHIRD, the final data analyses were performed in October 2023. The TCRD follows the guidelines outlined in
在获得 2019 年发布的 TCRD 和 2020 年发布的 TNHIRD 的研究变量后，于 2023 年 10 月进行了最终数据分析。TCRD 遵循
the Standards for Oncology Registry Entry (STORE) manual [19]. To determine OCSCC-related morbidity and mortality, data from the TNHIRD were obtained. The extracted information was then utilized to calculate disease-specific survival (DSS) and overall survival (OS), respectively.
《肿瘤学注册表标准》（Standards for Oncology Registry Entry， STORE）手册[19]。为了确定与OCSCC相关的发病率和死亡率，从TNHIRD获得了数据。然后利用提取的信息分别计算疾病特异性生存期 （DSS） 和总生存期 （OS）。

Statistical analysis 统计分析

Survival curves were generated using the Kaplan-Meier method and compared for statistical significance with the log-rank test. We evaluated the relationships between the variables under study and survival outcomes through both univariable and multivariable Cox proportional hazards regression analyses. A stepwise selection method was utilized, integrating all variables from the univariable analysis into the multivariable model. The results were expressed as hazard ratios (HRs) with their respective confidence intervals (CIs). All tests were two-tailed and the level of significance was set at .
使用 Kaplan-Meier 方法生成生存曲线，并与对数秩检验进行比较的统计学显着性。我们通过单变量和多变量Cox比例风险回归分析评估了所研究变量与生存结果之间的关系。采用逐步选择方法，将单变量分析中的所有变量整合到多变量模型中。结果以风险比（HRs）及其各自 的置信区间（CIs）表示。所有测试均为双尾测试，显著性水平设定为 。

Results 结果

Patient characteristics 患者特征

Table 1 presents the general characteristics of patients based on their surgical margin status. The group with margins of less than exhibited a significantly higher prevalence of several variables compared to the positive margin group (all values , except for age). These factors included: 1) tongue subsite, 2) younger age, 3) smaller DOI, 4) pT1 - 2 disease, 5) pN0 disease, 6) p-Stage I - II, and 7) treatment with surgery alone. Notably, the group with positive margins exhibited approximately twice the incidence of involvement compared to the group with margins ( versus ). Significant differences emerged in treatment modalities between the positive margin and less than margin cohorts: surgery alone was administered to of the positive margin group versus of the less than margin group; surgery plus chemotherapy to versus ; surgery plus RT to versus ; and surgery plus CRT to versus , respectively ( ). A significant majority of patients with positive margins underwent postoperative CRT at a rate of . A notable lack of matching was evident between the two groups, with patients with positive margins also presenting with multiple additional high-risk factors.
表 1 根据患者的手术切缘状态列出了患者的一般特征。与正切缘组相比，边缘小于 的组表现出几个变量的患病率显着更高（除年龄外的所有 值 ）。这些因素包括：1）舌亚位，2）年龄较小，3）DOI较小，4）pT1-2疾病，5）pN0疾病，6）p-I-II期，7）单独手术治疗。值得注意的是，与边缘组相比，切缘为正的组 表现出大约两倍的受累发生率 （ 与 ）。阳性切缘组和小于 切缘队列在治疗方式上存在显著差异：正切缘组与 小切 缘组仅 进行手术;手术加化疗与 ; 手术加放疗与 ;和手术加 CRT 分别与 （ ）。绝大多数切缘阳性患者术后 CRT 的发生率为 。两组之间明显缺乏匹配，切缘阳性的患者还表现出多种额外的高危因素。
Five-year survival rates
五年生存率
The 5-year DSS rates based on margin status were as follows: for margins ; for margins measuring ; for margins ; and for positive margins, ( ; Fig. 2A). The OS rates in the four groups were , and 43
基于保证金状况的 5 年期 DSS 利率如下：保证金 ;用于边距测量 ;对于边距 ;对于正边距， （ ;图2A）。四组的OS率分别为 和43
Fig. 1. Flow diagram illustrating the progression of patients through the study.
图 1.流程图说明了患者在研究中的进展。
Table 1 表1
General characteristics of patients with oral cavity squamous cell carcinoma ) based on different margin statuses.
口腔鳞状细胞癌患者的一般特征 ）基于不同的切缘状态。
Characteristic (n, %) 特征 （n， %）

正边距
Positive margins

正利润率与
Positive margins
versus
Tumor subsite 肿瘤亚位点
Tongue  舌
Buccal  颊的
Other sites  其他网站
Sex 性 0.3597 0.0836
Men  男人
Women  女人
Age, years (mean standard deviation)
年龄、岁（平均 标准差）		 0.0391 0.0030
Depth of invasion, (mean standard deviation)
侵袭深度（ 平均 标准差）
Depth of invasion,
侵袭深度，
3688 (45.7)
Tumor differentiation 肿瘤分化 0.1223
Well differentiated
差异化 程度高
Moderately differentiated
中度分化 		651 (64.3)
Poorly differentiated
分化 不良
Pathologic T status 病理 T 状态
1947 (21.6)
T3 1051 (11.6)
3041 (33.7)
Pathologic status
病理状态
pN0 444 (43.8)
788 (8.7)
pN2  pN2（英语：pN2 ）
pN3  pN3 型
Pathologic stage 病理阶段
I
II 1797 (22.3)
III 1151 (12.7)
IV 3749 (46.5) 3894 (43.2)
Treatment modality 治疗方式
S alone  单独 S 195 (19.2)
S plus CT  S 加 CT 264 (3.3)
S plus RT  S 加 RT
S plus CT and RT
S 加 CT 和 RT
WCCI (mean standard deviation)
WCCI（平均 标准差）		 0.5441 0.5638
Abbreviations: S, surgery; CT, chemotherapy; RT, radiotherapy; WCCI, weighted Charlson comorbidity index.
缩写：S，手术;CT、化疗;放疗、放疗;WCCI，加权查尔森合并症指数。
%, respectively ( ; Fig. 2B). Notably, patients with margins had significantly better DSS ( , Fig. 2C) and OS compared to those with positive margins ( , Fig. 2D)
%，分别 （ ;图2B）。值得注意的是，与切缘阳性的患者相比，切缘 患者 的DSS（ 图2C）和OS明显更好（ 图2D）
Univariable and multivariable Cox regression analysis for patients with margins versus positive margins
切缘与 正切缘患者的单变量和多变量 Cox 回归分析
The results of univariable and multivariable analyses are shown in Table 2. After adjusting for potential confounders in multivariable analyses, the following variables were found to be independently associated with a reduced 5 -year DSS rate: positive margins, a DOI , a pT2 - 4 tumor, pN1 -3 disease, and a higher weighted Charlson comorbidity index (WCCI). Independent factors that had an adverse impact on 5-year OS included positive margins, older age, a pT2 - 4 tumor, pN1 -3 disease, and a higher WCCI (Table 2).
单变量和多变量分析的结果如表2所示。在多变量分析中调整潜在混杂因素后，发现以下变量与 5 年 DSS 率降低独立相关：阳性切缘、DOI 、pT2-4 肿瘤、pN1-3 疾病和更高的加权 Charlson 合并症指数 （WCCI）。对 5 年 OS 有不利影响的独立因素包括阳性切缘、年龄较大、pT2-4 肿瘤、pN1-3 疾病和较高的 WCCI（表 2）。
Propensity score-matched analysis of patients with margins versus positive margins
切缘与 正切缘患者的倾向评分匹配分析
To mitigate the differences in disease severity between patients with margins less than and positive margins, we used PS matching. This approach led to the formation of two well-balanced groups, each comprising 253 patients (Table 3). The results of the PS-matched analysis revealed that patients with margins had more favorable outcomes compared to those with positive margins. Specifically, the 5year DSS rates were versus , respectively ( ) and the 5 -year OS rates versus , respectively ( ; Fig. 2 E-
为了减轻切缘小 于和正切缘的患者之间疾病严重程度的差异，我们使用了PS匹配。这种方法导致了两个平衡的组的形成，每个组包括253名患者（表3）。PS 匹配分析的结果显示，与切缘阳性的患者相比，切缘患者 的结局更有利。具体而言，5 年 DSS 率分别为 （ ） 和 5 年 OS 率 与 （ ;图2 E-

F).

Discussion 讨论

The existing NCCN guidelines advocate for postoperative CRT in patients with OCSCC who have positive surgical margins and are not suitable candidates for re-resection [1]. However, the definition of a positive margin remains inconsistent. Our study revealed that patients with surgical margins of less than exhibit distinct clinicopathological features - including treatment modalities - and clinical outcomes compared to those with positive margins. Consequently, it is recommended to develop distinct treatment protocols and follow-up strategies for these two margin groups.
现有的NCCN指南提倡对手术切缘阳性且不适合再切除的OCSCC患者进行术后CRT[1]。然而，正边际的定义仍然不一致。我们的研究表明，与切缘阳性的患者相比，手术切缘小于 的患者表现出明显的临床病理特征（包括治疗方式）和临床结果。因此，建议为这两个边缘组制定不同的治疗方案和随访策略。
While a majority of studies define clear margins as those greater than [20], the definition of a positive margin remains a contentious issue. The guidance from the Royal College of Pathologists defines a positive margin as the presence of invasive cancer within of the surgical edge [15]. In a systematic review and meta-analysis, the resection margin thresholds were carefully examined and divided into distinct groups based on size (i.e., , , and ). Interestingly, the results revealed that the group exhibited the highest risk among all the subgroups [5]. In two previous studies conducted by Bulbul et al. [21] and Hakim et al. [22], the authors explored the impact of resection margins on local control and survival rates. In both investigations, margins measuring less than were classified as positive . However, our study revealed that patients with margins of
虽然大多数研究将净边际定义为大于 [20] 的边际，但正边际的定义仍然是一个有争议的问题。英国皇家病理学家学会（Royal College of Pathologists）的指导意见将阳性切缘定义为手术边缘内存在浸润性癌症 [15]。在系统评价和荟萃分析中，仔细检查切缘阈值，并根据大小（即 、、 和 ）分为不同的组。有趣的是，结果显示，该 组在所有亚组中表现出最高的风险[5]。在Bulbul等[21]和Hakim等[22]之前进行的两项研究中，作者探讨了切除边缘对局部控制和存活率的影响。在这两项调查中，测量值低于的利润率 被归类为正 。然而，我们的研究表明，边缘
Fig. 2. Kaplan-Meier plots comparing disease-specific survival and overall survival outcomes for patients with different margin statuses. Panels A and B compare patients with margins to , and positive margins. Panels and focus on patients with margins and positive margins before propensity score matching. Panels E and F present the comparison between the groups with margins and positive margins after propensity score matching.
图 2.Kaplan-Meier 图比较了具有不同边缘状态的患者的疾病特异性生存期和总生存期结果。图 A 和 B 比较了边缘 为 和正边缘的患者。在倾向评分匹配之前，面板 并 重点关注边缘 和正边缘的患者。图 E 和 F 显示了倾向评分匹配后边缘 和正边缘的组之间的比较。
less than were treated (Table 1 , treatment modality) and experienced outcomes (Fig. 2A-B) that were comparable to those with close margins, rather than positive margins. This was evident despite the fact that the DOI of patients with margins of less than was lower when compared to patients with a margin of less than .
少于 治疗（表1，治疗方式）和经历的结局（图2A-B），与边缘接近的人相当，而不是正边缘。尽管与切缘小于 的患者相比，切缘小于 的患者的 DOI 较低，但这一点是显而易见的。
Notably, there was a significant disparity in the treatment modalities employed between the group with positive margins and the group with margins of less than . This discrepancy is likely attributable to the more aggressive tumor behavior and advanced stage observed in the positive margin cohort. Within the positive margin group, of patients underwent only surgical intervention, whereas of patients with margins of less than were treated with surgery alone.
值得注意的是，切缘为正的组和切缘小于 的组在采用的治疗方式存在显着差异。这种差异可能归因于在阳性切缘队列中观察到的更具侵袭性的肿瘤行为和晚期阶段。在切缘阳性组中， 切缘小于仅手术治疗 的患者。
Table 2 表2
Univariable and multivariable analyses of risk factors for 5 -year disease-specific and overall survival in patients with oral cavity squamous cell carcinoma classified according to the presence of positive margins versus margins before propensity score matching
口腔鳞状细胞癌患者 5 年疾病特异性和总生存期危险因素的单变量和多变量分析，根据存在阳性切缘与倾向评分匹配 前切缘进行分类
Risk factor 风险因素 Disease-specific survival
疾病特异性生存期
-
-
Overall survival 总生存期
Univariable analysis 单变量分析

逐步多变量分析
Stepwise multivariable
analysis
Univariable analysis 单变量分析 Stepwise multivariable analysis
逐步多变量分析
HR (95% CI) HR（95% CI） HR (95% CI) HR（95% CI）
Margins 边缘
Positive 阳性 0.0103 0.0222
1 1 1 1
Tumor subsite 肿瘤亚位点
Tongue 舌 0.6717 - ns 0.8445 -
Buccal 颊的 0.4240 - 0.1599 -
Other sites 其他网站 1 - 1 -
Sex 性
Men 男人 0.9017 - 0.7776 - ns
Women 女人 1 - 1 -
Age, years 年龄、岁月 0.0011 - ns 0.0483
Depth of invasion,
侵袭深度，
1 1 1 -
0.0416 -
Tumor differentiation 肿瘤分化
Well differentiated 差异化程度高 1 - 1 -
Moderately differentiated
中度分化		 0.1721 - ns 0.0375 -
Poorly differentiated 分化不良 - ns - ns
Pathologic T status 病理 T 状态
1 1 1 1
0.0003 0.0075 0.0004 0.0102
0.0119 0.0030
0.0002
Pathologic N status 病理学 N 状态
1 1 1 1
0.0003
Pathologic stage 病理阶段
1 - 1 -
II 0.0986 - ns 0.1281 - ns
III 0.0021 - ns 0.0002 - ns
IV - - ns
0.0002 0.0005
Abbreviations: HR, hazard ratio; CI, confidence interval; S, surgery; CT, chemotherapy; RT, radiotherapy; WCCI, weighted Charlson comorbidity index; ns, not significant.
缩写：HR，风险比;CI， 置信区间;S， 手术;CT、化疗;放疗、放疗;WCCI，加权查尔森合并症指数;ns，不显著。
The rationale for why approximately of patients with positive margins did not receive adjunctive RT or CRT remains unclear. Potential explanations might include patient refusal, advanced age, limited compliance due to performance status and/or comorbidities, and insufficient family support. Conversely, the decision for surgery alone in about of patients with margins of less than could reflect surgical confidence in the adequacy of the margins and the perception that such margins do not significantly impact patient outcomes. Despite appearing to be a group with less aggressive tumors, more than of patients with margins of less than still required adjuvant therapy, with 13.5 % receiving RT and 36.9 % receiving CRT. In this group, 41.5 of patients had pT3-4 tumors, and presented with pathologically positive lymph nodes (Table 1), indicating potential candidates for adjuvant therapy [2]. Furthermore, some oncology teams specializing in head and neck cancer advocate for adjuvant therapy in cases with margins of less than rather than relying solely on surgical management .
为什么大约 切缘阳性的患者没有接受辅助放疗或 CRT 的原因尚不清楚。可能的解释包括患者拒绝、高龄、体能状态和/或合并症导致的依从性有限以及家庭支持不足。相反，在大约 切缘小于 切缘的患者中单独决定手术可以反映手术对切缘充分性的信心，以及这种切缘不会显着影响患者结局的看法。尽管似乎是一组侵袭性较弱的肿瘤，但与 边缘小于 仍需要辅助治疗的患者相比，13.5%的患者接受放疗，36.9%的患者接受CRT。该组 患者有pT3-4肿瘤， 病理阳性淋巴结（表1），提示辅助治疗的潜在候选者[2]。此外，一些专门研究头颈癌的肿瘤学团队主张在边缘小于 而不是仅仅依靠手术治疗 的情况下进行辅助治疗。
In the group with a margin of less than , there was a higher prevalence of tongue subsite, tumors with a DOI of less than and pT2 tumors, and pathological node negativity (pNO). This indicates that patients with a margin of less than had less invasive tumors and were treated with less aggressive measures. Consequently, some surgeons will resect smaller tumors with narrower surgical margins compared to pT3-4 tumors. Taking into account oral function, less tongue tissue may also be removed. Additionally, a surgical margin of less than margin may be detected when a tumor is initially misdiagnosed as benign before total excision. In line with this, Allon et al. [23] reported that even experienced head and neck surgeons failed to suspect the presence of malignancy in over of their cases of oral mucosa tumors. However, of patients with a margin of less than still experienced a favorable prognosis with surgery alone, surpassing the outcomes of patients with positive margins.
在边缘小于 的组中，舌亚位点、DOI 小 于 和 pT2 肿瘤的患病率较高，病理淋巴结阴性 （pNO） 的患病率更高。这表明边缘小于 的患者肿瘤侵袭性较小，并且采用侵袭性较低的措施进行治疗。因此，与 pT3-4 肿瘤相比，一些外科医生会切除手术切缘更窄的较小肿瘤。考虑到口腔功能，也可以切除较少的舌头组织。此外，当肿瘤在完全切除前最初被误诊为良性时，可能会检测到手术切缘小 于切缘。与此一致，Allon等[23]报道，即使是经验丰富的头颈外科医生也未能怀疑口腔黏膜肿瘤病例中存在恶性肿瘤 。然而， 在切缘小于 的患者中，仅手术仍具有良好的预后，超过了切缘阳性患者的预后。
The positive margin group exhibited distinct characteristics, including deeper DOI, a higher prevalence of pT4 stage tumors, and advanced pathological stage. Notably, a majority of these tumors were found on the buccal side, which can be attributed to the desires of both surgeons and patients to preserve skin integrity for cosmetic purposes, despite the inherent challenges involved. However, prior research has emphasized the importance of considering skin preservation only when the distance between the tumor and the skin, as determined by imaging, is equal to or greater than [24]. Additionally, the presence of buccal pT4 tumors with positive margins could potentially be associated with supra-notch T4b [25] or involvement of the pterygoid plate area. These challenging anatomical regions can pose significant obstacles for surgeons, making it difficult to achieve sufficient resection margins or even effectively remove the tumor [26]. Moreover, identifying deep tumor margins, such as pseudopodia or skip lesions, is not always straightforward using preoperative imaging, which can further complicate the surgeon's decision-making process. Significantly, a remarkable of patients within this specific group displayed involvement, indicating an elevated level of tumor aggressiveness. Collectively, these observations explain the high proportion of patients with advanced
阳性切缘组表现出明显的特征，包括更深的 DOI、更高的 pT4 期肿瘤患病率和晚期病理分期。值得注意的是，这些肿瘤中的大多数是在颊侧发现的，这可以归因于外科医生和患者都希望出于美容目的保持皮肤完整性，尽管存在固有的挑战。然而，先前的研究强调，只有当肿瘤与皮肤之间的距离（通过影像学确定）等于或大于 时，才考虑皮肤保护的重要性[24]。此外，切缘阳性的颊pT4肿瘤可能与切迹上T4b[25]或翼状板区受累有关。这些具有挑战性的解剖区域会给外科医生带来重大障碍，使其难以获得足够的切除切缘，甚至难以有效切除肿瘤[26]。此外，使用术前成像识别深部肿瘤边缘（例如伪足或跳跃性病变）并不总是那么简单，这可能会使外科医生的决策过程进一步复杂化。值得注意的是，该特定组中的大量 患者表现出 受累，表明肿瘤侵袭性水平升高。总的来说，这些观察结果解释了晚期患者的高比例
Table 3 表3
General characteristics of patients with oral cavity squamous cell carcinoma ( ) classified according to the presence of positive margins versus margins after propensity score matching.
口腔鳞状细胞癌 （ ） 患者的一般特征根据倾向评分匹配 后是否存在阳性切缘与切缘 进行分类。
Characteristic (n, %) 特征 （n， %） Propensity score-matched cohort
倾向得分匹配队列

正边距
Positive
margins

边缘
Margins
SMD
Tumor subsite 肿瘤亚位点 0.8063
Tongue  舌 4.20
Buccal  颊的 -4.14
Other sites  其他网站 0.00
Sex 性 0.8788
Men  男人 1.34
Women  女人 -1.34
Age, years (mean )
年龄、岁（平均 值）
9.43
9.66
-2.51 0.7705
Depth of invasion,
侵袭深度， 		0.1701
-6.48
6.48
Tumor differentiation 肿瘤分化 0.7079

差异化 程度高
Well differentiated
-6.65

中度分化 ，
Moderately
differentiated ,
5.05

分化 不良
Poorly differentiated
1.29
Pathologic T status 病理 T 状态 0.4048
5.34
-6.74
-10.25
8.88
Pathologic N status 病理学 N 状态 0.5248
pN0 -3.96
-1.20
-5.50
45 (17.8) 10.89
Pathologic stage 病理阶段 0.5744
I 34 (13.4) 5.99
II -2.88
III -8.76
IV 141 (55.7) 136 (53.8) 3.97
Treatment modality 治疗方式 0.7804
S alone  单独 S 108 (42.7) 7.24
S plus CT  S 加 CT -2.50
S plus RT  S 加 RT -3.64

S 加 CT 和 RT （ 225 ，
S plus CT and RT ( 225 ,
-3.98

WCCI（平均 标准差）
WCCI (mean standard
deviation)
-12.38 0.1556
Abbreviations: SMD, standardized mean difference; SD, standard deviation; S, surgery; CT, chemotherapy; RT, radiotherapy; WCCI, weighted Charlson comorbidity index.
缩写：SMD，标准化均差;SD， 标准差;S， 手术;CT、化疗;放疗、放疗;WCCI，加权查尔森合并症指数。
stages (76.2 %) and 68.7 % patients underwent postoperative CRT. In addition, these results support our initial hypothesis that the two groups would exhibit distinct clinicopathological characteristics.
分期（76.2%）和68.7%的患者接受了术后CRT。此外，这些结果支持了我们最初的假设，即两组将表现出不同的临床病理特征。
Our study found that patients with a positive resection margin had significantly less favorable 5 -year DSS and OS outcomes compared to those with a resection margin of less than (Fig. 2C-D). Even after PS matching, the results showed that the 5 -year DSS rate of patients with a margin of less than remained higher compared to those with positive margins ( versus , respectively, Fig. 2E, 0.0127). Similarly, the 5 -year OS rate was found to be higher versus , respectively; Fig. 2F, ). Multivariable analysis supported these findings, with the positive margin group exhibiting a significant for both DSS ( 0.0103 ) and (HR ) compared to the group with a margin of less than . This supports our second hypothesis that the difference in 5 -year survival rates between the two groups would exceed . Therefore, it is crucial not to classify a margin of less than as a positive margin. In our study, we utilized both PS matching and multivariable analysis to enhance risk stratification and facilitate a more accurate comparison between the two groups. The multivariable analysis indicated improved outcomes for the group with margins of less than . However, the absence of data on critical RFs such as perineural invasion and lymphovascular invasion introduces uncertainty regarding the adequacy of the matching between the groups. Additionally, while the hazard ratios of 1.38 for DSS and 1.28 for OS were statistically significant, their clinical significance may not be substantial enough to serve as a definitive basis for treatment decisions.
我们的研究发现，与切除切缘小于 的患者相比，切除切缘阳性的患者的 5 年 DSS 和 OS 结果明显较差（图 2C-D）。即使在 PS 匹配后，结果显示，与切缘阳性的患者相比，切缘小于 的 5 年 DSS 率仍然 更高（ 分别与 图 2E 相比， 0.0127）。同样，发现 5 年 OS 率 分别高于 ;图2F， ）。多变量分析支持这些发现，与边际小于的组相比，正切缘组 的 DSS （ 0.0103） 和 （HR ） 均显著 。这支持了我们的第二个假设，即两组之间 5 年生存率的差异将超过 。因此，不要将小于 的边际归类为正边际至关重要。在我们的研究中，我们利用PS匹配和多变量分析来增强风险分层，并促进两组之间更准确的比较。多变量分析表明，边缘小于 的组的结局有所改善。然而，由于缺乏关于关键 RF 的数据，例如神经周围浸润和淋巴血管浸润，这为组间匹配的充分性带来了不确定性。此外，虽然 DSS 的风险比为 1.38，OS 的风险比为 1.28，具有统计学意义，但它们的临床意义可能不足以作为治疗决策的明确基础。
Margin status plays a crucial role in predicting patient outcomes and is the only prognostic factor that surgeons have control over. A study by Azzopardi et al. [27] has indicated that performing re-resection might improve survival rates in patients with close or affected resection margins. Our recommendation is to classify resection margins of less than 1 as an intermediate and prioritize this patient group for reresection to achieve adequate margins, whenever possible. However, for patients ineligible for re-resection, adjuvant RT alone is suggested in the absence of other RFs. Patients with positive resection margins who cannot undergo re-resection should still be considered at high risk and should receive adjuvant CRT. Further research is necessary to enhance risk stratification in these two patient groups.
切缘状态在预测患者预后方面起着至关重要的作用，并且是外科医生可以控制的唯一预后因素。Azzopardi等[27]的一项研究表明，进行再切除术可能会提高切除边缘接近或受累的患者的生存率。我们的建议是将小于 1 的切除切缘归类为中间切缘， 并尽可能优先切除该患者组以获得足够的切缘。然而，对于不适合再切除的患者，建议在没有其他射频的情况下单独进行辅助放疗。 切缘阳性且无法进行再切除的患者仍应被视为高危患者，应接受辅助 CRT。需要进一步的研究来加强这两个患者组的风险分层。
We acknowledge several limitations to our study. First, registrybased investigations are susceptible to the influence of unmeasured confounding factors, which may affect the reliability of the results. Second, perineural invasion, lymphatic invasion, and vascular invasion are recognized as independent adverse prognostic factors for DSS and OS in patients with OCSCC [2]. Regrettably, data on perineural invasion and lymphovascular invasion were incorporated into the study dataset starting only in 2018 [18]; therefore, these variables warrant comprehensive examination in subsequent research endeavors to fully understand their impact on patient outcomes. Third, this study was conducted in a region with a high prevalence of betel nut chewing, which resulted in a significant number of patients with OCSCC in the buccal subsites. Therefore, further research is needed to determine the applicability of our findings to Western countries. Finally, the prognosis of OCSCC patients can be affected by a multitude of factors, which may confound the relationship between surgical margin status and clinical outcomes. The determination of what constitutes an oncologically safe margin is multifaceted and cannot be solely defined by the millimetric distance between the tumor and the specimen edge.
我们承认我们的研究存在一些局限性。首先，基于注册的调查容易受到未测量混杂因素的影响，这可能会影响结果的可靠性。其次，神经周围浸润、淋巴浸润和血管浸润被认为是OCSCC患者DSS和OS的独立不良预后因素[2]。遗憾的是，神经周围浸润和淋巴血管浸润的数据直到2018年才被纳入研究数据集[18];因此，这些变量需要在随后的研究工作中进行全面检查，以充分了解它们对患者预后的影响。第三，这项研究是在槟榔咀嚼率高的地区进行的，这导致了口腔亚部位的大量OCSCC患者。因此，需要进一步的研究来确定我们的研究结果对西方国家的适用性。最后，OCSCC患者的预后可能受到多种因素的影响，这可能会混淆手术切缘状态与临床结果之间的关系。肿瘤学安全切缘的确定是多方面的，不能仅由肿瘤和标本边缘之间的毫米距离来定义。

Conclusions 结论

In conclusion, this study demonstrates that OCSCC with margins and positives margins displayed distinct clinicopathological characteristics and were linked to distinct clinical outcomes. When reresection is not a viable option, positive margins should remain a high , whereas margins less than could be considered an intermediate RF. Collectively, our findings contribute to a nuanced comprehension of risk stratification and treatment approaches based on margin status in patients with OCSCC.
综上所述，本研究表明，边缘 和阳性边缘的OCSCC表现出不同的临床病理特征，并与不同的临床结局相关。当切除不是一个可行的选择时，阳性切缘应保持较高 ，而切缘小于 可被视为中等 RF。 总的来说，我们的研究结果有助于对 OCSCC 患者基于切缘状态的风险分层和治疗方法进行细致入微的理解。

CRediT authorship contribution statement
CRediT 作者贡献声明

Chung-Jan Kang: Writing - review & editing, Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Li-Yu Lee: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Shu-Hang Ng: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Chien-Yu Lin: Writing - original draft,
Chung-Jan Kang：写作 - 审查和编辑，写作 - 原始草稿，可视化，验证，监督，软件，资源，项目管理，方法论，调查，形式分析，数据管理，概念化。Li-Yu Lee：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。吴淑航：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。Chien-Yu Lin：写作 - 原稿，
Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Kang-Hsing Fan: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Wen-Cheng Chen: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Jin-Ching Lin: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Yao-Te Tsai: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Shu-Ru Lee: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. ChihYen Chien: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Chun-Hung Hua: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Cheng Ping Wang: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Tsung-Ming Chen: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Shyuang-Der Terng: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Chi-Ying Tsai: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Hung-Ming Wang: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Chia-Hsun Hsieh: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Chih-Hua Yeh: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Chih-Hung Lin: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Chung-Kan Tsao: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Nai-Ming Cheng: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Tuan-Jen Fang: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Shiang-Fu Huang: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Li-Ang Lee: Writing original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Ku-Hao Fang: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Yu-Chien Wang: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Wan-Ni Lin: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Li-Jen Hsin: Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Tzu-Chen Yen: Writing original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Yu-Wen Wen: Writing - review & editing, Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition,
可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。范康兴：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。陈温：写作 - 原始草案，可视化，验证，监督，软件，资源，方法，调查，形式分析，概念化。Jin-Ching Lin：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。Yao-Te Tsai：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法论、调查、形式分析、概念化。Shu-Ru Lee：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。ChihYen Chien：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。华俊雄：写作 - 原始草案，可视化，验证，监督，软件，资源，方法，调查，形式分析，概念化。王成平：写作-初稿、可视化、验证、监督、软件、资源、方法论、调查、形式分析、概念化。陈宗明：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法论、调查、形式分析、概念化。Shyuang-Der Terng：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。 蔡志英：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。王鸿明：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法论、调查、形式分析、概念化。谢佳勋：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法论、调查、形式分析、概念化。Chih-华 Yeh：写作 - 原始草稿，可视化，验证，监督，软件，资源，方法，调查，形式分析，概念化。Chih-Hung Lin：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。Chung-Kan Tsao：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。郑乃明：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。Tuan-Jen Fang：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。黄湘福：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法论、调查、形式分析、概念化。Li-Ang Lee：撰写原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。 方酷昊：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。Yu-Chien Wang：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。林万妮：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法论、调查、形式分析、概念化。Li-Jen Hsin：写作 - 原始草稿、可视化、验证、监督、软件、资源、方法、调查、形式分析、概念化。Tzu-Chen Yen：撰写原始草稿，可视化，验证，监督，软件，资源，方法，调查，形式分析，概念化。Yu-温 温：写作 - 审查和编辑，写作 - 原始草稿，可视化，验证，监督，软件，资源，项目管理，方法论，调查，资金获取，
Formal analysis, Data curation, Conceptualization. Chun-Ta Liao: Writing - review & editing, Writing - original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
形式分析、数据管理、概念化。廖春塔：写作 - 审查和编辑，写作 - 原始草稿，可视化，验证，监督，软件，资源，项目管理，方法论，调查，形式分析，数据管理，概念化。

Declaration of competing interest
利益争夺声明

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
作者声明，他们没有已知的相互竞争的经济利益或个人关系，这些利益或关系可能会影响本文所报告的工作。

Acknowledgements 确认

The authors are grateful to the Research Service Center for Health Information at Chang Gung University, Taiwan, for their assistance in designing the study, managing data, and conducting statistical analysis.
作者感谢台湾长庚大学健康信息研究服务中心在设计研究、管理数据和进行统计分析方面的帮助。

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    • Corresponding authors at: Department of Biomedical Sciences, College of Medicine, Chang Gung University, No. 259. Wenhua 1st Rd., Guishan Dist., Taoyuan City 33302, Taiwan. Division of Thoracic Surgery, Chang Gung Memorial Hospital, No.5, Fuxing St. Guishan Dist., Taoyuan City 33302, Taiwan (Yu-Wen Wen) Department of Otorhinolaryngology, Head and Neck Surgery, Linkou Chang Gung Memorial Hospital and Chang Gung University, at Linkou, No. 5, Fu-Hsing ST., Kwei-Shan, Taoyuan, Taiwan (Chun-Ta Liao).
      通讯作者：长庚大学医学院生物医学系，第259期。台湾桃园市龟山区文华一路 33302台湾桃园市复兴街桂山区复兴街5号长庚医院胸外科 33302 （Yu-温 温） 林口长庚纪念医院和长庚大学耳鼻咽喉头颈外科，地址：台湾桃园市桂山市福兴街5号林口（廖春大）。
    E-mail addresses: ywwen@mail.cgu.edu.tw (Y.-W. Wen), liaoct@adm.cgmh.org.tw (C.-T. Liao).
    电子邮件地址： ywwen@mail.cgu.edu.tw （Y.-W.温）、liaoct@adm.cgmh.org.tw（C.-T.廖）。
    Yu-Wen Wen and Chun-Ta Liao contributed equally to this work.
    Yu-温 温 和 Chun-Ta Liao 对这项工作做出了同样的贡献。