第一部分 长径≤1cm高风险甲状腺结节患者主动监测的随访结局及比较分析

背景：主动监测（Active surveillance，AS）已被认为是长径≤1cm低危甲状腺微小乳头状癌（Papillary thyroid microcarcinoma，PTMC）患者安全、可行的治疗方案，但是中国尚缺乏大样本的研究报道。目前国际常用的甲状腺结节风险分层系统均使用超声特征来评估甲状腺结节的恶性风险，为了防止PTMC的过度诊断和过度治疗，均建议高风险甲状腺结节进行细针穿刺的界值为1cm。因此，本研究依据2015年美国甲状腺协会超声甲状腺结节风险分层系统来筛选符合主动监测条件的长径≤1cm的高风险甲状腺结节患者，评估这类患者进行主动监测的肿瘤学结局，并与同期行即刻手术(Immediate surgery，IS)的患者比较肿瘤学结局、不良事件发生率以及医疗费用等情况，全面评估两种管理方式的利弊，为临床决策提供来自中国的研究数据。

方法：本部分进行的是一项单中心、大样本队列研究，连续纳入符合本研究主动监测标准的长径≤1cm高风险甲状腺结节患者，评估主动监测过程中这类患者的肿瘤学结局（疾病进展、疾病复发/转移率等）, 并与同期接受即刻手术的同类患者比较肿瘤学结局、不良事件发生率以及医疗费用等情况。

结果：在中位47.1个月的随访期间（范围：6.0-284.3个月），702例长径≤1cm高风险甲状腺结节患者选择主动监测，32例（4.4%）患者出现疾病进展，其中20例（2.7%）肿瘤长径增大≥3 mm，12例（1.6%）发现颈部淋巴结转移。主动监测组患者2年、5年和10年的疾病进展累计发生率分别为0.8%、4.6%和11.3%，其中年龄≤45岁患者的疾病进展累计发生率高于＞45岁患者（5年：6.3% vs. 2.4%，P = 0.01）。共60例患者接受延迟手术，其中意愿改变患者34例，疾病进展患者26例（肿瘤长径增大≥3 mm患者14例，颈淋巴结转移患者12例）。另有6例肿瘤增大患者选择继续进行主动监测。所有进行主动监测的患者均未发生远处转移，也没有患者因甲状腺癌而死亡。与即刻手术组患者相比，延迟手术组患者在性别、年龄、手术方式、病理亚型、被膜侵犯、多灶、淋巴结转移与否以及TNM分期方面均无统计学差别。与全部主动监测组患者相比，即刻手术组（381例）患者的暂时性声带麻痹（2.4% vs. 0.1%，P < 0.001）和暂时性甲状旁腺功能减退（12.6% vs. 1.4%，P < 0.001）发生率明显高于主动监测组，两组均无永久性声带麻痹和永久性甲状旁腺功能减退发生，即刻手术组的再手术比例明显高于主动监测组（2.9% vs. 0.3%，P < 0.001），其他并发症方面两组间无统计学差别。主动监测组中延迟手术患者与即刻手术患者间不良事件发生率无统计学差别。即刻手术组患者5年平均医疗花费是主动监测组的2.3-2.9倍。

结论：符合条件的长径≤1cm高风险甲状腺结节患者进行主动监测能够获得与即刻手术相似且良好的肿瘤学结局，同时还能避免手术相关不良事件的发生和获得更少的短期医疗花费。因此，主动监测可作为这类患者合适的管理方案。

第二部分 长径≤1cm高风险甲状腺结节患者长期生活质量和心理状态的比较分析: 主动监测vs. 即刻手术

背景：对于包括肿瘤在内很多疾病，生活质量和心理状态的评估非常重要，其会明显影响治疗决策，甚至治疗结局。了解主动监测（Active surveillance，AS）和即刻手术（Immediate surgery，IS）对高风险甲状腺结节患者生活质量和心理状态的影响也是整个治疗过程中非常重要的一环。目前仍然缺乏主动监测和即刻手术两种管理方式对长径≤1cm的高风险甲状腺结节患者生活质量和心理状态长期影响的研究。

方法：本部分对752例长径≤1cm的高风险甲状腺结节患者的长期生活质量和心理状态进行了分析，其中主动监测组584例，即刻手术组168例。所有患者均接受至少两次生活质量和心理状态量表的评估，通过三种量表进行评估：THYCA-QoL量表、HADS量表和EORTC QLQ-C30量表。在排除主动监测组中疾病进展或意愿改变的患者和即刻手术组中接受二次手术的患者后，使用倾向性匹配评分，以3：1的比例（主动监测：即刻手术 = 492：164）匹配两组患者，随后采用混合线性模型对生活质量和心理状态评估数据进行分析。

结果：主动监测组从初始评估到末次随访的中位时间为24.0个月（范围：5.2-87.6个月），即刻手术组为14.2个月（范围：5.1-37.3个月）。主动监测组患者的长期生活质量优于即刻手术组患者，主要表现在THYCA-QoL量表中的声音（P < 0.001），交感神经（P = 0.005），咽喉/口腔（P < 0.001），感官（P < 0.001），以及瘢痕问题（P < 0.001）；EORTC QLQ-C30量表中的躯体功能（P = 0.003），角色功能（P < 0.001），社会功能（P < 0.001），整体健康状况（P < 0.001），疲劳（P = 0.003），疼痛（P = 0.003），食欲减退（P = 0.008）和经济困难（P < 0.001）方面。与初始评估（手术后一周）相比，即刻手术组患者的生活质量会随着随访时间延长而逐渐改善，主要体现在THYCA-QoL量表中的声音（P = 0.011），咽喉/口腔（P < 0.001）；EORTC QLQ-C30量表中的躯体功能（P = 0.002），社会功能（P = 0.006），恶心和呕吐（P < 0.001），疼痛（P = 0.008）和食欲下降（P = 0.022）方面。

结论：在长期随访过程中，主动监测组患者表现出比即刻手术组更好的生活质量。虽然两组间的生活质量差距会逐渐缩小，但与手术疤痕、角色功能、社会功能、整体健康状况、疲劳和经济困难相关的差异仍然持续存在，可能影响患者的日常生活和社会活动。因此，从生活质量方面考虑，主动监测可作为高风险甲状腺结节患者更合适的管理方案。

第三部分 肿瘤进展评估指标探索：肿瘤长径和体积变化对肿瘤增大评估的价值和意义

背景：疾病进展的判定是主动监测过程中非常重要的一环，决定着患者后续治疗方案的选择，因此使用何种标准来定义疾病进展显得尤为重要。主动监测过程中的最常见的疾病进展是肿瘤增大，目前常用的两种评估方式为长径和体积，但是尚未有研究比较肿瘤长径和体积变化对评估肿瘤增大的价值和意义。

方法：本部分研究收集了主动监测患者定期超声评估下肿瘤大小的变化情况，所有患者均接受至少两次标准的超声评估。根据本研究设定的不同肿瘤增大判断标准，比较肿瘤长径和体积变化对肿瘤增大评估的价值和意义。

结果：本部分共纳入468例符合主动监测条件的高风险甲状腺结节患者，共包含高风险甲状腺结节569个，其中14例（2.5%）高风险甲状腺患者出现肿瘤长径增大≥3mm，体积变化峰值超过50%和100%的结节分别为185个（32.5%）和86个（15.1%）。在555个稳定结节中，体积波动超过50%和100%的结节分别为171个（30.8%）和72个（13.0%）。在包含基线及前3次随访数据的212个稳定结节中，基线三径线之和≤1 cm的结节体积波动峰值超过50%（48.5% vs. 28.5%，P = 0.004）和100% （26.5% vs. 8.3%，P < 0.001）的比例明显高于三径线之和＞1 cm的结节，两组间体积波动极差也存在统计学差别（P = 0.007）。

结论：体积测量在评估高风险甲状腺结节的大小变化时更为敏感，但可能受到更多因素的影响，尤其是基线肿瘤大小会显著影响体积测量结果的评估。因此，肿瘤体积变化并不适合用于肿瘤增大的评估，肿瘤长径仍然是一种更简单、稳定和实用的评估指标。

Part 1. Follow-up outcomes and comparative analysis of active surveillance in patients with high-risk sub-centimeter thyroid nodules

Background: Active surveillance (AS) has been considered a safe and feasible treatment option for low-risk papillary thyroid microcarcinoma (PTMC) patients, but there is still a lack of prospective, large-sample studies in China. International thyroid nodule risk stratification systems use ultrasound features to assess malignant risk, and currently, all stratification systems recommend a threshold of 1cm for high-risk nodules to undergo fine-needle aspiration pathology diagnosis to prevent overdiagnosis and overtreatment of PTMC. Therefore, this study aims to use the 2015 American Thyroid Association ultrasound thyroid nodule risk stratification criteria to select patients with high-risk sub-centimeter thyroid nodule who meet the criteria for AS and evaluate the oncology outcomes, incidence of adverse events, and medical costs of these patients, comparing above issues with those patients undergoing immediate surgery (IS) in the same period. The pros and cons of these two management strategy will comprehensively be evaluated to provide research data for clinical decision-making in China.

Methods: In this section, we conduct a prospective, single-center, large-sample cohort study focusing on high-risk thyroid nodule patients with a long diameter ≤ 1cm who meet the AS criteria of this study. The study assesses oncological outcomes (disease progression, recurrence/metastasis rate, etc.), adverse events rate, and medical costs of these patients during AS, and compares them with patients who undergo IS during the same period.

Results: During a median follow-up of 47.1 months (range: 6.0 to 284.3 months) among 702 patients with high-risk thyroid nodules with a longest diameter of 1 cm or less who underwent AS, 32 patients (4.4%) had disease progression, including 20 patients (2.7%) with an increase in tumor longest diameter of 3 mm or more and 12 patients (1.6%) with the discovery of neck lymph node metastasis. The cumulative incidence rates of disease progression at 2, 5, and 10 years in the AS group were 0.8%, 4.6%, and 11.3%, respectively. The 5-year cumulative incidence of disease progression was higher in patients aged 40 years or younger than in those older than 40 years (6.3% vs. 2.4%，P = 0.01). A total of 60 patients underwent delayed surgery, including 26 patients with disease progression (14 with an increase in tumor longest diameter of 3 mm or more and 12 with neck lymph node metastasis), 34 patients with a change in preference, and 6 patients with an increase in tumor size who chose to continue AS. No distant metastases or deaths from thyroid cancer occurred in any of the patients undergoing AS. Compared with the IS group, there was no significant difference in gender, age, operation, pathological subtype, capsular invasion, multifocality, lymph node metastasis and TNM stage in the delayed surgery group. As compared with all the patients in the AS group, the IS group (381 patients) had significantly higher rates of transient vocal cord paralysis (2.4% vs. 0.1%, P < 0.001) and transient hypoparathyroidism (12.6% vs. 1.4%, P < 0.001); there were no cases of permanent vocal cord paralysis or permanent hypoparathyroidism in either group. However, the rate of reoperation was significantly higher in the IS group than in the AS group (2.9% vs. 0.3%, P < 0.001). The average medical costs for patients in the IS group were 2.3 to 2.9 times as high as those for patients in the AS group.

Conclusions: AS of high-risk sub-centimeter thyroid nodules in patients without high-risk factors has good oncological outcomes and could be a safe alternative to surgery, while reducing unfavorable events and medical costs. AS is thus a feasible treatment option for patients with high-risk sub-centimeter thyroid nodules in China.

Part 2. A long-term study comparing the quality of life and psychological status of patients with high-risk sub-centimeter thyroid nodules undergoing active surveillance with those undergoing immediate surgery

Background: For diseases requiring long-term follow-up, it is particularly important to monitor changes in the long-term quality of life (QoL) and psychological status of the patients, which may fluctuate and change over time, potentially affecting treatment outcomes. However, only a few studies have evaluated the QoL of patients with high-risk thyroid nodules under AS. Limited information is available on the long-term impact of active surveillance (AS) and immediate surgery (IS) on the QoL and psychological status of patients with high-risk sub-centimeter thyroid nodules.

Methods: A prospective study was conducted on 752 patients showing high-risk sub-centimeter thyroid nodules, among whom 584 chose AS and 168 chose IS. All patients underwent at least two assessments regarding their QoL and psychological status, using three questionnaires: THYCA-QoL, HADS and EORTC QLQ-C30. To mitigate selection bias, a propensity score algorithm was used to match the two groups in a 3:1 ratio (AS:IS=492:164), after excluding patients with disease progression or preference change in the AS group and those who underwent a second surgery in the IS group. Subsequently, the mixed linear model was used to analyze the QoL data.

Results: The median duration from the initial assessment to the final follow-up in the AS and IS groups was 24.0 months and 14.2 months, respectively. The AS group exhibited better QoL outcomes compared to the IS group, particularly evident in voice (P < 0.001), sympathetic (P = 0.005), throat/mouth (P < 0.001), sensory (P < 0.001) and problems with scar (P < 0.001) domains, as indicated by the THYCA-QoL questionnaire. Additionally, the EORTC QLQ-C30 questionnaire revealed improved outcomes in physical function (P = 0.003), role function (P < 0.001), social function (P < 0.001), global health status (P < 0.001), fatigue (P = 0.003), pain (P = 0.003), appetite loss (P = 0.008), and financial difficulties (P < 0.001). In comparison to the initial assessment (one week after surgery), the IS group displayed gradual enhancements in QoL, particularly in voice (P = 0.011), throat/mouth (P < 0.001), physical function (P = 0.002), social function (P = 0.006), nausea & vomiting (P < 0.001), pain (P = 0.008), and appetite loss (P = 0.022) domains as per both questionnaires.

Conclusions: Patients with high-risk sub-centimeter thyroid nodules who choose IS tend to experience a poorer long-term QoL compared to those who choose AS. Although the situation may improve over time, certain issues might persist, making AS a favorable option for many patients.

Part 3. The value and significance of criteria to evaluate tumor enlargement during the active surveillance of high-risk sub-centimeter thyroid nodules

Background: Tumor enlargement is the most common parameter identifying disease progression during active surveillance (AS), but the value and significance of the changes in tumor diameter and volume in the evaluation of tumor growth have not been compared.

Methods: This section compares and analyzes the criteria for evaluating tumor enlargement (diameter and volume) during AS, collecting data on tumor size changes from regular ultrasound assessments of AS patients, all of whom received at least two standard ultrasound assessments. According to the different criteria of tumor enlargement, the value and significance of tumor diameter and volume change in the evaluation of tumor enlargement were compared.

Results: A total of 569 high-risk sub-centimeter thyroid nodules were identified in 468 patients. 14 nodules (2.5%) exhibited a diameter increase ≥ 3 mm. The number of nodules with a peak volume change exceeding 50% and 100% was 185 (32.5%) and 86 (15.1%), respectively. Among the 555 stable nodules, the number of nodules with volume fluctuations surpassing 50% and 100% was 171 (30.8%) and 72 (13.0%), respectively. Among 212 stable nodules at the baseline and in the initial three follow-ups, the percentage of peak volume fluctuations exceeding 50% (48.5% vs. 28.5%, P = 0.004) and 100% (26.5% vs. 8.3%, P ＜ 0.001) in the nodules with the sum of three diameters (SOTDs) ≤ 1 cm was significantly higher than that of nodules with SOTDs＞1 cm. A statistically significant difference was also observed in the range distribution of SOTDs ≤ 1 cm and SOTDs＞1cm (P = 0.007).

Conclusions: Volume measurement may be more sensitive in assessing the size changes of high-risk sub-centimeter thyroid nodules, but it may be influenced by more factors, especially the baseline tumor size significantly causing fluctuations in volume measurements. Therefore, tumor diameter measurement alone serves as a better surrogate for disease progression in sonographically high-risk thyroid nodules than volume because it provides more measurement consistency.