Evaluating the Impact of Immediate Lymphatic Reconstruction for the Surgical Prevention of Lymphedema
评估即时淋巴重建对手术预防淋巴水肿的影响

Breast cancer–related lymphedema affects approximately 20 to 45 percent of breast cancer survivors after surgical intervention.^1–7 This surgical sequela is associated with decreased patient quality-of-life measures, increased susceptibility to infection, and increased medical expenditure.^8,9 Treatment for breast cancer–related lymphedema is largely palliative in nature and focused on reducing symptoms and preventing disease progression. Conservative measures require strict patient adherence to lifelong therapies, including manual lymphatic drainage, compression bandaging/garments, pneumatic pump use, and physical therapy.^1,10,11 Despite improvements in microsurgical techniques such as vascularized lymph node transfer and lymphovenous bypass for the treatment of chronic lymphedema, none of these options has proven curative. As long-term overall survival increases in tandem with advancements in treatment, efforts toward minimizing or eliminating breast cancer–related lymphedema are paramount. The advent of the lymphatic microsurgical preventive healing approach has introduced the concept of surgical prevention for lymphedema.
大约 20% 到 45% 的乳腺癌幸存者在接受手术治疗后会出现乳腺癌相关淋巴水肿。^1-7 这种手术后遗症与患者生活质量下降、易感染和医疗支出增加有关。⁸⁹ 乳腺癌相关淋巴水肿的治疗主要是姑息性的，侧重于减轻症状和防止疾病进展。保守措施要求患者严格遵守终身疗法，包括人工淋巴引流、加压包扎/穿衣、使用气动泵和物理疗法。¹¹⁰¹¹ 尽管用于治疗慢性淋巴水肿的显微外科技术有所改进，如血管化淋巴结转移和淋巴静脉搭桥、但这些方法均未被证明具有治疗效果。随着治疗技术的进步，长期总生存率也在不断提高，因此最大限度地减少或消除与乳腺癌相关的淋巴水肿至关重要。淋巴显微外科预防性治疗方法的出现引入了手术预防淋巴水肿的概念。

In the seminal study by Boccardo et al., lymphedema rates were 4 percent with 4 years’ follow-up in a high-risk patient cohort where the majority of patients underwent axillary lymph node dissection with regional lymph node radiotherapy.¹² This finding has been replicated at other institutions, where similar decreases in rates of lymphedema after immediate lymphatic reconstruction were found in comparable patient cohorts.^13,14 Some criticisms of these studies include variation in the criteria used to diagnose “lymphedema,” heterogeneity of measurement modalities used, and varying follow-up periods.¹⁵
在 Boccardo 等人的开创性研究中、在高危患者群中，大多数患者都接受了腋窝淋巴结清扫术和区域淋巴结放疗，随访4年后，淋巴水肿发生率为4%。¹² 其他机构也重复了这一发现，在类似的患者群中，立即淋巴重建后的淋巴水肿率也有类似的下降。¹³¹⁴ 这些研究受到的一些批评包括诊断 "淋巴水肿 "的标准不同、"使用的测量模式不一致，以及随访时间长短不一。¹⁵

At our institution, the lymphatic microsurgical preventive healing approach is termed “immediate lymphatic reconstruction,” as divided lymphatics are reconstructed at the time of tumor extirpation.¹⁶ We use multiple lymphedema measurement modalities preoperatively and during postoperative surveillance. Moreover, we impose follow-up criteria to capture the long-term effects of this technique.
在我院，淋巴显微外科预防性愈合方法被称为 "即时淋巴重建"，因为分裂的淋巴管是在肿瘤切除时重建的。此外，我们还规定了随访标准，以了解该技术的长期效果。

Our present study aims to introduce and review our institutional experience with immediate lymphatic reconstruction in a node-positive breast cancer patient population undergoing axillary surgery. To this end, we performed a retrospective review of a quality improvement database to identify all patients who underwent axillary surgery with immediate lymphatic reconstruction at our institution and describe our surgical outcomes.
本研究旨在介绍和回顾我院在接受腋窝手术的结节阳性乳腺癌患者中进行即时淋巴重建的经验。为此，我们对质量改进数据库进行了回顾性审查，以确定本机构所有接受腋窝手术并立即进行淋巴重建的患者，并描述我们的手术结果。

PATIENTS AND METHODS 患者和方法

A retrospective review of our lymphatic surgery Research Electronic Data Capture database was performed. Institutional review board approval was obtained (protocol no. 2019P-000190). Consecutive patients with a diagnosis of node-positive unilateral breast cancer who underwent attempted immediate lymphatic reconstruction after axillary surgery from September of 2016 through February of 2019 were identified. No patients with a history of breast cancer or breast and/or axillary surgery were eligible for inclusion. Furthermore, no patients undergoing sentinel lymph node biopsy alone were eligible for immediate lymphatic reconstruction. Patient demographics, cancer characteristics, intraoperative specifics, and surveillance measurements were extracted for analysis. The study design is illustrated in Figure 1.
我们对淋巴手术研究电子数据采集数据库进行了回顾性审查。研究获得了机构审查委员会的批准（方案编号：2019P-000190）。从 2016 年 9 月到 2019 年 2 月，我们对诊断为结节阳性单侧乳腺癌并在腋窝手术后尝试立即进行淋巴重建的连续患者进行了鉴定。没有乳腺癌或乳腺和/或腋窝手术史的患者符合纳入条件。此外，仅接受前哨淋巴结活检的患者也不符合即时淋巴重建的条件。研究人员提取了患者的人口统计学特征、癌症特征、术中具体情况和监测测量数据进行分析。研究设计见图1。

Preoperative Evaluation 术前评估

Certified lymphedema therapists at our institution used multiple lymphedema measurement modalities to obtain comprehensive baseline data for all patients who presented for immediate lymphatic reconstruction. These measurement modalities included (1) circumferential arm measurements at 4-cm intervals that were converted to volumes using the truncated cone formula,¹⁷ (2) perometry, and (3) bioimpedance spectroscopy (L-Dex U400; ImpediMed, Carlsbad, Calif.).
我们医院的认证淋巴水肿治疗师采用多种淋巴水肿测量方法，为所有立即进行淋巴重建的患者获取全面的基线数据。这些测量方法包括：(1) 以4厘米为间隔测量手臂周径，并使用截顶锥公式将其转换为体积，¹⁷ (2) 周径测量法，以及 (3) 生物阻抗光谱法（L-Dex U400; ImpediMed, Carlsbad, Calif.）。

In addition, all patients were administered the 36-Item Short-Form Health Survey questionnaire at routine intervals.^18,19 We administer the 36-Item Short-Form Health Survey to all patients preoperatively. This survey provides data on physical functioning (physical component scale) and mental health, emotional, and social functioning (mental component scale). Pertinent patient data including demographics, medical history, cancer characteristics and treatment, and baseline lymphedema measurements are entered into a Research Electronic Data Capture²⁰ lymphedema quality improvement clinical database to facilitate surveillance.
此外，所有患者都在常规时间间隔内接受了 36 项短式健康调查问卷。¹⁸¹⁹ 我们在术前对所有患者进行36项短式健康调查。该调查提供有关身体功能（身体部分量表）和心理健康、情感及社会功能（心理部分量表）的数据。患者的相关数据，包括人口统计学、病史、癌症特征和治疗以及淋巴水肿的基线测量值，都会被输入研究电子数据采集²⁰ 淋巴水肿质量改进临床数据库，以方便监测。

Surgical Technique 手术技术

At our institution, sentinel lymph node biopsies are performed as permanent sections and axillary lymph node dissections occur in a staged manner. A single surgeon with fellowship training in lymphatic surgery (D.S.) performed all attempted immediate lymphatic reconstructions from September of 2016 through February of 2019 at the time of nodal extirpation. The type of axillary nodal intervention performed was determined by the lymphatic surgeon intraoperatively. Following axillary surgery, the lymphatic surgeon attempted to visualize the boundaries of a level I and II dissection including the axillary vein superiorly, serratus anterior medially, thoracodorsal vessels posteriorly, and latissimus muscle laterally.²¹ If all structures were visible, the procedure was termed an axillary lymph node dissection. If any of these structures was not visible, the procedure was termed an axillary sampling procedure.
在我们医院，前哨淋巴结活检是作为永久切片进行的，而腋窝淋巴结切除则是分阶段进行的。从 2016 年 9 月到 2019 年 2 月，由一名接受过淋巴手术研究培训的外科医生（D.S.）在结节切除时进行了所有尝试过的即时淋巴重建手术。腋窝结节干预的类型由淋巴外科医生在术中决定。腋窝手术后，淋巴外科医生尝试观察I级和II级解剖的边界，包括腋窝静脉上侧、前锯肌内侧、胸背血管后侧和阔筋肌外侧。²¹ 如果所有结构都可见，则称为腋窝淋巴结清扫术。如果其中任何结构不可见，则称为腋窝取样手术。

Immediately before the initiation of the axillary intervention by the breast surgical oncology service, 0.25 cc of fluorescein isothiocyanate mixed with albumin was injected into the upper medial operative extremity as described previously.²² Following completion of the axillary lymph node dissection, using the same exposure provided by the breast surgeon, the axillary bed was evaluated, and any major venous branches draining into the axillary vein were identified. Tributaries of the axillary vein were then evaluated for adequate length and the presence of a proximal intact valve. In cases of inadequate vein length or significant venous back-bleeding, the lymphatic reconstruction was aborted.
在乳腺肿瘤外科开始进行腋窝介入治疗之前，按照之前的描述，将 0.25 cc 异硫氰酸荧光素与白蛋白混合液注入手术肢体的上内侧。²² 在完成腋窝淋巴结清扫后，使用乳腺外科医生提供的相同暴露方式，对腋窝床进行评估，并确定排入腋窝静脉的主要静脉分支。然后评估腋窝静脉的支流是否有足够的长度，近端是否有完整的瓣膜。如果静脉长度不足或静脉回流明显，则放弃淋巴重建。

Using a Mitaka MM51 microscope equipped with a 560-nm filter (Mitaka Kohki Co., Ltd., Mitaka, Tokyo), divided lymphatic channels were visualized and their location mapped from the axillary vein. Each lymphatic channel was isolated and measured using high magnification and fluorescent technology for visualization. The distal ends of lymphatic channels were cut to confirm active lymphatic flow using filter technology. Afferent lymphatic vessels not suitable for anastomosis were clipped. A U stitch was then passed through the prepared tributary vein and lymphatic channels to facilitate parachuting the lymphatic channels into the vein using the technique described by Boccardo and Campisi.²³ The lymphatic reconstruction was then secured using 9-0 nylon sutures (Ethicon, Inc., Somerville, N.J.), which were passed full thickness through the tributary vein into the perilymphatic tissues in a simple, interrupted manner. The initial U stitch was then cut to allow lymphatic flow into the vein. Confirmation of lymphatic flow and anastomotic patency was visualized using the Mitaka MM51 microscope, as documented in a previous study.²² A fat graft was then harvested from the axilla that was then wrapped around the anastomotic site to secure it. [See Video (online), which demonstrates the surgical technique used in immediate lymphatic reconstruction of the left axillary nodal bed.] The axillary incision was closed in standard fashion and a no. 15 Blake drain was placed exiting the dependent portion of the axillary bed away from the anastomotic site.
使用配备了 560 纳米滤光片的 Mitaka MM51 显微镜（Mitaka Kohki Co., Ltd., Mitaka, Tokyo），从腋窝静脉开始观察并绘制淋巴管的位置图。利用高倍放大镜和荧光技术对每条淋巴管进行分离和测量。利用过滤技术切割淋巴管远端，以确认活跃的淋巴流动。剪断不适合吻合的传入淋巴管。²³ 然后使用 9-0 尼龙缝线（Ethicon, Inc、Somerville, N.J.）缝合，以简单、间断的方式将缝线全厚度穿过支流静脉进入淋巴周围组织。然后切断最初的 U 形缝线，让淋巴液流入静脉。²² 然后从腋窝抽取脂肪移植到吻合部位，将其包裹固定。[请参阅视频（在线），该视频展示了左侧腋窝结节床即时淋巴重建的手术技巧。］以标准方式缝合腋窝切口，并在腋窝外侧放置No.15 Blake引流管从远离吻合部位的腋窝依赖部分引出。

Postoperative Surveillance
术后监控

On discharge, patients are advised to follow routine incisional care. When drain outputs are less than 20 cc/day for 2 consecutive days, the drain is removed, and this is usually accomplished by 14 days postoperatively. Our surveillance protocol for immediate lymphatic reconstruction patients included postoperative visits at 4 weeks, 3 months, and then every 3 months postoperatively for 2 years. During each surveillance visit, certified lymphedema therapists assessed and documented any signs or symptoms consistent with lymphedema (e.g., heaviness, swelling, numbness). All objective measurements from the preoperative evaluation were repeated at each surveillance visit. Studies have shown the success and cost-effectiveness of postoperative surveillance programs in patients at high risk for the development of breast cancer–related lymphedema.^24–26 We monitor patients closely using three measurement modalities (i.e., perometry, bioimpedance spectroscopy, and volumetry by circumferential measurements). If the patient did not develop any signs or symptoms consistent with lymphedema or objective findings (any positive quantitative change by volumetry, L-Dex, or circumferential measurements) consistent with lymphedema during this time frame, patients were then surveilled every 6 months for the subsequent 2 years. In total, patients are actively surveilled for 4 years. The need for additional surveillance is determined on a case-by-case basis. Bioimpedance spectroscopy is a sensitive modality championed for postoperative patient surveillance, as it can noninvasively detect changes in lymph fluid by assessing the “impedance,” or opposition to current traveling through the body.²⁷
出院时，建议患者进行常规切口护理。当引流管排出量连续两天少于 20 毫升/天时，引流管将被移除，这通常在术后 14 天内完成。我们对即刻淋巴重建患者的监控方案包括术后 4 周、3 个月和术后 2 年内每 3 个月的复诊。在每次监测访视期间，经认证的淋巴水肿治疗师都会评估并记录任何与淋巴水肿相符的体征或症状（如沉重、肿胀、麻木）。术前评估中的所有客观测量结果都会在每次复查时重复进行。研究表明，对于乳腺癌相关淋巴水肿的高危患者，术后监测计划是成功且具有成本效益的。^24-26 我们使用三种测量方法（即周径测量法、生物阻抗光谱法和周径体积测量法）对患者进行密切监测。如果患者在此期间没有出现任何与淋巴水肿相一致的体征或症状，也没有任何与淋巴水肿相一致的客观检查结果（体积测量法、L-Dex 或周径测量法的任何积极定量变化），那么在随后的 2 年中，我们将每 6 个月对患者进行一次监测。患者总共要接受 4 年的主动监测。是否需要进行额外的监测要根据具体情况而定。生物阻抗光谱是一种用于术后患者监测的灵敏模式，因为它可以通过评估 "阻抗 "或电流通过人体时的阻抗，无创检测淋巴液的变化。²⁷

All surveillance data were entered into a lymphatic surgery database by trained staff. The 36-Item Short-Form Health Survey questionnaires were sent to patients by automated e-mails from the database at 3, 6, and 12 months, and then annually following immediate lymphatic reconstruction. All results from completed online surveys were automatically populated within the Research Electronic Data Capture²⁰ database.
所有监测数据均由经过培训的工作人员输入淋巴手术数据库。在淋巴重建手术后的3、6、12个月，以及每年的3、6、12个月，数据库会自动向患者发送36项短式健康调查问卷。所有在线调查的结果都会自动输入研究电子数据采集²⁰ 数据库。

Lymphedema is defined at our institution as having both (1) any positive quantitative measurement meeting criteria for lymphedema and the (2) presence of symptoms (i.e., tightness, heaviness, swelling) consistent with lymphedema as determined by a certified lymphedema therapist. Objective measurements consistent with a lymphedema diagnosis included a 10-point increase in bioimpedance (L-Dex) value from baseline; a 10 percent volume increase in the dominant, affected extremity; or a 7 percent increase in the nondominant affected extremity using volumetry. If the patient met these criteria while undergoing adjuvant treatment, with the exclusion of hormone therapy and immunotherapy, or within 6 months of their last oncologic treatment, lymphedema was classified as transient (i.e., “transient lymphedema”). A diagnosis of lymphedema was given if the patient met the above-specified criteria 6 months after their last oncologic treatment (surgery, adjuvant radiation therapy, or chemotherapy). Regional lymph node radiation was defined at our institution as targeted treatment to the internal mammary, supraclavicular, and/or axillary regions.^28,29
我院对淋巴水肿的定义是：(1) 任何符合淋巴水肿标准的阳性定量测量值；(2) 经认证的淋巴水肿治疗师判断，出现与淋巴水肿相符的症状（即紧绷、沉重、肿胀）。符合淋巴水肿诊断的客观测量值包括：生物阻抗（L-Dex）值比基线值增加 10 个点；主要受累肢体的体积增加 10%；或使用容积测量法测量非主要受累肢体的体积增加 7%。如果患者在接受辅助治疗（不包括激素治疗和免疫治疗）期间或最后一次肿瘤治疗后 6 个月内符合上述标准，则淋巴水肿被归类为短暂性淋巴水肿（即 "短暂性淋巴水肿"）。如果患者在最后一次接受肿瘤治疗（手术、辅助放疗或化疗）6个月后符合上述标准，则可诊断为淋巴水肿。我院将区域淋巴结放射定义为乳腺内、锁骨上和/或腋窝区域的靶向治疗。²⁸²⁹

Statistical Analysis 统计分析

Descriptive statistics of the data were performed. Continuous data were represented using mean and standard deviation or median and range or first and third quartiles. Frequencies and percentages were used to summarize categorical variables. We used t tests for continuous variables and chi-square tests for categorical variables to compare demographics between the cohort who underwent successful immediate lymphatic reconstruction with 6-month minimum follow-up (n = 32) and all other patients who underwent attempted immediate lymphatic reconstruction (n = 65). R 3.5.3 (R Development Core Team, 2019) was used for statistical analyses.
对数据进行了描述性统计。连续数据用均值和标准差或中位数和范围或第一和第三四分位数表示。频率和百分比用于总结分类变量。我们对连续变量采用t检验，对分类变量采用卡方检验，以比较成功接受即时淋巴重建且随访时间至少为6个月的患者（n = 32）和其他所有尝试接受即时淋巴重建的患者（n = 65）的人口统计学特征。统计分析使用R 3.5.3 (R Development Core Team, 2019)。

RESULTS 结果

Ninety-seven women with unilateral node-positive breast cancer underwent attempted immediate lymphatic reconstruction at our institution during the study period. Forty-one patients had a minimum 6-month follow-up. Nine of these cases (22 percent) were excluded, as immediate lymphatic reconstruction was aborted intraoperatively. Inadequate recipient vein (e.g., lack of vein availability or back-bleeding) occurred in five of the aborted cases; lack of identifiable divided lymphatic channel occurred in four cases. A total of 18 patients had preoperative baseline measurements but did not present for 6-month follow-up and were thus ineligible for study inclusion at the time of analysis. Thirty patients underwent successful immediate lymphatic reconstruction with a mean patient age of 54 years and body mass index of 28 ± 6 kg/m². Patients in this cohort had similar demographics when compared to the entire patient population (Table 1).
在研究期间，本院为 97 名单侧结节阳性乳腺癌患者尝试进行了即时淋巴重建。有 41 名患者接受了至少 6 个月的随访。其中九例（22%）因术中放弃即刻淋巴重建而被排除。其中五例因受体静脉不足（如缺乏可用静脉或背部出血）而流产；四例因缺乏可识别的分割淋巴通道而流产。共有 18 名患者在术前进行了基线测量，但没有进行 6 个月的随访，因此在分析时不符合纳入研究的条件。30名患者成功接受了即刻淋巴重建术，患者平均年龄为54岁，体重指数为28 ± 6 kg/m²。与所有患者相比，该组患者的人口统计学特征相似（表1）。

Of the 32 patients who met study eligibility criteria, 88 percent of women in this cohort underwent adjuvant radiotherapy of whom 93 percent received regional lymph node irradiation. Furthermore, 59 percent of women had adjuvant chemotherapy, with the majority (74 percent) undergoing a taxane-based regimen (Table 2).
在符合研究资格标准的32名患者中，88%的女性接受了辅助放疗，其中93%接受了区域淋巴结照射。此外，59%的女性接受了辅助化疗，其中大多数（74%）接受了以类固醇为基础的方案（表 2）。

Intraoperatively, the median number of positive lymph nodes for both the axillary sampling and axillary lymph node dissection groups was one, with the total lymph nodes removed during these interventions being 10 and 13, respectively. All immediate lymphatic reconstructions were performed by a single lymphatic surgeon (D.S.) at our institution. Three breast surgeons performed 88 percent of all nodal dissections. A median of three divided lymphatic channels were visualized in each case (range, one to six). Of these, a median of one lymphatic channel was bypassed (range, one to three). The median distance of the bypassed channel to the distal aspect of the visualized axillary vein was 3.00 cm (range, 0.25 to 5.5 cm). The median bypass time after completion of axillary intervention was 85 minutes (range, 54 to 205 minutes). Table 3 reports the intraoperative data by axillary sampling versus axillary lymph node dissection cases. The median patient follow-up time was 11.4 months (range, 6.2 to 26.9 months). There was no statistical difference between the mean number of bypasses performed in the group of patients who underwent axillary sampling (n = 1.57) compared to those who underwent an axillary lymph node dissection (n = 1.48) (p = 0.79). A summary of surveillance measurements is provided in Table 4. No intraoperative or postoperative complications were observed in this cohort.
术中，腋窝取样组和腋窝淋巴结清扫组阳性淋巴结的中位数均为1个，这两组切除的淋巴结总数分别为10个和13个。本院所有即时淋巴重建手术均由一名淋巴外科医生（D.S.）完成。在所有结节切除术中，88%由三名乳腺外科医生完成。在每个病例中，可观察到的分裂淋巴管中位数为三条（范围为一到六条）。其中，中位数为一条淋巴管被绕过（范围为一到三条）。被旁路的淋巴管到可视腋静脉远端的中位距离为 3.00 厘米（范围为 0.25 至 5.5 厘米）。完成腋窝干预后的中位旁路时间为85分钟（范围为54至205分钟）。表3报告了腋窝取样与腋窝淋巴结清扫病例的术中数据。患者随访时间的中位数为11.4个月（6.2至26.9个月）。与接受腋窝淋巴结清扫术（n = 1.48）的患者相比，接受腋窝取样术（p = 0.79）的患者组所进行的旁路平均次数没有统计学差异。表4中提供了监控测量的摘要。该组患者未观察到术中或术后并发症。