乳腺癌前哨淋巴结活检示踪剂研究进展

传统的示踪剂核素和蓝染料存在一定缺点。近年来国内外学者试图研发一款功能优化的新型示踪剂,有助于前哨淋巴结活检术(sentinel lymph node biopsy,SLNB)的推广。吲哚菁绿价格较低,使用安全,但穿透力有限(1 cm)且缺乏靶向性。超声造影剂可实时动态地观察显影淋巴管和淋巴结,但成功率和准确性相对较低。超顺磁氧化铁作为前哨淋巴结示踪剂,操作方便,可避免医源性核素污染,具有良好的应用前景。     

Sentinel lymph node biopsy in breast cancer using blue dye with or without isotope localization

BACKGROUND: The purpose of this study was to determine the feasibility of sentinel lymph node (SLN) biopsy using blue dye with or without isotope localization to predict the presence of axillary and internal mammary lymph node (IMN) metastases in patients with breast cancer. We also investigated whether multiple sectioning of the SLN could improve the accuracy of frozen section examination. METHOD:One-hundred twenty-six patients underwent dye-guided or dye- and gamma probe-guided SLN biopsy followed by complete axillary lymph node dissection (ALND). No ALND was performed in the 14 patients with small tumors and a negative SLN. In addition, 69 patients underwent IMN biopsy. RESULTS: The axillary SLN was identified in 123 of 140 (88%) patients. An accuracy rate of 90% was obtained by frozen section examination of the SLN, which increased to 100% in patients examined with a greater number of sections. Lymphatic flow to the IMN and/or a radioactive hot spot in the IMN was found in 9 of 102 (9%) patients, while a hot node was detected using a gamma probe in only 2 of these patients. No involvement of the IMNs was found histologically in these 9 patients. IMN involvement was found in 7 of 61 (11%) patients without lymphatic flow to the IMNs or a hot spot by lymphoscintigraphy or who did not undergo lymphoscintigraphy. CONCLUSION: ALND can be avoided in patients with small breast cancers and a negative SLN. SLN biopsy guided by lymphatic mapping is unreliable for identifying metastases to IMNs.     

乳腺癌前哨淋巴结活检术新型示踪剂的研究进展

随着前哨淋巴结活检术成为临床腋窝淋巴结阴性的早期乳腺癌患者的标准处理模式,关于活检示踪剂的研究成为乳腺癌研究的热点之一。目前,临床上应用较多的示踪剂包括蓝染料、核素及二者的结合,但这两种示踪剂存在的某些不足导致发达国家仅有60%的患者进行前哨淋巴结活检,中国仅占约5%,其他发展中国家更少。近年来,各种新型示踪剂的研究层出不穷,如吲哚菁绿、使用微气泡的对比增强超声和超顺磁性氧化铁颗粒等。该文回顾了这三种物质的特性及作为示踪剂的相关研究,这些新型示踪技术仍处于初级研究阶段,有待于进一步实验以便临床应用。     

新型荧光示踪剂在乳腺癌前哨淋巴结活检术中的应用研究

背景与目的：吲哚菁绿（indocyanine green,ICG）与利妥昔单抗（rituximab,Rit）偶联可使ICG在淋巴结显像中具有靶向性。探讨ICG-Rit用于乳腺癌前哨淋巴结活检（sentinel lymph node biopsy,SLNB）的可行性。方法：入组山东省肿瘤防治研究院（山东省肿瘤医院）乳腺病中心96例原发性乳腺癌患者（100例次SLNB）。ICG与Rit质量比为93.75 μg∶375.00 μg。术前行ICG-Rit、联合示踪剂（亚甲蓝及核素示踪剂）乳房注射,联合法行SLNB,对检出淋巴结进行荧光显像检测,记录荧光显像淋巴结及灰度值,分析ICG-Rit淋巴结显像情况并评价对比联合法的一致性。观察患者过敏反应并检测术后嗜酸性粒细胞计数。结果：ICG-Rit病例显像率为97.0%（97/100）。ICG-Rit显像前哨淋巴结（sentinel lymph node,SLN）的均数为2.44,中位数为2;低于核素法检出SLN的均数（2.80）和中位数（3）。ICG-Rit对比联合法SLNB的准确率为97.0%（97/100）,灵敏度为96.2%（25/26）,假阴性率为3.8%（1/26）,kappa值为0.973（P＜0.001）。显像淋巴结灰度值最高254,显像淋巴结灰度值集中在220~254,＜220者术中荧光不易察觉,缺乏连续性。入组患者术前未见过敏反应,术后嗜酸性粒细胞计数未增高。结论：ICG-Rit能够减少对非SLN（non-SLN,n-SLN）的显像。对比联合法,准确率和符合率高,安全性良好。     

Controversies in sentinel node biopsy for breast cancer

Sentinel node biopsy for breast cancer patients has recently been applied as a less invasive, highly accurate alternative to axillary lymph node dissection. Numerous studies have shown that sentinel nodes accurately diagnose axillary staging. However, many problems remain to be answered and must be addressed before sentinel node biopsy becomes the standard surgical procedure for patients with breast cancer. We reviewed and discussed here three of these problems; axillary sampling as an alternative to sentinel node biopsy, dye method vs. combination of dye and radiocolloid for sentinel node biopsy, and intraoperative sentinel node examination. Further investigation will continue to be necessary as we learn how to better provide procedure of sentinel node biopsy.     

乳晕下注射示踪剂行前哨淋巴结活检的可行性

目的探讨乳晕下联合注射核素和美蓝行前哨淋巴结活检的可行性。方法选择2004年10月至2007年2月早期乳腺癌患者195例，将患者抽签随机分为两组：一组将示踪剂注射在肿瘤周围（肿瘤周围组）；另一组将示踪剂注射在乳晕下（乳晕下组）。对所有患者均先行前哨淋巴结活检，再行腋窝淋巴结清扫。将所有的前哨淋巴结和非前哨淋巴结均进行常规切片和HE染色检查，对常规病理检查阴性的前哨淋巴结行多层切片和免疫组化检查。结果全组195例，肿瘤周围组98例，乳晕下组97例。肿瘤周围组与乳晕下组前哨淋巴结活检成功率分别为92．9％和97．9％（P=0．17）。经常规病理检查或多层切片加免疫组化检查后，肿瘤周围组有25例SLN阳性，乳晕下组29例SLN阳性。经腋窝淋巴结清扫后，肿瘤周围组有2例SLN为假阴性，假阴性率为7．4％（2／27），乳晕下组有3例假阴性，假阴性率为9．4％（3／32），两组间差异无统计学意义。肿瘤周围组和乳晕下组对腋窝淋巴结预测的准确度分别为97．8％和96．8％，灵敏度分别为92．6％和90．6％，差异均无统计学意义。结论乳晕下注射两种示踪剂行前哨淋巴结活检与肿瘤周围注射相比具有同样预测腋窝淋巴结状况的准确性，同时能避免肿瘤周围注射存在的缺点，是较佳的注射途径。     

染料法乳腺癌前哨淋巴结活检的多因素分析

目的:染料法是乳腺癌前哨淋巴结活检的方法之一,其成功率受多种因素影响.本研究旨在探讨影响染料法乳腺癌前哨淋巴结活检成功率的相关因素.方法:2007年1月-2008年8月乳腺癌患者141例,于乳晕周围注射1%亚甲蓝,实施前哨淋巴结活检,随后行腋窝淋巴结清扫,常规HE染色进行病理诊断.采用非条件logistic回归进行单因素和多因素分析.结果:126例患者检出前哨淋巴结,15例检测失败.前哨淋巴结活检成功率89.4%,假阴性率为6.82%.单因素分析结果显示,活检成功率与患者年龄、体质量指数(body mass index,BMI)、肿瘤大小、术前腋窝淋巴结状态、肿瘤分级及腋窝淋巴结阳性数≥4枚显著相关.多因素分析结果显示,年龄(OR=4.587,P=0.024)、BMI(OR=4.882,P=0.011)及腋窝淋巴结阳性数≥4枚(OR=3.143,P=0.013)是前哨淋巴结活检成功率的独立影响因素.结论:亚甲蓝示踪法是乳腺癌前哨淋巴结活检的可靠方法,其成功率与患者年龄、BMI和腋窝淋巴结转移数相关.     

染料法前哨淋巴结活检在乳腺癌手术中的应用价值

目的探讨前哨淋巴结活检（SLNB）在乳腺癌手术中的临床应用价值。方法采用亚甲蓝作为示踪染料对乳腺癌开展SLNB，并且对术中冰冻检查前哨淋巴结（SLN）阴性的病例分组施行部分腋窝淋巴结清扫术（PALND）及常规全腋窝淋巴结清扫（TALND），观察术后并发症、生存率等指标并比较分析。结果SLN检出率97．6％，假阴性率14．3％；接受PALND组术后并发症发生率明显低于传统的TALND组，差异有统计学意义（P〈0．05），而总生存率间的差异无统计学意义（P〉0．05）。结论腋区SLNB能准确反映乳腺癌腋窝淋巴转移状态，为临床缩小乳腺癌手术范围和减少术后并发症提供重要参考价值。     

Recurrence after sentinel lymph node biopsy with or without axillary lymph node dissection in patients with breast cancer

BACKGROUND: A regional nodal recurrence is a major concern after a sentinel lymph node biopsy (SLNB) alone in patients with breast cancer. In this study we investigated patterns and risk factors of regional nodal recurrence after SLNB alone. PATIENTS AND METHODS: Between January 1999 and March 2005, a series of 1,704 consecutive breast cancer cases in 1,670 patients (34 bilateral breast cancer cases) with clinically negative nodes or suspicious nodes for metastasis who underwent SLNB at a single institute (Saitama Cancer Center) were studied. All 1,704 cases were classified based upon presence or absence of a metastatic lymph node, treated with or without axillary lymph node dissection (ALND). The site of first recurrence was classified as local, regional node, or distant. The regional node recurrences were subclassified as axillary, interpectoral, infraclavicular, supraclavicular, or parasternal. RESULTS: After a median follow-up period of 34 months (range, 2-83 months), first recurrence occurred in local sites in 32 (1.9%) cases, regional nodes in 26 (1.5%) cases, and distant sites in 61 (3.6%) cases. In 1,062 cases with negative nodes treated without ALND and 459 cases with positive nodes treated with ALND, 11 (1.0%) and 15 (3.3%) recurred in regional nodes, respectively, and 4 (0.4%) and 2 (0.6%) recurred in axillary nodes, respectively. Of 822 cases of invasive breast cancer with negative nodes treated with SLNB alone, 10 (1.4%) recurred in regional nodes, and 4 (0.5%) recurred in axillary nodes. In the 10 patients with regional nodal failure, all of the tumors were negative for estrogen receptor (ER) and/or progesterone receptor (PR) and were nuclear grade (NG) 3. CONCLUSIONS: The axillary recurrence rate was low in patients treated with SLNB alone. Omitting ALND is concluded to be safe after adequate SLNB. Risk factors for regional nodal failure after SLNB alone are negative hormone receptor status and high NG.     

术前淋巴显像在乳腺癌前哨淋巴结活检中的作用

目的探讨术前淋巴显像在乳腺癌前哨淋巴结活检（sentinel lymph node biopsy，SLNB）中的作用。方法回顾性分析了716例联合术前淋巴显像与术中1探测仪和蓝染料检测乳腺癌SLNB的结果。结果全组SLNB成功率98．2％（703／716），验证组SLNB的假阴性率16．0％（15／94）。淋巴显像共成功地确定出620例患者（86．6％）的前哨淋巴结（sentinel lymph node，SLN），并在36例患者（5．0％）中发现了腋窝以外的前哨淋巴结。淋巴显像确定SLN的失败率与原发肿瘤的部位、肿瘤的病理类型和注射同位素到显像的时间无显著相关性（均P〉0．05）。注射示踪剂前已进行肿瘤切除活检的患者，其淋巴显像成功率低于未行肿瘤切除活检者；淋巴结转移患者淋巴显像的成功率低于淋巴结阴性患者。术中确定SLN的成功率在术前淋巴显像成功组和失败组之间存在显著的统计学差异（99．5％ vs 91．0％，P〈0．01）。术前淋巴显像是否成功确定SLN与SLNB的假阴性率无显著相关性（P=0．731）。结论乳腺癌SLN术前淋巴显像可以预测术中SLNB的成功率，同时术前淋巴显像有助于确定腋窝以外的SLN，但术前淋巴显像并非乳腺癌SLNB所必需。     

乳腺癌前哨淋巴结活检的研究进展

前哨淋巴结活检（SLNB）是本世纪继早期乳腺癌保乳治疗后第二个最重要的进展,前哨淋巴结活检是种多学科结合的新方法,比腋窝淋巴结清扫更能准确的进行腋窝分期,乳腺癌前哨淋巴结活检很快运用到临床实践。适当选择病人,由有经验的多学科团队进行前哨淋巴结活检,其精确度超过95％,前哨淋巴结活检广泛应用在可触及的和不可触及的T1和T2的肿瘤病人。最近研究表明,前哨淋巴结活检技术可应用在多中心多病灶的和新辅助化疗后和局部晚期乳腺癌病人。前哨淋巴结活检的重要因素包括注射技术,病例选择,病理分析和活检精确度等,为此简要综述如下。     

Isolated retromammary lymph node metastasis of breast cancer without axillary lymph node involvement: a case report with a false-negative sentinel lymph node biopsy

A 54-year-old woman visited our hospital with a palpable tumor in her left breast, which was diagnosed as invasive ductal carcinoma. Breast-conserving surgery was performed, in association with a sentinel lymph node (SLN) biopsy and back-up dissection of the axillary lymph nodes. One dyed axillary lymph node with high radioactivity was defined as an SLN, and intraoperative frozen-section analysis of the SLN was negative for metastasis. The final pathological diagnosis of the tumor was invasive ductal carcinoma, and one small lymph node, located in the retromammary space, just under the tumor, was positive for metastasis. The backup axillary lymph nodes were not metastatic. This patient was diagnosed false-negative by SLN biopsy, despite being positive for retroMLN metastasis. It should be recognized that retroMLNs are difficult to detect preoperatively, or intra-operatively, using dye or radiocolloid, if they are located in the post-tumoral retro-mammary space. RetroMLNs may be a pitfall in SLN biopsies.     

Sentinel node biopsy to avoid axillary lymph node dissection in breast cancer

The role of sentinel node biopsy in breast cancer has increased over the last few years. Sentinel nodes can predict the status of all axillary lymph nodes precisely and select patients with negative nodes for whom axillary dissection is unnecessary. Many problems remain, such as the ideal injection technique, ideal agents, and ideal histological detection of sentinel node metastases, and must be addressed before sentinel node biopsy becomes the standard of care for patients with breast cancer.     

早期乳腺癌前哨淋巴结活检的前沿进展

医学影像技术的飞速发展提高了早期乳腺癌腋窝淋巴结影像学诊断的能力,能够检测到腋窝淋巴结更早、更小的转移灶,通过影像学引导下穿刺活检明确淋巴结的转移状况,从而为患者提供更完善的术前腋窝分期。对于术前超声影像学检查为腋窝淋巴结阴性的患者是否可以避免术中腋窝前哨淋巴结活检,目前有两项大型临床试验正在进行中。山东大学附属山东省肿瘤医院乳腺病中心通过微泡超声造影显像技术引导腋窝前哨淋巴结术前穿刺活检,正在探索一种高效、准确和超微创的腋窝前哨淋巴结活检技术。术前影像学检查大大提高了临床腋窝淋巴结阳性患者的检出率,但也让一部分患者失去了通过腋窝前哨淋巴结活检替代腋窝淋巴结清扫的机会,对临床查体淋巴结阴性但超声发现可疑淋巴结并通过穿刺活检确诊转移的患者是否适合前哨淋巴结活检,本文也进行了相关的探讨和研究。另外,对内乳前哨淋巴结活检的相关研究结果进行了汇总。     

Dye- and gamma probe-guided sentinel lymph node biopsy in breast cancer patients: using patent blue dye and technetium-99m-labeled human serum albumin

BACKGROUND: Sentinel lymph node (SLN) biopsy is a promising method for the diagnosis of the axillary nodal status. We examined the availability of the SLN biopsy using two mapping procedures: the dye- and gamma probe-guided method, and preoperative lymphoscintigraphy by gamma camera imaging. METHODS: We enrolled 48 patients with breast cancer. Technetium-99m-labeled human serum albumin was injected into the subdermal tissue above the primary tumor or biopsy cavity, and preoperative gamma camera imaging was performed. After induction of general anesthesia, patent blue dye was injected into the peritumoral area prior to the surgical procedure. A handheld gamma-detection probe was used to assist in SLN detection. Careful dissection was performed to identify blue-stained afferent lymphatic vessels and nodes. An SLN was defined as any blue and/or radioactive node, and was excised. After SLN biopsy, axillary lymph node dissection of level I, II, and III was completed, in order to confirm the diagnostic ability of the SLN biopsy. RESULTS: Intraoperative SLN identification of axillary lesions was successful in 43 of 48 patients (90%). The dye- and gamma probe-guided method was successful in 25 patients (52%), the dye-guided method alone succeeded in 11 patients (23%), and the gamma probe-guided method alone succeeded in 7 patients (15%). Preoperative lymphoscintigraphy revealed axillary focal accumulations in 29 of 48 patients (60%). All patients who underwent successful preoperative SLN identification by lymphoscintigraphy had successful intraoperative SLN identification. A diagnostic accuracy of 95%, a sensitivity of 89%, and a specificity of 100% were achieved in the diagnosis of axillary metastasis. Internal mammary SLNs were identified in four patients intraoperatively, but we could not detect cancer metastasis in the internal mammary SLNs. CONCLUSIONS: The dye-guided and gamma probe-guided methods were complementary. Preoperative lymphoscintigraphy was useful to predict intraoperative SLN identification. Further study is necessary to assess the role of SLN biopsy of the internal mammary lymph nodes.     

中国乳腺癌前哨淋巴结活检现状调查研究

背景与目的：前哨淋巴结活检（sentinel lymph node biopsy,SLNB）已经成为乳腺癌临床腋窝淋巴结阴性患者的标准腋窝分期方案。由中国抗癌协会乳腺癌专业委员会发起的SLNB调查研究,旨在了解中国大型医院乳腺癌SLNB的开展现状。方法：在全国范围内纳入2017年手术量大于200例的医院,共110家医院完成问卷调查。调查问卷包括SLNB的开展现状、免除腋窝清扫及新辅助化疗（neoadjuvant chemotherapy,NAC）中SLNB的应用等热点问题。采用χ ² 检验、Fisher确切概率法或Kolmogorov-Smirnov检验对数据进行分析。结果：参与调研的110家医院均开展了SLNB,其中,85家（77.27%）医院对超过50%的临床腋窝淋巴结阴性（cN ₀ ）乳腺癌患者常规进行SLNB。肿瘤专科医院（χ ² =5.62,P=0.018）、保乳手术（breast-conserving surgery,BCS）量较大的医院（D=0.33,P=0.032）开展SLNB的比例更高。大部分医院（93/110,84.55%）未开展内乳SLNB。最常用的示踪方法为染料（主要是亚甲蓝,69/110,62.73%）,仅14.55%（16/110）的医院使用核素联合染料双示踪法。几乎所有的医院（107/110,97.27%）均采用术中快速冰冻切片对前哨淋巴结（sentinel lymph node,SLN）进行病理学诊断。对于cN ₀ 、SLN 1~2枚转移的BCS患者,大部分医院（61/110,55.45%）仅对少于10%的该类患者免除后续腋窝淋巴结清扫（axillary lymph node dissection,ALND）。对于cN ₀ 、SLN 1~2枚转移的全乳切除患者,84家（76.36%）医院对少于10%的此类患者免除后续ALND。对于接受NAC的患者,50家（45.45%）医院在NAC后进行SLNB,60家（54.55%）医院在NAC前进行SLNB。行NAC较多的医院（χ ² =4.365,P=0.037）、在NAC期间常规使用磁共振成像（magnetic resonance imaging,MRI）评估的医院（χ ² =10.967,P=0.004）,更倾向于在NAC后行SLNB。结论：尽管示踪剂的规范应用尚有待改进,早期乳腺癌患者的SLNB已经成为中国评估腋窝状态的标准方式。对于SLN转移负荷较低的患者,国内学者对于免于腋窝清扫仍较为保守。接受NAC的患者,SLNB的应用时机仍存在争议。     

Probability of axillary lymph node metastasis when sentinel lymph node biopsy is negative in women with clinically node negative breast cancer: a bayesian approach

BACKGROUND: Although sentinel lymph node biopsy(SLNB)is highly accurate in predicting axillary nodal status in patients with breast cancer, it has been shown that the procedure is associated with a few false negative results. The risk of leaving metastatic nodes behind in the axillary basin when SLNB is negative should be estimated for an individual patient if SLNB is performed to avoid conventional axillary lymph node dissection(ALND). METHODS: A retrospective analysis of 512 women with T1-3N0M0 breast cancer was conducted to derive a prevalence of nodal metastasis by T category as a pre-test(i.e., before SLNB)probability and to examine potential confounders on the relationship between T category and axillary nodal involvement. Probability of nodal metastasis when SLNB was negative was estimated by means of Bayes' theorem which incorporated the pre-test probability and sensitivity and specificity of SLNB. RESULTS: Axillary nodal metastasis was observed in 6.1% of T1a-b, 25.1% of T1c, 28.7% of T2, 35.0% of T3 tumors. Point estimates for the probability of nodal involvement when SLNB was negative ranged from 0.3-1.3% for T1a-b, 1.6-6.3% for T1c, 2.0-7.5% for T2, and 2.6-9.7% for T3 tumors with representative sensitivities of 80%, 85%, 90% and 95%, respectively. The risk may be higher when the tumor involves the upper outer quadrant of the breast, while it may be lower for an underweight woman. CONCLUSIONS: The probability of axillary lymph node metastasis when SLNB is negative can be estimated using a Bayesian approach. Presenting the probability to the patient may guide the decision of surgery without conventional ALND.     

1~2枚腋窝前哨淋巴结转移的乳腺癌患者非前哨淋巴结转移影响因素分析

目的探讨前哨淋巴结活组织检查(SLNB)后非前哨淋巴结(SLN)转移的影响因素。 方法回顾性分析2015年3月至2020年9月湖北省十堰市太和医院收治的837例双染料示踪法SLNB有1~2枚转移且行腋窝淋巴结清扫的乳腺癌患者资料,分为非SLN有转移组(54例)和无转移组(783例),采用χ²检验比较2组患者的肿瘤直径、病灶位置、脉管侵犯、病理类型、多发病灶、SLN转移灶类型、分子分型、ER、PR、HER-2、Ki-67等临床病理特征,采用秩和检验比较2组患者的组织学分级和SLN转移率。采用Logistic回归分析影响乳腺癌患者腋窝非SLN转移的危险因素。 结果2组患者的肿瘤直径、脉管侵犯、组织学分级、SLN转移率比较,差异均有统计学意义(χ²＝3.940、45.882,Z＝-2.225、-4.540,P＝0.047、<0.001、0.027、<0.001)。多因素分析结果显示：有脉管侵犯、SLN转移率≥50%且<100%和SLN转移率为100%均为影响非SLN转移的独立危险因素( OR ＝4.826,95%CI: 2.675~8.706,P <0.001;OR＝3.822,95%CI：1.538~9.501,P＝0.004;OR＝4.761,95%CI: 2.014~11.256,P<0.001)。 结论有脉管侵犯或SLN转移率≥50%的乳腺癌患者,非SLN转移的风险增加,应行腋窝淋巴结清扫术。     

Axillary recurrence after negative sentinel lymph node biopsy under local anesthesia in breast cancer

The procedure known as sentinel lymph node biopsy (SLNB) under local anesthesia (LA) allows surgical teams to avoid the uncertainties of frozen tissue examination and to perform axillary dissection on patients who have been informed of the risks of lymph node invasion prior to the procedure.