前哨淋巴结时代乳腺癌的精准区域处理：演进与展望

区域淋巴结状况是乳腺癌重要的预后指标之一,可以指导分期和辅助治疗策略的制定。近30年来乳腺癌前哨淋巴结活检术（sentinel lymph node biopsy,SLNB）研究发展迅速,循证医学Ⅰ类证据支持其为临床腋窝淋巴结阴性早期乳腺癌患者安全、有效的腋窝分期技术,前哨淋巴结阴性及低肿瘤负荷患者SLNB替代腋窝淋巴结清扫术后腋窝复发风险和并发症极低。乳腺癌局部区域控制新理念——应该综合考虑远处转移风险、全身治疗效果与不良反应以及局部区域治疗（手术/放疗）效果与不良反应——推动了SLNB适应人群不断扩展,新辅助治疗与SLNB、内乳SLNB将进一步促进区域淋巴结处理降阶梯,豁免腋窝手术临床研究值得期待。SLNB标志着乳腺癌区域淋巴结迈入微创化精准诊疗时代。本文就前哨淋巴结时代乳腺癌的精准区域处理的演进过程和最新进展进行总结,以期为广大临床工作者提供参考。     

乳腺癌前哨淋巴结规范化处理

前哨淋巴结活检术（sentinel lymph node biopsy, SLNB）标志着乳腺癌淋巴结手术进入微创时代,循证医学I类证据支持SLNB是临床腋窝淋巴结阴性早期乳腺癌患者安全、有效的腋窝诊断技术,前哨淋巴结阴性及低肿瘤负荷患者行SLNB替代腋窝淋巴结清扫术后,腋窝淋巴结复发风险和并发症极低。作为乳腺癌区域淋巴结微创诊断技术,SLNB安全有效替代腋窝淋巴结清扫术应建立在规范化操作前提下。目前SLNB在我国早期乳腺癌患者中逐渐趋于规范化和普及化,本文将对临床实践中SLNB的适应证、示踪剂应用、学习曲线掌握、手术规范操作和组织标本处理等问题进行综述。      

乳腺癌内乳区淋巴结转移研究进展

 内乳区淋巴结的转移状况是乳腺癌的独立预后指标,也是乳腺癌分期的重要依据之一。内乳区淋巴结转移的患者预后较差。内乳区淋巴结的总体转移率为18 %～33 %,仅有内乳区淋巴结转移而无腋窝淋巴结转移的发生率为2 %～11 %,其转移受腋窝淋巴结状况、患者年龄、原发肿瘤的位置和特点等多因素影响。随着前哨淋巴结活检技术的不断发展,内乳区前哨淋巴结活检术可能以最小的风险评估内乳区淋巴结状况,并进一步完善乳腺癌的淋巴结分期,有助于为患者制定更为准确的个体化治疗方案。     

乳腺癌新辅助化疗后前哨淋巴结活检的临床意义

目的探讨新辅助化疗后乳腺癌前哨淋巴结活检的可行性。方法对57例行^99Tc联合亚甲蓝示踪前哨淋巴结活检术和腋窝淋巴结清扫术乳腺癌患者的资料进行分析,其中31例ⅡB、Ⅲ期患者先行2～3个疗程新辅助化疗后再行前哨淋巴结活检及腋窝淋巴结清扫术,另26例Ⅰ、Ⅱ期患者直接行前哨淋巴结活检及腋窝淋巴结清扫术。结果新辅助化疗组和非新辅助化疗组平均腋窝淋巴结数、前哨淋巴结（sentinel lymph node,SLN）数、SLN检出率、SLN假阴性率均无显著差异（P均〉0．05）。新辅助化疗纽化疗前临床分期在N2以上者,SLN检出率均显著下降（P〈0．05）。结论新辅助化疗后前哨淋巴结活检能准确预测腋窝淋巴结的状况。化疗前的N分期是SLNB检出率的影响因素。     

Axillary surgery in breast cancer patients

Surgeons have routinely removed ipsilateral axillary lymph nodes from women with breast cancer for over 100 years. The procedure provides important staging information, enhances regional control of the malignancy and may improve survival. As screening of breast cancer has increased, the mean size of newly diagnosed primary invasive breast cancers has steadily decreased and so has the number of women with lymph node metastases. Recognising that the therapeutic benefit of removing normal nodes may be low, alternatives to the routine level I/II axillary lymph node dissection have been sought. A decade ago sentinel lymph node biopsy (SLNB) was introduced. Because of its high accuracy and relatively low morbidity, this technique is now widely used to identify women with histologically involved nodes prior to the formal axillary node dissection. Specifically, SLNB has allowed surgeons to avoid a formal axillary lymph node biopsy in women with histologically uninvolved sentinel nodes, while identifying women with involved sentinel nodes who derive the most benefit from a completion axillary node dissection. Despite the increasing use of SLNB for initial management of the axilla in women with breast cancer, important questions remain regarding patient selection criteria and optimal surgical methods for performing the biopsy. This article discusses the evolution of axillary node surgery for women with breast cancer.     

乳腺癌前哨淋巴结活检规范化操作指南（2022精要版）

乳腺癌是女性最常见的恶性肿瘤，区域淋巴结状况作为重要的预后指标，可指导患者的淋巴结分期，并对后续治疗策略产生影响。前哨淋巴结活检术（sentinel lymph node biopsy，SLNB）标志着乳腺癌淋巴结外科处理进入微创时代，但其安全有效替代腋窝淋巴结清扫术应建立在规范化操作前提下。中国抗癌协会乳腺癌专业委员会组织业内专家依据循证医学方法制定《乳腺癌前哨淋巴结活检规范化操作指南》，内容涉及SLNB适应证、示踪剂选择与应用、组织标本处理、腋窝SLNB、新辅助治疗与SLNB、内乳SLNB。本指南将为乳腺癌相关医务工作者的临床实践提供有益指导和参考。      

Current trends of sentinel lymph node biopsy for breast cancer —A surgeon’s perspective

Sentinel lymph node biopsy (SLNB) is standard care for patients with early-stage breast cancer, and axillary lymph node dissection (ALND) is considered unnecessary when sentinel lymph nodes (SLNs) are tumor-free. Additional non-SLN metastasis in patients with positive SLNs can be estimated using several risk factors such as primary tumor size, metastatic tumor size in SLNs, lymphatic vessel invasion, and so on. All patients with positive SLNs may be treated with further ALND based on their own risk for nonSLN metastasis. Recent randomized clinical trials have already proved less surgical morbidity and better QOL for SLNB alone compared with ALND. However, trials concerning the efficacy of ALND in positive SLNB patients in preventing local regional recurrence and improving overall survival compared with no ALND, and also, concerning the effectiveness of ALND compared with axillary radiation therapy (RT), have not yielded clear results. The prognostic significance of micrometastasis in SLNs or bone marrow also remains to be determined. So far SLNB is not acceptable for patients with positive nodes in the axilla at initial diagnosis even if their axillary metastases are down-staged to negative by neoadjuvant chemotherapy. Although basically SLNB does not need to be performed for patients with pure ductal carcinoma in situ (DCIS), it is recommended for patients with an initial diagnosis of DCIS which is large, palpable, high grade, or found in younger patients. Because these types of DCIS have higher incidences of accompanying invasive lesions. In addition if patients will undergo mastectomy, SLNB is recommended because of the inability to perform SLNB after mastectomy. SLNB may be acceptable for patients with T3 or T4b tumors, even though SLN identification is lower yet SLN involvement is higher compared with T1 or T2 tumors, and systemic adjuvant therapy is more important for patients with T3 or T4b tumors. SLNB is a bridge to further axillary treatment such as ALND or axillary RT, and which strategy, including no further treatment, is best considered individually based on recurrence risk, treatment responsiveness and use or non-use of systemic therapy.     

Role of FDG PET-CT in evaluation of locoregional nodal disease for initial staging of breast cancer

Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is not indicated or recommended in the initial staging of early breast cancer. Although it is valuable for detecting distant metastasis, providing prognostic information, identifying recurrence and evaluating response to chemotherapy, the role of FDG PET/CT in evaluating locoregional nodal status for initial staging of breast cancer has not yet been well-defined in clinical practice. FDG PET/CT has high specificity but compromised sensitivity for identifying axillary nodal disease in breast cancer. Positive axillary FDG PET/CT is a good predictor of axillary disease and correlates well with sentinel lymph node biopsy (SLNB). FDG PET/CT may help to identify patients with high axillary lymph node burden who could then move directly to axillary lymph node dissection (ALND) and would not require the additional step of SLNB. However, FDG PET/CT cannot replace SLNB or ALND due to unsatisfactory sensitivity. The spatial resolution of PET instruments precludes the detection of small nodal metastases. Although there is still disagreement regarding the management of internal mammary node (IMN) disease in breast cancer, it is known that IMN involvement is of prognostic significance, and IMN metastasis has been associated with higher rates of distant metastasis and lower overall survival rates. Limited clinical observations suggested that FDG PET/CT has advantages over conventional modalities in detecting and uncovering occult extra-axillary especially IMN lesions with upstaging the disease and an impact on the adjuvant management.     

Current trends of sentinel lymph node biopsy for breast cancer--a surgeon's perspective.

Sentinel lymph node biopsy (SLNB) is standard care for patients with early-stage breast cancer, and axillary lymph node dissection (ALND) is considered unnecessary when sentinel lymph nodes (SLNs) are tumor-free. Additional non-SLN metastasis in patients with positive SLNs can be estimated using several risk factors such as primary tumor size, metastatic tumor size in SLNs, lymphatic vessel invasion, and so on. All patients with positive SLNs may be treated with further ALND based on their own risk for non-SLN metastasis. Recent randomized clinical trials have already proved less surgical morbidity and better QOL for SLNB alone compared with ALND. However, trials concerning the efficacy of ALND in positive SLNB patients in preventing local regional recurrence and improving overall survival compared with no ALND, and also, concerning the effectiveness of ALND compared with axillary radiation therapy (RT), have not yielded clear results. The prognostic significance of micrometastasis in SLNs or bone marrow also remains to be determined. So far SLNB is not acceptable for patients with positive nodes in the axilla at initial diagnosis even if their axillary metastases are down-staged to negative by neoadjuvant chemotherapy. Although basically SLNB does not need to be performed for patients with pure ductal carcinoma in situ (DCIS), it is recommended for patients with an initial diagnosis of DCIS which is large, palpable, high grade, or found in younger patients. Because these types of DCIS have higher incidences of accompanying invasive lesions. In addition if patients will undergo mastectomy, SLNB is recommended because of the inability to perform SLNB after mastectomy. SLNB may be acceptable for patients with T3 or T4b tumors, even though SLN identification is lower yet SLN involvement is higher compared with T1 or T2 tumors, and systemic adjuvant therapy is more important for patients with T3 or T4b tumors. SLNB is a bridge to further axillary treatment such as ALND or axillary RT, and which strategy, including no further treatment, is best considered individually based on recurrence risk, treatment responsiveness and use or non-use of systemic therapy.     

Clinical evidence of breast cancer micrometastasis in the era of sentinel node biopsy

Sentinel node biopsy for early-stage breast cancer has been established as an excellent surgical and staging procedure developed to enhance the detection of minimal lymph node involvement such as micrometastases. Multisection and the proper use of immunohistochemical staining have led to the increased detection of micrometastases, and this has given rise to new questions about the treatment to be employed concerning micrometastasis. That is whether complete axillary lymph node dissection (ALND) and adjuvant systemic therapy are really required for patients with micrometastasis because of the low prevalence of nonsentinel lymph node metastasis. Some currently published case studies report that selected patients with micrometastases without further ALND would not suffer from a high incidence of regional recurrence. However, the long-term prognostic risk of systemic recurrence and local failure associated with residual axillary disease in the sentinel lymph node-positive patient electing for no further axillary surgery has not been defined. Numerous studies have investigated the impact of occult metastases, which may be regarded as micrometastases or a small tumor deposit. Although data from randomized controlled trials are lacking, these studies suggest that the prognosis of breast cancer patients with micrometastases should not be considered the same as that in truly node-negative patients. Patients with micrometastases should have some adjuvant systemic therapy. Ongoing randomized trials will provide prospective answers to the question of the optimal treatment for micrometastasis.     

Prognosis of breast cancer patients treated with sentinel node biopsy in Japan

BACKGROUND: Sentinel node biopsy predicts accurate pathological nodal staging. The survival of node-negative breast cancer patients should be evaluated between the patients treated with sentinel node biopsy alone and those treated with axillary lymph node dissection. METHODS: Ninety-seven patients with negative axillary nodes underwent sentinel node biopsy immediately followed by axillary lymph node dissection between January 1998 and June 1999 (the ALND group). Since then, if sentinel lymph nodes were negative on the frozen-section diagnosis, 112 patients underwent sentinel node biopsy alone without axillary lymph node dissection between July 1999 and December 2000 (the SNB group). We retrospectively observed the outcome of the two study groups. RESULTS: Median follow-up was 52 months in all patients. Relapse-free survival rates at 3 years in the ALND and SNB groups were 94% and 93%, respectively. Five of the 112 patients in the SNB group had overt axillary metastases. Three of them with axillary metastases alone were treated with delayed axillary lymph node dissection. These three patients have been free of other events for 3 years after local salvage treatment. CONCLUSIONS: Sentinel node biopsy will emerge as a standard method to diagnose axillary nodal staging for clinically node-negative breast cancer patients.     

The potential therapeutic effect of sentinel lymphadenectomy.

Sentinel lymph node (SLN) biopsy in a minimally invasive staging procedure for early breast cancer patients that is currently being investigated in many institutional and multi-institutional studies. Its main perspectives are the omission of axillary dissection in sentinel lymph node-negative patients and an improved staging as a result of more intensive histopathological methods for the detection of nodal involvement. The hypothesis presented in this article suggests that sentinel lymphadenectomy may also serve as a therapeutic intervention in some patients. The background for this comes from historical studies before the general use of systemic adjuvant treatment, which suggest that some node-positive breast cancer patients seem to be curable by locoregional treatment alone. Recent studies show that many patients have nodal metastases limited to the SLNs, where (considering the sigmoid growth model of solid tumours) small metastases may grow faster than larger ones. Large metastases are associated with worse prognosis. It is suggested that, in consequence of its expected therapeutic effects, sentinel lymphadenectomy, i.e. the removal of the lymph nodes most likely to harbour metastases, should be preferred to the omission of axillary dissection, or any other surgical staging procedure based on predictive models of nodal involvement derived from primary tumour characteristics.     

核素标记法联合亚甲蓝在早期乳腺癌前哨淋巴结活检中的应用价值

[目的]探讨核素标记法联合亚甲蓝在早期乳腺癌前哨淋巴结活检中的临床应用价值。[方法]对65例临床确诊的早期乳腺癌患者联合应用99mTc-硫胶体和亚甲蓝标记法进行前哨淋巴结活检,并行腋淋巴结清扫术。[结果]前哨淋巴结活检成功率为100.00%,准确率98.46%,假阴性率6.25%。[结论]核素标记和亚甲蓝联合定位法在前哨淋巴结活检中具有明确的实用性,能有效预测早期乳腺癌腋窝淋巴结转移状况。     

Axillary lymph node dissection in early-stage invasive breast cancer: is it still standard today?

Evaluation of axillary lymph node status by sentinel lymph node biopsy (SLNB) and complete axillary lymph node dissection (ALND) are an inherent part of breast cancer treatment. Increased understanding of tumor biology has changed the prognostic and therapeutic impact of lymph node status. Non-invasive imaging techniques like axillary ultrasound, FDG-PET, or MRI revealed moderate sensitivity and high specificity in evaluation of lymph node status. Therefore, they are not sufficient for lymph node staging. Otherwise, the impact of remaining micrometastases and even macrometastases for prognosis and treatment decisions is overestimated. Considering tumor biology, the distinction of axillary metastases in isolated tumor cells (ITC, pN0(i+)); micrometastases (pN1mi), and macrometastases (pN1a) is not comprehensible. Increasing data support the thesis that remaining axillary metastases neither increase the axillary recurrence rate nor decrease overall survival. It is doubtful that axillary tumor cells are capable to complete the complex multistep metastatic process. If applied, axillary metastases are sensitive to systemic treatment and are targeted by postoperative tangential breast irradiation. Therefore, the controversy about the clinical relevance of tumor cell clusters or micrometastases in SLN is a sophisticated but not contemporary discussion. Currently, there is no indication for axillary surgery in elderly patients with favorable tumors and clinically tumor-free lymph nodes. Nonetheless, a rational and evidence-based approach to the management of clinically and sonographically N0 patients with planned breast-conserving surgery and limited tumor size is needed now.     

Axillary recurrence in women with a negative sentinel lymph node and no axillary dissection in breast cancer

OBJECTIVES: Sentinel lymph node biopsy (SLNB) is widely used for staging breast cancer. SLNB accurately determines axillary lymph node status with a low false negative rate. There remains concern that omitting axillary dissection may lead to recurrence in the axilla, and impact long term survival. The purpose of this study was to determine the frequency of axillary lymph node recurrence in patients who had a negative sentinel lymph node and did not undergo axillary node dissection. METHODS: Data was collected on all patients who had negative SLNB at Roswell Park Cancer Institute between July 1997 and June 2002. Demographics, type of operation, postoperative systemic, and radiation therapy, co-morbidity score, hormone receptor status, and the pathologic features of the tumor were abstracted for each patient. For each woman with recurrence, the dates of recurrence, the site(s) of recurrence, and the treatment for recurrence were recorded. RESULTS: With a median follow-up of 33 months, 15 of 335 (4.5%) women who had negative SLNBs and who did not undergo completion axillary dissection developed a cancer recurrence. Only two patients (0.6%) had an axillary recurrence. CONCLUSIONS: The rate of axillary recurrence following a negative sentinel node biopsy is the same or less than axillary lymph node dissection (ALND) alone. Concerns that omitting completion axillary dissection following a negative SLNB will increase the rate of axillary recurrence appear unfounded.     

Can axillary dissection be avoided by improved molecular biological diagnosis?

Axillary dissection is presently a routine staging procedure in the management of breast cancer. The use of adjuvant systemic treatment is largely based on the diagnosis of axillary metastases. Routine axillary dissection leads to acute and chronic side-effects in a large proportion of patients. The sentinel node technique is presently explored with the aim of decreasing the need for standard axillary dissection. A complementary way forward is to analyse the primary breast cancer for molecular markers with prognostic significance with reference to the risk for metastatic capacity and thereby obtain a 'biological staging' and identify those patients in need of systemic adjuvant therapy. A large number of molecular biological factors have been shown to have prognostic significance in breast cancer e.g. c-erbB-2, p53, uPA, PAI-1 and VEGF. This article reviews the expression of these and other factors in the primary breast cancers in relation to the risk for axillary and systemic metastatic disease, with the long-term aim of excluding routine axillary dissection.     

The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients

Several independent randomized controlled trials are initiated to investigate whether sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients with negative axillary ultrasound findings, who are treated with breast conserving therapy. A consequence of omitting sentinel lymph node biopsy is absence of pathological lymph node status information. We aimed to investigate the impact of omitting sentinel lymph node biopsy on adjuvant systemic treatment recommendations. Data from all consecutive patients with invasive breast cancer and negative axillary ultrasound findings treated with breast conserving therapy and sentinel lymph node biopsy between 2008 and 2012 were collected from a prospective database. Two methods, Adjuvant! Online and the Dutch breast cancer guideline 2012, were used to determine the adjuvant systemic treatment recommendations of every patient. At first, each patient was considered to be lymph node negative, and secondly the patients’ true pathological lymph node status was used. A total of 303 patients were consecutively included. Pathological lymph node status was pN0 in 72.3 %, pN0(i+) in 12.9 %, pN1mi+ in 5.6 %, pN1 in 7.3 %, and pN2 in 2.0 % of the patients. The decision to recommend adjuvant systemic treatment changed due to the pathological lymph node status in 1.0 % of the patients (3/303) when using Adjuvant! Online and in 3.6 % (11/303) when using the 2012 Dutch breast cancer guideline. The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients with negative axillary ultrasound findings treated with breast conserving therapy is limited. The safety of omitting the sentinel lymph node biopsy should be confirmed by the initiated randomized controlled trials.     

Axillary recurrence in sentinel lymph node-negative breast cancer patients

BackgroundSentinel lymph node biopsy (SLNB) was developed to axillary lymph node dissection (ALND) in the treatment of breast cancer. SLNB is predictive of axillary node status. Major concern is the occurrence of a false-negative SLN. Purpose of this study is to determine the rate of axillary recurrence in our series of unselected patients.Patients and methodsAll patients with a negative SLNB from November 1999 to December 2006 have been treated and followed at our unit. Information on patients' characteristics, treatment and follow-up has been collected.ResultsEight-hundred and four patients with negative SLNB did not receive ALND. After a median follow-up of 38.8 months, 21 patients had distant metastases, four had axillary relapse, nine had an in-breast recurrence and two had both. All patients with axillary recurrence received axillary dissection and systemic adjuvant therapy. They are all presently alive and free from disease.ConclusionData from this series, the largest from a general hospital, showed that isolated axillary node recurrence after negative SLNB is rare (<1%) and comparable with those reported from referral cancer institutions. We confirm that SLNB for the treatment of early breast cancer patients of a community-based hospital is safe and reliable.     

Feasibility of targeted axillary dissection for de-escalation of surgical treatment after neoadjuvant chemotherapy in breast cancer

BackgroundTargeted axillary dissection, which combines sentinel lymph node biopsy with removal of the proven involved node noted during the staging process, has been shown to improve axillary staging and decrease false negative rates after neoadjuvant chemotherapy in patients with breast cancer.Objective(s)The main goal of this study was to assess the ability to identify and remove the clipped node and the false negative rate of targeted axillary dissection.MethodsWe performed a prospective study among patients with biopsy-confirmed nodal metastases who received neoadjuvant chemotherapy. A clip was placed on the sample node prior systemic therapy. After neoadjuvant chemotherapy, all patients underwent sentinel lymph node biopsy (dual tracer), localization and excision of the clipped node and axillary lymph node dissection. The clipped node was preoperatively localized in all cases placing an iodine-125 seed guided by ultrasound. The pathology of the sentinel nodes and clipped node was compared with other nodes.ResultsA total of 455 patients with invasive breast cancer were studied. Of the 148 patients with NAC, 32 met the eligibility criteria and were enrolled in the study. Mean age at diagnosis was 52.3 years. Systematic lymphadenectomy was performed in all patients, with an average of 14.3 lymph nodes removed. Detection rate of the clipped node alone was 96.9%, and 100% for targeted axillary dissection. Ability of clipped node alone to predict nodal status showed a FNR of 10,5% while SLNB alone performed by dual tracer and targeted axillary dissection, showed FNRs of 5.3% and 5.0%, respectively. Sentinel lymph nodes matched clipped node in 23 patients (74.2%).Conclusion (s)In node positive breast cancer patients, targeted axillary dissection is a reliably approach for axillary staging after neoadjuvant chemotherapy. The preoperative location of the clipped node is mandatory to increase the detection rate and optimize the results of the technique.     

Efficacy of sentinel lymph node biopsy in male breast cancer

BACKGROUND: Sentinel lymph node biopsy (SLNB) is rapidly becoming the standard of care in the treatment of women with early stage breast cancer. Male breast cancer although relatively rare, has typically been treated with mastectomy and axillary lymph node dissection (ALND). Men who develop breast carcinoma have the same risk as their female counterparts of developing the morbidities associated with axillary dissection. SLNB has been championed as a procedure aimed at preventing those morbidities. We recently have evaluated the role of SLNB in the treatment of men with early stage breast cancer. METHODS: Among the 18 men treated at the University of Michigan Medical Center for breast cancer from May 1998 to November 2002, 6 were treated with SLNB. RESULTS: The mean tumor size was 1.6 cm. The mean patient age was 59.8 years. All of the patients had one or more sentinel lymph nodes identified. Two of the six did not have confirmatory axillary dissection. Three of the six had positive sentinel lymph nodes (50%). Only one of the three patients with a positive sentinel node had more nodes positive. One of the six patients had a positive node on frozen section and underwent immediate complete axillary dissection. This patient had no additional positive nodes. No patients in our series had immunohistochemical studies of the lymph nodes. CONCLUSIONS: Men with early stage breast carcinoma may be offered the management option of SLNB since in the hands of experienced surgeons it has a success rate apparently equal to that in their female counterparts.