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.     

Implications of the sentinel lymph node procedure for local and systemic adjuvant treatment

PURPOSE OF REVIEW: The objective of the sentinel lymph node procedure in breast cancer is to perform an accurate axillary staging and provide good local control, while sparing the patients the morbidity of an axillary lymph node dissection. Since its routine clinical use, questions were raised concerning the implications for local and systemic adjuvant treatment. This review provides an update of the recent literature. RECENT FINDINGS: As a result of a more detailed histopathologic work-up of the sentinel lymph node, higher rates of lymph node metastases are detected. This leads to an upstaging of a subset of node-negative patients and an increase in the overall percentage of node-positive patients. However, the clinical implications of micrometastases and isolated tumor cells remain unclear. Furthermore, sentinel lymph nodes may be found in the internal mammary lymph node chain but the treatment of these nodes is subject of debate. SUMMARY: Current guidelines recommend axillary lymph node dissection in patients with a positive sentinel node. The surgical removal of the internal mammary lymph node is only indicated in the context of a clinical trial. Radiation therapy of the axilla is an acceptable alternative for patients who refuse an axillary lymph node dissection (clinical trial). The value of radiotherapy to the internal mammary lymph node has never been established. Systemic treatment decisions in patients with a macrometastasis or micrometastasis in the sentinel lymph node follow the guidelines of node-positive patients, whereas in patients with isolated tumor cells only, guidelines for node-negative patients are followed. The results of ongoing clinical trials will be important for the development of further guidelines.     

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.     

Controversies in sentinel lymph node biopsy for breast cancer

Sentinel lymph node biopsy, validated in melanoma staging, is currently under investigation for breast cancer staging. Reports suggest that the sentinel lymph node has a high predictive value in determining the presence of axillary metastases. Identification of a sentinel lymph node that is free of metastatic tumor cells may eliminate the necessity of performing a standard axillary lymph node dissection with its attendant morbidity. Numerous techniques are utilized to identify the sentinel node with approximately the same success rate. This paper will address some of the controversial areas of sentinel lymph node biopsy and offer an option for physicians who want to develop a sentinel lymph node program in their hospital.     

Minimal axillary lymph node involvement in breast cancer has different prognostic implications according to the staging procedure

It is still controversial whether the identification of micrometastases and isolated tumor cells in the axillary lymph nodes of patients with breast cancer has any prognostic value. We evaluated the prognostic role of isolated tumor cells and micrometastases in the axillary lymph nodes in 3,158 consecutive patients pT1-2 pN0-N1mi (with a single involved lymph node) and M0, referred to the Division of Medical Oncology after surgery performed at the European Institute of Oncology from April 1997 to December 2002. Median follow-up was 6.3 years (range 0.1–11 years). Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) were performed in 2,087 and 1,071 patients, respectively. A worse metastasis-free survival was observed for patients with micrometastatic disease compared to node-negative patients, if staged with ALND (log-rank P < .0001; HR: 3.17; 95% CI 1.72–5.83 at multivariate analysis), but not for patients who underwent SLNB (log-rank P = 0.36). The presence of a single micrometastatic lymph node is associated with a higher risk of distant recurrence as compared to node-negative disease only for patients undergoing ALND for staging purposes. Treatment recommendations for systemic therapy should not take into account the presence of a single micrometastatic lymph node identified during complete serial sectioning of sentinel node(s).     

Contralateral uptake and metastases in sentinel lymph node mapping for recurrent breast cancer

BACKGROUND AND OBJECTIVES: Sentinel lymph node mapping as a constitutive component in the staging process for invasive breast cancer continues to gain acceptance. We have identified two patients with recurrent invasive breast cancer in whom contralateral sentinel lymph node uptake and metastases, respectively, were detected. Such findings have not been previously reported in our review of the medical literature between 1966 and October 2004. METHODS: Sentinel lymph node mapping was performed on two patients with recurrent invasive breast cancer at our institution. At the time of their index diagnosis, both had received breast conserving surgery and an axillary lymph node dissection with post-operative radiotherapy (RT). All lymph nodes and margins of resection were without tumor. Both patients remained with no evidence of disease for years until routine serial screening mammography was interpreted as suspicious. Each underwent a stereotactic biopsy of the ipsilateral breast corresponding to the mammographic abnormality. Pathology confirmed invasive ductal carcinoma. Both patients refused the recommended salvage mastectomy. PRINCIPAL RESULTS: During a second attempt at breast conservation, sentinel lymph node mapping--which is typically contraindicated for patients with prior axillary surgery--revealed contralateral axillary uptake for both patients. The respective contralateral sentinel node was excised with pathology revealing no tumor in one case, and a microscopic focus of metastatic carcinoma in the second case. MAJOR CONCLUSION: Some patients may benefit from sentinel lymph node mapping prior to salvage mastectomy. Identifying uptake in a contralateral sentinel lymph node may change the multi-disciplinary management of recurrent invasive breast cancer to include a contralateral axillary dissection, chemotherapy, and/or RT to the contralateral axilla.     

Sentinel node micrometastases in breast cancer: clinical outcome

Aim: The sentinel lymph node biopsy has steadily replaced axillary lymph node dissection for staging clinically node‐negative breast cancer. This study assesses surgical and adjuvant practice in relation to micrometastases and isolated tumor cells found on biopsy in a single surgeon cohort. Methods: Clinicopathological characteristics were collated from 700 breast cancer patients undergoing sentinel lymph node biopsies between 1999 and 2007. The status and details of the node biopsies, continuing treatment and adverse outcomes were reported. Patient details at the time of diagnosis were entered into Adjuvant! online to look at likely prognosis. For both isolated tumor cells and micrometastases, data input was conducted twice, once as node‐negative and again as node‐positive, thus providing two predicted benefit data series. Results: A total of 665 women were eligible for inclusion, 67 with micrometastases and 20 with isolated tumor cells. Overall 33 patients developed recurrence with nine breast‐cancer related deaths. Women with isolated tumor cells or micrometastases were more likely to receive adjuvant radiotherapy to the axilla compared with women with node‐negative disease. Compared to those with isolated tumor cells, a higher number of women with micrometastases received systemic chemotherapy despite similar predicted benefits. Individual comparisons showed significantly higher rates of recurrence in women with isolated tumor cells than in node‐negative disease (P < 0.0001). Conclusion: The biological behavior of early breast cancer with isolated tumor cells on sentinel node biopsy is similar to both micrometastases and macrometastases, i.e. they behave in a node‐positive fashion. This is an early indication that these patients should be treated with more aggressive adjuvant therapy.     

Intraoperative examination of axillary sentinel lymph nodes in breast carcinoma patients.

BACKGROUND: Routine histologic examination of axillary sentinel lymph nodes predicts axillary lymph node status and may spare patients with breast carcinoma axillary lymph node dissection. To avoid the need for two separate surgical sessions, the results of sentinel lymph node examination should be available intraoperatively. However, routine frozen-section examination of sentinel lymph nodes is liable to yield false-negative results. This study was conducted to ascertain whether extensive intraoperative examination of sentinel lymph nodes by frozen section examination would attain a sensitivity comparable to that obtained by routine histologic examination without intraoperative frozen section examination. METHODS: In a consecutive series of 155 clinically lymph node negative breast carcinoma patients, the axillary sentinel lymph nodes were examined intraoperatively, before complete axillary lymph node dissection. The frozen sentinel lymph nodes were sectioned subserially at 50-microm intervals. For each level, one section was stained with hematoxylin and eosin and the other section immunostained for cytokeratins using a rapid immunocytochemical assay. RESULTS: Sentinel lymph node metastases were detected in 70 of the 155 patients (45%). In 37 cases the sentinel lymph nodes were the only axillary lymph nodes with metastases. Immunocytochemistry did not increase the sensitivity of the examination. Five patients had metastases in the nonsentinel axillary lymph nodes despite having negative sentinel lymph nodes. The general concordance between sentinel and axillary lymph node status was 96.7%; the negative predictive value of intraoperative sentinel lymph node examination was 94.1%. CONCLUSIONS: The intraoperative examination of axillary sentinel lymph nodes is effective in predicting the axillary lymph node status of breast carcinoma patients and may be instrumental in deciding whether to spare patients axillary lymph node dissection.     

Adjuvant treatments in breast cancer: interest of completion of axillary dissection in case of micrometastases or isolated tumor cells in sentinel lymph node

Prognostic signification of micrometastases ou isolated tumor cells (ITC) has not yet been clearly precised. Management of the axilla in case of micrometastases or ITC depends on the local pratices: no surgical completion or axillary lymph node dissection (ALND). Axillary lymph node status is the most important prognostic factor in patients with breast cancer; morbidity of ALND is now well known whereas its therapeutic benefit has not been demonstrated. This study is based on a retrospective database of 1375 patients who underwent sentinel node (SN) biopsy for breast cancer. In case of micrometastase or ITC in SN with completion axillary dissection, we examined if non-sentinel lymph node status has changed the indications of adjuvant treatments (chimiotherapy or radiotherapy). The results of our study show that non-sentinel lymph node status modify systemic therapy for a very few patients (less than 4% concerning chimiotherapy and less than 15% concerning radiotherapy).     

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.     

Detection of micrometastases in sentinel lymph nodes of the breast applying monoclonal antibodies AE1/AE3 to pancytokeratins

Sentinel lymph node excision in breast cancer is a minimally invasive diagnostic procedure for accurate staging of the axilla and for avoiding unnecessary axillary dissection. In patients with palpable breast cancer we injected microcolloidal particles of human serum albumin labelled with technetium-99m the day before surgery. The sentinel node was detected intraoperatively with a handheld gammaprobe and then removed. Complete axillary dissection was performed and the nodes inspected by routine histological examination. The axillary lymph node status was correctly predicted by the sentinel node technique in 32 of 33 breast cancer patients. Two cases of micrometastases escaped routine histopathological detection but were identified by immunohistochemical analysis applying the antibody AE1/AE3 to pancytokeratins. Immunohistochemical examination of the sentinel node improves the diagnostic security of patients with breast carcinoma by detection of micrometastases.     

Lymph node metastasis from ductal carcinoma in situ with microinvasion.

BACKGROUND: Widespread use of mammography has increased the detection of ductal carcinoma in situ with microinvasion (DCISM) in pathology specimens. Currently there is disagreement regarding the incidence of axillary metastasis from DCISM. The controversy centers on whether complete lymphadenectomy is indicated for axillary staging, given its morbidity and the reportedly minimal rate of axillary involvement in these patients. Intraoperative lymphatic mapping and sentinel lymphadenectomy (SLND) may obviate complete axillary lymph node dissection in selected breast carcinoma patients. In intraoperative lymphatic mapping, isosulfan blue dye is used to demonstrate the course of lymphatic flow from the breast tumor to the first draining or sentinel lymph node. This blue-stained lymph node is selectively excised for pathologic examination; its tumor status is used to predict the tumor status of the other axillary lymph nodes. The authors examined whether SLND would be suitable for staging DCISM. METHODS: From February 1992 to January 1997, 14 patients with DCISM underwent intraoperative lymphatic mapping and SLND at the John Wayne Cancer Institute in Santa Monica, California. Clinical and pathologic data were prospectively collected. RESULTS: Primary DCISM tumors ranged in size from 0.9 to 6.5 cm. Nine patients presented with mammographic abnormalities, two patients presented with Paget's disease and a palpable lesion, and three patients presented with palpable lesions. Two patients (14.3%) had tumor-involved sentinel lymph nodes. One of these patients had two sentinel lymph nodes, both of which contained single cancer cells identified by immunohistochemistry. The other patient had 1 sentinel lymph node, in which a 0.3-cm metastasis was revealed by light microscopy. Completion axillary dissection was performed on both patients and revealed no further tumor positive lymph node metastases. CONCLUSIONS: SLND can detect lymph node micrometastases (tumor deposits <2 mm) in patients with DCISM. The clinical relevance of these micrometastases is unknown, but their existence shows that DCISM can involve the lymph nodes.     

Histologic detection and clinical implications of micrometastases in axillary sentinel lymph nodes for patients with breast carcinoma.

BACKGROUND: Sentinel lymph node (SLN) biopsy is used increasingly in patients with clinically lymph node negative, early-stage breast carcinoma, because it can spare axillary dissection when the sentinel lymph nodes are negative. The question arises, however, whether complete axillary lymph node dissection (ALND) also is necessary in patients with only micrometastases (< or = 2 mm in greatest dimension) in axillary SLNs. The authors carried out the current study to ascertain the risk of non-SLN axillary metastases in such patients and to assess the detection rate of SLN micrometastases in relation to the sectioning interval and the number of sections examined. METHODS: The authors examined 109 patients with micrometastatic SLNs from a series of 634 patients with carcinoma of the breast who underwent SLN biopsy and complete ALND as part of the surgical treatment for their disease. The SLNs were sectioned completely at 50-microm intervals, and the sections were examined intraoperatively. RESULTS: The overall frequency of metastases in axillary non-SLNs was 21.8%. The frequency was correlated significantly with the size of the SLN micrometastatic focus (P = 0.02): 36.4% of patients with foci > 1 mm had metastases in axillary lymph nodes--a percentage approaching 44.7% of patients with macrometastatic SLNs--whereas only 15.6% of patients with micrometastases < or = 1 mm had other involved axillary lymph nodes. CONCLUSIONS: Outside of clinical trials, patients with T1 and small T2 breast carcinoma and micrometastatic SLNs should undergo complete ALND for adequate staging. However, patients with SLN micrometastases up to 1 mm in greatest dimension have a significantly lower risk of additional axillary metastases, raising the question of whether ALND may be avoided in this subgroup of patients.     

High risk of non-sentinel node metastases in a group of breast cancer patients with micrometastases in the sentinel node

Axillary lymph node dissection (ALND) in breast cancer patients with positive sentinel nodes is under debate. We aimed to establish two models to predict non-sentinel node (NSN) metastases in patients with micrometastases or isolated tumor cells (ITC) in sentinel nodes, to guide the decision for ALND. A total of 1,577 breast cancer patients with micrometastases and 304 with ITC in sentinel nodes, treated by sentinel lymph node dissection and ALND in 2002-2008 were identified in the Danish Breast Cancer Cooperative Group database. Risk of NSN metastases was calculated according to clinicopathological variables in a logistic regression analysis. We identified tumor size, proportion of positive sentinel nodes, lymphovascular invasion, hormone receptor status and location of tumor in upper lateral quadrant of the breast as risk factors for NSN metastases in patients with micrometastases. A model based on these risk factors identified 5% of patients with a risk of NSN metastases on nearly 40%. The model was however unable to identify a subgroup of patients with a very low risk of NSN metastases. Among patients with ITC, we identified tumor size, age and proportion of positive sentinel nodes as risk factors. A model based on these risk factors identified 32% of patients with risk of NSN metastases on only 2%. Omission of ALND would be acceptable in this group of patients. In contrast, ALND may still be beneficial in the subgroup of patients with micrometastases and a high risk of NSN metastases.     

Y a-t-il un rationnel pour irradier les aires ganglionnaires des tumeurs du sein de stades pN1mi et pN0(i+) ?

The advent of sentinel lymph node technique has led to a shift in lymph node staging, due to the emergence of new entities, namely micrometastases and isolated tumour cells. In addition, the therapeutic role of axillary lymph node dissection is more and more questioned and radiotherapy has been shown to be equivalent to complementary axillary lymph node dissection in patients without clinical node involvement. This article looks at the literature in favour of performing axillary irradiation in patients with pN1mi stage breast cancer who have undergone a mastectomy without a complementary axillary lymph node dissection, and in favour of abstention of any further treatment of the axilla in patients with pN0(i+) or pN1mi tumours who have undergone breast conserving surgery and a sentinel lymph node procedure followed by systemic treatment. The impact of regional lymph nodes irradiation in case of axillary involvement 2 mm or less is also discussed.     

Predictive Factors for the Status of Non-sentinel Nodes in Breast Cancer Patients with Tumor Positive Sentinel Nodes

In patients with tumor positive sentinel nodes, axillary lymph node dissection is routinely performed while a majority of these patients have no tumor involvement in the non-sentinel nodes. The authors tried to identify a subgroup of patients with a tumor positive sentinel node without non-sentinel node tumor involvement. In 135 consecutive patients with tumor positive sentinel nodes and axillary lymph node dissection performed, the incidence of non-sentinel node involvement according to tumor and sentinel node related factors was examined. The size of the sentinel node metastasis, size of primary tumor and number of tumor positive sentinel nodes were the three factors significantly predicting the status of the non-sentinel nodes. The size of the sentinel node metastasis was the strongest predictive factor (P < 0.0001). In a subgroup of 41 patients with a stage T1 tumor and micrometastatic involvement in the sentinel node only 2 patients (5%) had non-sentinel node involvement. In patients with small primary tumors and micrometastatic involvement of the sentinel nodes, the chance of non-sentinel node involvement is small but cannot be discarded. Because the clinical relevance of micrometastases in lymph nodes is still unclear it is not advisable to omit axillary lymph node dissection even in these patients.     

早期乳腺癌腋窝亚LevelⅡ淋巴结清扫的初步研究

目的：探索基层医院早期乳腺癌腋窝淋巴结外科处理的适宜方法。方法：对9例符合研究条件的病例先美兰染色（meythylene blue staining）实施前哨淋巴结活检（sentinel lymph node biopsy,SLNB）,再补充实施腋窝淋巴结清扫术（axillary lymph node dissection,ALND）;ALND术中显露腋静脉,以腋静脉下2cm为界缝线标记,术后将标本从缝线处分离,对淋巴结进行分组取材,将前哨淋巴结、腋静脉下2cm内淋巴结（亚levelⅡ淋巴结）、腋窝其余淋巴结（其余淋巴结）分组送病理检查,观察各组淋巴结数量及肿瘤细胞腋淋巴结转移规律。结果：找到前哨淋巴结6例;5例前哨淋巴结、亚levelⅡ淋巴结、其余淋巴结均为阴性;1例前哨淋巴结、亚levelⅡ淋巴结、其余淋巴结均为阳性;另有1例患者前哨淋巴结未找到,而亚levelⅡ淋巴结检出阳性。结论：基层医院对于早期乳腺癌腋窝淋巴结清扫,可以用美兰染色行前哨淋巴结活检,若前哨淋巴结阳性或未找到前哨淋巴结,行ALND;若前哨淋巴结阴性,行亚levelⅡ淋巴结清扫。     

Stage migration in breast cancer: surgical decisions concerning isolated tumour cells and micro-metastases in the sentinel lymph node.

AIMS: Sentinel lymph node biopsy has replaced the axillary lymph node dissection (ALND) in primary surgery for breast cancer in many hospitals and is expected to become the standard of care in due time. Since the sentinel lymph node is subjected to more extensive pathologic examination than the lymph nodes in the axillary dissection specimen, more patients are found to be node positive (N+); however many of them contain micro-metastases (相似文献   

早期乳腺癌腋窝亚LevelⅡ淋巴结清扫的初步研究

目的:探索基层医院早期乳腺癌腋窝淋巴结外科处理的适宜方法。方法:对9例符合研究条件的病例先美兰染色(meythylene blue staining)实施前哨淋巴结活检(sentinel lymph node biopsy,SLNB),再补充实施腋窝淋巴结清扫术(axillary lymph node dissection,ALND);ALND术中显露腋静脉,以腋静脉下2cm为界缝线标记,术后将标本从缝线处分离,对淋巴结进行分组取材,将前哨淋巴结、腋静脉下2cm内淋巴结(亚levelⅡ淋巴结)、腋窝其余淋巴结(其余淋巴结)分组送病理检查,观察各组淋巴结数量及肿瘤细胞腋淋巴结转移规律。结果:找到前哨淋巴结6例;5例前哨淋巴结、亚levelⅡ淋巴结、其余淋巴结均为阴性;1例前哨淋巴结、亚levelⅡ淋巴结、其余淋巴结均为阳性;另有1例患者前哨淋巴结未找到,而亚levelⅡ淋巴结检出阳性。结论:基层医院对于早期乳腺癌腋窝淋巴结清扫,可以用美兰染色行前哨淋巴结活检,若前哨淋巴结阳性或未找到前哨淋巴结,行ALND;若前哨淋巴结阴性,行亚levelⅡ淋巴结清扫。