Ganglion sentinelle envahi : faut-il faire le curage ou pas ? Essai randomisé SERC

Contribution of axillary lymph node dissection (ALND) is questioned for positive sentinel node (SN), micro-metastasis and isolated tumor cells but also for macro-metastasis. The aim of this work is to precise why a prospective randomized trial is necessary and the design of this trial. Why? For positive SN, the scientific level evidence appears insufficient for validation of ALND omission as a new standard. Rational is presented with non-sentinel node involved rate and number of NSL involved at complementary ALND, axillary recurrence rate, disease free survival rate and adjuvant treatment decision impact. How? The proposed Sentinelle Envahi et Randomisation du Curage (SERC) trial will randomly assign to observation only or complementary ALND with positive SN. The aim is to demonstrate the non-inferiority of ALND omission versus ALND.     

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).     

低负荷前哨淋巴结阳性早期乳腺癌患者腋窝处理策略

前哨淋巴结阳性患者的常规处理是进一步行腋窝淋巴结清扫,但腋窝淋巴结清扫会带来血清肿、上肢功能障碍、水肿等并发症。Z0011、IBCSG 23-01和AMAROS的Ⅲ期随机对照临床研究探索均为在临床N0期患者中安全减免前哨淋巴结活检阳性后的腋窝淋巴结清扫,为这部分患者的腋窝处理提供了新选择,但也给辅助放疗决策带来了新问题。本文将主要基于上述三项临床研究和腋窝淋巴结转移复发风险相关最新文献,针对包括手术和辅助放疗在内的低负荷前哨淋巴结阳性患者腋窝处理策略进行综述。     

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.     

Number of Metastatic Sentinel Nodes As Predictor of Axillary Involvement in Patients with Breast Cancer

BACKGROUND AND OBJECTIVES: More than half of patients with positive sentinel node (SN) have no metastases in non-sentinel nodes (NSNs) on axillary lymph node dissection (ALND). The aim of this study was to investigate factors predictive of NSNs involvement, in order to identify patients with metastatic disease confined to the SN which might avoid ALND. METHODS: ALND was performed in 167 patients with metastatic SN. Axillary NSNs status was correlated with the size of SN metastases, the size of the primary tumor and the occurrence of lymphovascular invasion. In 72 cases, the radiotracer (Tc-99m albumin colloid) marked multiple (in most cases 2 or 3) nodes. In this group, NSNs status was correlated with the number of metastatic radioactive nodes (1 or > 1), and with the above mentioned histopathologic factors. RESULTS: NSNs metastases were found in 57/167 cases (34.1%), the rate increasing proportionate to the size of both SN metastases (p < 0.0001) and primary tumor (p = 0.0075), while no significant correlation was found for lymphovascular invasion (p = 0.1769). At univariate and multivariate analysis of findings from the 72 cases with multiple probe-detected hot nodes, positivity in more than one hot node was the strongest predictor of NSN involvement (p = 0.0019). CONCLUSIONS: The identification and excision of multiple hot nodes can be useful in the prediction of NSNs involvement in patients with metastatic SN.     

Patients’ Choice on Axillary Lymph Node Dissection Following Sentinel Lymph Node Micrometastasis — First Report on Prospective Use of a Nomogram in Very Low Risk Patients

The optimal locoregional treatment of patients diagnosed with sentinel node (SN) micrometastasis is controversial. A previously reported and validated nomogram was used to calculate the risk of non-SN metastasis in patients with SN micrometastasis over a period of 2 years. Patients were given detailed information about the risk, consequences and treatment options of non-SN involvement, the risk and potential complications of unnecessary completion axillary lymph node dissection (ALND), the imperfectness of the nomogram, and other factors that may influence their selection of further treatment. They also received a questionnaire to monitor factors influencing their decisions. Of the 25 patients participating in the study, 10 have opted for ALND. The only factor that seemed to influence their choice was fear from disease recurrence. Giving detailed information to SN micrometastatic patients is a patient-centered alternative to current recommendations on performing ALND in all such patients or omitting ALND in all of them.     

Pathologic examination of sentinel lymph nodes in breast cancer by a single haematoxylin-eosin slide versus serial sectioning and immunocytokeratin staining: clinical implications

BACKGROUND: The objective was to determine the additional value of pathologic examination using three-level sectioning and immunocytokeratin (ICK) staining of sentinel lymph node (SN) biopsies in cT1-2N0M0 breast carcinoma patients regarding lymph node staging and eligibility of systemic therapy taking primary tumor characteristics in account. METHODS: SN slides of 277 patients out of a total group of 961 patients known to have tumor-positive SNs detected by three-level sectioning and ICK staining were re-examined. Haematoxylin-eosin (HE) slide level three was scanned for tumor deposits, and when present, extra capsular extension, maximum tumor diameter and number of positive SNs was noted. In addition, slides of the axillary dissection of non-SNs were reviewed, with determination of metastasis size and number of positive non-SNs. Primary tumor characteristics (grade, diameter, estrogen receptor) were recorded. RESULTS: In the single-HE examination, 26 cases SN micrometastasis and 6 macrometastasis were missed, 3 cases of micrometastasis were incorrectly classified as isolated tumor cells, and 9 patients with macrometastasis were misclassified as micrometastasis. In addition, in the tumor-negative single-HE examination, additional axillary lymph node dissection (ALND) revealed 6 cases of non-SN metastasis. Taking primary tumor factors into account for adjuvant systemic therapy, 21 patients would have been denied the choice for systemic therapy if single-HE examination was carried out only. CONCLUSIONS: Single-HE examination of SN may result in a reduction of locoregional and systemic treatment according to treatment guidelines then current in the Netherlands.     

The evolving role of axillary lymph node dissection in the modern era of breast cancer management

The standard of practice in breast cancer surgery is that all patients with a positive sentinel node mandate an axillary lymph node dissection (ALND). Recently, this dogma has been challenged by a trial from ACOSOG (American College Of Surgeons Oncology Group) (Trial Z0011) which demonstrated that patients (without clinically/radiologically apparent axillary metastases) undergoing breast conserving surgery (i.e lumpectomy followed by whole breast radiotherapy) with positive sentinel nodes failed to derive any significant benefit by having an axillary lymph node dissection (ALND) [2]. The logical progression from this study is to question the validity of performing routine axillary lymph node dissections on all patients with positive sentinel lymph nodes (SLN). In addition to the Z0011 trial, there is emerging data that additional patients exist who fail to derive any benefit from axillary surgery. The aim of this article is to discuss the potential subpopulations of patients that may avoid unnecessary ALND in the modern era of breast cancer management.     

Cancer du sein et creux axillaire: état de l'art et perspectives

A therapeutic surgical de-escalation has been observed since many years with an actual prolongation for axillary lymph node area treatment. Axillary lymph node dissection (ALND) omission has been studied before and after validation of sentinel node (SN) biopsy procedure. A non-inferiority of ALND omission has been reported in case of non-involved SN. ALND omission has been studied in case of SN involvement without consensus in relation with scientific level of proof and with selective indications. The purpose of this work is to make a synthesis of the experiences on this subject then to envisage the current and future perspectives.     

Sentinel lymph node mapping and biopsy for breast cancer: a review of the literature relative to 4791 procedures

The status of axillary nodes is the most important prognostic factor in breast cancer to select patient subgroups for adjuvant chemotherapy; the current standard of care for surgical management of invasive breast cancer is complete removal of the tumor by either mastectomy or lumpectomy followed by axillary lymph node dissection (ALND). The recent introduction of intraoperative lymphatic mapping and sentinel lymph node biopsy (SLND) represents a major new opportunity for appropriate and less invasive surgical management of many tumors. There is an almost uniformly enthusiasm concerning the potential of this technique in breast carcinoma management, shown by published data. A peculiar attention to the so-called "sentinel node debate" in breast cancer surgery is a constant in the last years issues of the major medical journals. Even patients have become more aware about medical enthusiasm and their request of concise information on the topic and the possibilities of this approach is an increasing reality in medical practice. The aim of this paper is to review recent literature to offer an overview about the main controversial methodological aspects and a wide analysis of reported results. The most significative international literature papers from Medline were retrieved from 1993 to September 1999, and 4782 procedures were analysed. This extensive review of the literature has confirmed accuracy, feasibility and reliability of the SN detecting technique in axillary mapping. Provided a good proficiency in SN localisation and pathological evaluation, human resources and efforts should be mainly focused on its clinical validation as an alternative to ALND instead of on further phase I-lI clinical studies.     

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.     

An axilla scoring system to predict non-sentinel lymph node status in breast cancer patients with sentinel lymph node involvement

Background. Axillary lymph node dissection (ALND) is the current standard of care for breast cancer patients with sentinel lymph node (SN) involvement. However, the SN is the only involved axillary node in a significant proportion of these patients. Here we examined factors predictive of non-SN involvement in patients with a metastatic SN, in order to develop a scoring system for predicting non-SN involvement.Materials and Methods. This study was based on a prospective database of 337 patients who underwent SN biopsy for breast cancer, of whom 81 (24) were SN-positive; we examined factors predictive of non SN involvement in the 71 of these 81 women who underwent complementary ALND. All clinical and histological criteria were recorded and analysed according to non-SN status, by using Chi-2 analysis, Students t-test, and multivariate logistic regression.Results. Univariate analysis showed a significant association between non-SN involvement and histological primary tumor size (p=0.0001), SN macrometastasis (p=0.01), the method used to detect SN metastasis (H&E versus immunohistochemistry) (p=0.03), the number of positive SNs (p=0.049), the proportion of involved SNs among all identified SNs (p=0.0001) and lymphovascular invasion (p=0.006). Histological primary tumor size (p=0.006), SN macrometastasis (p=0.02) and the proportion of involved SNs among all identified SNs (p=0.03) remained significantly associated with non-SN status in multivariate analysis. Based on the multivariate analysis, we developed an axilla scoring system (range 0–7) to predict the likelihood of non-SN metastasis in breast cancer patients with SN involvement.Conclusion. In patients with invasive breast cancer and a positive SN, histological primary tumor size, the size of SN metastases, and the proportion of involved SNs among all identified SNs were independently predictive of non-SN involvement.     

前哨淋巴结活检在早期乳腺癌患者腋窝管理中的研究进展

传统的观点认为腋窝淋巴结清扫(axillary lymph node dissection,ALND)是前哨淋巴结(sentinellymph node,SLN)阳性乳腺癌患者的标准治疗方法,而ALND容易引起上肢水肿、功能障碍等术后并发症,影响患者生活质量.近几年研究显示,对于SLN阳性的早期乳腺癌,并非所有患者都需...     

The benefits and limitations of sentinel lymph node biopsy

Opinion statement The status of the axilla is the single most important prognostic indicator of overall survival in patients with breast cancer. Staging is based on tumor size and on the presence of lymph node metastases. The number of lymph nodes, although prognostic, no longer impacts treatment options. Sentinel lymph node (SLN) mapping and dissection is a more sensitive and accurate technique for nodal evaluation and has been applied to staging of axillary lymph nodes in patients with breast cancer, providing prognostic information, with less surgical morbidity than with axillary lymph node dissection (ALND). When analyzed by an experienced pathologist with serial sectioning and immunohistochemical evaluation, SLN is the most accurate detection tool used in staging of breast cancer. In many centers that use these staging principles, ALND is no longer performed for histologically negative axillary SLNs. In addition, this technique may also be therapeutic because in most patients, the SLN is the only positive axillary node. SLN biopsy is justified in women with ductal carcinoma in situ who have a high risk of invasive carcinoma, such as those with large tumors, a mass, or high-grade lesions. SLN biopsy is performed in the setting of neoadjuvant chemotherapy and demonstrates accurate evaluation of the axilla in 90% of the cases. Women with locally advanced breast cancer may derive great benefit from a minimally invasive approach to the axilla because the extent of nodal involvement is unlikely to change further treatment. For clinically palpable nodes, ALND should be performed for therapeutic and local control. The use of sentinel node mapping in pregnancy is controversial. Vital blue dye is contraindicated in pregnant patients, although some have used radioactive colloid alone to map this subgroup of patients.     

Micro-metastases in axillary lymph nodes: an increasing classification and treatment dilemma in breast cancer due to the introduction of the sentinel lymph node procedure

BACKGROUND: Sentinel lymph node (SN) biopsy will increasingly replace axillary lymph node dissection (ALND) for staging in breast cancer. For daily practice, examination of the SN by serial sectioning (SS) and/or immunohistochemistry (IHC) is being promoted. Use of these techniques may result into stage migration due to the increased detection of micro-metastases. The consequence may be overshooting of patients with adjuvant therapy, as the prognostic relevance of (small) micro-metastases and isolated tumor cells is unclear. METHODS: The prognostic impact of micro-metastases is determined by reviewing ALND studies with a follow up of at least 5 years, including more than 100 patients, before the SN era. Furthermore, studies in which conventionally haematoxylin-eosin (H&E) negative SNs are investigated for occult metastases by SS and/or IHC are reviewed. RESULTS: In only one of eight studies, occult metastases were an independent risk factor for reduced survival. The outcome is dependent on the size of the nodal metastasis. IHC and SS as used in the SN procedure indeed induce a shift from pNO to pN1a (according to TNM). CONCLUSION: By the thorough pathologic examination of the SN, isolated tumor cells and micro-metastases are more frequently detected. We propose to classify small micro-metastases (<0.5 mm) in a separate pN1a(min) category (min for minimal) to prevent stage migration. As the prognostic relevance of isolated tumor cells and (small) micrometastases has not been proven, the value of adjuvant therapy can be questioned for patients with otherwise good prognostic factors.     

Clinicopathologic prognostic markers of survival: an analysis of 259 patients with malignant melanoma ≥1 mm

The histopathologic status of the sentinel node (SN) and the ulceration of the primary tumor are important indicators of the clinical outcome of melanoma patients. The purpose of this study was to investigate potential correlations between prognostic factors and the sentinel lymph node status as well as their influence on disease-free survival (DFS), distant metastases-free survival (DMFS), and overall survival (OS). The medical records of 259 melanoma patients who underwent sentinel lymph node dissection between 2000 and 2006 were analyzed. DFS, DMFS, and OS were assessed. A uni- and a multivariate analysis to determine prognostic factors were performed. Histologic type, Clark’s level, and Breslow’s tumor thickness were the only parameters that showed a significant correlation with a positive SN. The univariate analysis revealed SN positivity (DFS and DMFS: p < 0.001; OS: p = 0.039) and ulceration (DFS: p < 0.001; DMFS: p = 0.001; OS: p = 0.003) to be significant prognostic markers. However, ulceration was the only independent prognostic factor for OS that was upheld by the multivariate analysis (p = 0.006; HR 3.89; CI 1.48–10.27). In stage I/II melanoma patients, ulceration of the primary tumor was the strongest prognostic factor for RFS, DMFS, and OS and superior to the pathology status of the SN.     

The sentinel node in anal carcinoma

AIMS AND BACKGROUND: Anal cancer is a rare condition. The inguinal lymph nodes are the most common site of metastasis in this neoplasm. The inguinal lymph node status is an important prognostic indicator and the presence of metastases is an independent prognostic factor for local failure and overall mortality. Depending on the primary tumor size and histological differentiation, metastasis to superficial inguinal lymph nodes occurs in 15-25% of cases. METHODS AND STUDY DESIGN: To evaluate the inguinal lymph node status we performed a search for the sentinel node in a female patient affected by squamous and carcinoma. RESULTS: Identification and examination of the sentinel node was positive and postoperative histology showed the presence of bilateral lymph node metastases. CONCLUSIONS: We suggest that examination of the sentinel node in anal cancer could be an efficient way to establish the inguinal lymph node status, which would help the clinician to plan and perform adequate treatment.     

Detection of melanoma micrometastases in sentinel nodes - the cons

The sentinel node (SN) procedure in melanoma patients is important for prognostic information, but has no impact on survival. Micrometastases are identified in approximately 20% of the SNs. When a Completion Lymph Node Dissection (CLND) is performed for positive SN, additional non-SN lymph node involvement is also approximately 20%. Several classification criteria have been proposed to identify patients with SNs without a risk for additional nodes or a good prognosis. Micro anatomic analyses of metastatic SNs suggest that patients with sub-micrometastases (<0.1mm) in the SN may be judged as SN negative. Patients with this limited tumor burden in their SN have an excellent prognosis and are highly unlikely to benefit from CLND. New techniques such as ultrasound of the lymph nodal basin can be promising as an alternative for SN biopsy.     

Indications for sentinel lymph node biopsy in patients with breast cancer: retrospective and simulation analyses

BACKGROUND: The disease status of axillary lymph nodes at diagnosis is the most powerful predictor of prognosis for patients with breast cancer. Axillary lymph node dissection (ALND) has been the standard treatment. Recently, lymphatic mapping and sentinel lymph node biopsy (SNB) have been suggested as alternatives to ALND. However, a clear indication for SNB has not yet been established. The goal of this study was to determine which patients might best benefit from the SNB method. METHODS: A retrospective study compared the relationship of age, menopausal status, tumor size group, histology and clinical evaluation of nodes to histological axillary lymph node status in 5892 consecutive Japanese breast cancer patients who underwent ALND. A simulation analysis with reported SNB sensitivity and specificity was carried out. RESULTS: Clinical lymph node evaluation was the most relevant factor to predict axillary nodal status. However, even patients with no clinical nodal involvement (N0) showed only 71% axillary nodal negativity. Tumor group based on tumor size and histology also related to axillary nodal status. The simulation analysis revealed that of patients with negative lymph node probability, more than 66% were good candidates for SNB. CONCLUSION: The clinically negative node (N0) is the most important indication for SNB. Therefore, the candidates for SNB should be picked from the patients with N0. When no histological information is available, patients whose tumor is 20 mm or smaller are candidates for SNB. When histological information is available, the SNB indication extends to patients whose type of tumor has histologically good prognosis or a low probability of having nodal involvement, regardless of tumor size.     

Sentinel lymph node dissection only versus complete axillary lymph node dissection in early invasive breast cancer: A systematic review and meta-analysis

BackgroundThe Z0011-study, a landmark randomised controlled trial (RCT) challenged the benefits of complete axillary lymph node dissection (ALND) compared with sentinel lymph node dissection only (SLND) in breast cancer patients with positive sentinel nodes. The study, however, has been criticised for lack of power and low applicability. The aim of this review was to systematically assess the evidence on the comparative benefits and harms of ALND versus SLND for sentinel node positive breast cancer patients.MethodsWe systematically searched PubMed, Embase, the Cochrane Library, and reference lists of pertinent review articles from January 2006 to August 2011. We dually reviewed the literature and rated the risk of bias of each study. For effectiveness, we included RCTs and observational studies of at least 1 year follow-up. In addition, we considered studies conducted in sentinel node-negative women to assess the risk of harms. If data were sufficient, we conducted random effects meta-analysis of outcomes of interest.ResultsMeta-analysis of three studies with 50,120 patients indicated similar 5-year survival and regional recurrence rates between patients treated with ALND or SLND, although prognostic tumour characteristics varied among the 3 study-populations. Results from 6 studies on more than 11,500 patients reported a higher risk for harms for ALND than SLND. Long-term evidence on pertinent health outcomes is missing.ConclusionThe available evidence indicates that for some women with early invasive breast cancer SLND appears to be a justifiable alternative to ALND. Surgeons need to discuss advantages and disadvantages of both approaches with their patients.