Long-term tracing and staining of carbon nanoparticles for axillary lymph nodes in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy

BackgroundThe regression of positive nodes in breast cancer after neoadjuvant chemotherapy (NAC) remains unknown. This study aimed to investigate this regression by injecting and tracing carbon nanoparticles (CNs) into the fusion node prior to NAC in patients with breast cancer.MethodsGuided by ultrasound, 0.3 mL of CNs suspension was injected in the fusion node prior to NAC in 110 patients with local advanced breast cancer. Then the patients underwent breast surgery and total axillary lymph node dissection following 2–6 cycles of NAC. The distribution by intercostobrachial nerves (ICBN) of positive nodes and black-stained nodes was researched, and the relationship between the distribution and lymphovascular invasion were investigated by response to NAC.ResultsWhen patients were ranked by response to NAC (from sensitive to resistance), the number of positive nodes increased, as did the proportion of lymphovascular invasion, the number of black-stained nodes decreased. A significantly negative relationship was found between the number of positive nodes and the number of black-stained nodes (p < 0.001). The positive nodes in patients with sensitive consequence followed the rule from under the ICBN to above the ICBN. However, there was counter-example (skip metastasis) in the patients with resistance result.ConclusionThe regression of positive nodes follows the rule from upper to under, inner to outer in the patients with sensitive consequence to NAC. Long-term staining and tracing by CNs might provide an acceptable and feasible technique to investigate the regression of positive nodes, and would be a potential method for NAC-treated patients by using of ICBN.Trial registrationNCT 03355261. Retrospectively registered on November 28, 2017.     

Sentinel lymph node biopsy examination for breast cancer patients with clinically negative axillary lymph nodes after neoadjuvant chemotherapy

BACKGROUND: The feasibility and accuracy of sentinel lymph node (SLN) biopsy examination for breast cancer patients with clinically node-negative breast cancer after neoadjuvant chemotherapy (NAC) have been investigated under the administration of a radiocolloid imaging agent injected intradermally over a tumor. In addition, conditions that may affect SLN biopsy detection and false-negative rates with respect to clinical tumor response and clinical nodal status before NAC were analyzed. METHODS: Seventy-seven patients with stages II and III breast cancer previously treated with NAC were enrolled in the study. All patients were clinically node negative after NAC. The patients then underwent SLN biopsy examination, which involved a combination of intradermal injection over the tumor of radiocolloid and a subareolar injection of blue dye. This was followed by standard level I/II axillary lymph node dissection. RESULTS: The SLN could be identified in 72 of 77 patients (identification rate, 93.5%). In 69 of 72 patients (95.8%) the SLN accurately predicted the axillary status. Three patients had a false-negative SLN biopsy examination result, resulting in a false-negative rate of 11.1% (3 of 27). The SLN identification rate tended to be higher, although not statistically significantly, among patients who had clinically negative axillary lymph nodes before NAC (97.6%; 41 of 42). This is in comparison with patients who had a positive axillary lymph node before NAC (88.6%; 31 of 35). CONCLUSIONS: The SLN identification rate and false-negative rate were similar to those in nonneoadjuvant studies. The SLN biopsy examination accurately predicted metastatic disease in the axilla of patients with tumor response after NAC and clinical nodal status before NAC. This diagnostic technique, using an intradermal injection of radiocolloid, may provide treatment guidance for patients after NAC.     

乳腺癌新辅助化疗后前哨淋巴结分析的研究进展

腋窝淋巴结清扫术（ALND）作为评估腋窝淋巴结状态的金标准常应用于乳腺癌手术中。但随着医疗技术的发展,在保证生存率及尽量减少复发的前提下,临床上越来越重视患者的生存质量。ALND也因其会造成手臂淋巴水肿、肩部功能障碍等副作用,使用率逐渐下降,取而代之的是创伤更小、使患者的生活质量更好的前哨淋巴结活检术（SLNB）,SLNB也是早期浸润性乳腺癌患者腋窝淋巴结处理的标准方式。新辅助化疗（NAC）作为全身系统治疗重要组成部分,不仅可以缩小肿瘤,增加手术机会,还可以增加保乳率,为更多患者带来临床获益。但NAC后的SLNB因受NAC对淋巴管等作用的影响,存在检出率低及假阴性率（FNR）高的问题,这也使NAC后行SLNB备受争议,如何使更多符合标准的乳腺癌人群豁免ALND获得临床获益是亟待解决的临床问题。目前已有多种技术方法尝试用于提高乳腺癌NAC后SLNB检出率及降低FNR。相比单一示踪剂,联合蓝染料及核素两种传统示踪剂或结合纳米碳混悬液、吲哚菁绿、微泡超声造影、超顺磁氧化铁等新型示踪剂,或是采用纳米颗粒辅助腋窝分期对前哨淋巴结进行示踪,可显著提高SLNB的检出率。多项大型前瞻性试验证明,保证≥3枚前哨淋巴结被切除可显著降低SLNB的FNR;靶向ALND作为SLNB的补充,通过在术前对阳性淋巴结进行标记定位可实现精准切除淋巴结,利用雷达反射器、碳文身、放射性粒子、磁性粒子、术中超声等进行定位可进一步提高其准确性。另外,有研究提出结合影像检查如腋窝超声图像、CT淋巴成像等,能清楚显示淋巴结及其周围淋巴管解剖结构,增加临床医师的把握度,进一步提高检出率,降低FNR,但暂未得到大型试验数据证实。笔者对目前NAC后的前哨淋巴结分析的相关研究进行系统总结,旨在为临床提供思路和方向,关于在临床上具体如何抉择能使更多患者获益未来仍需大量研究来验证。     

Level III axillary lymph nodes involvement in node positive breast cancer received neoadjuvant chemotherapy

ObjectiveTo investigate the incidence, associated factors and prognosis of level III node involvement for breast cancer with positive axillary lymph nodes after neoadjuvant chemotherapy.MethodsA consecutive series of 521 node positive T_0–2 invasive breast cancer cases were included in this retrospective study. Axillary node metastases were proved by ultrasound guided needle biopsy (NB) if ultrasonographic abnormal node was detected or by sentinel node biopsy (SNB) if no abnormal node was detected. After 4 to 8 cycles of neoadjuvant chemotherapy (NCT）, axillary lymph nodes dissection included level III lymph nodes were completed for each case.ResultsThe pathologic complete response rate of axillary nodes was 31.1% (90/289) in NB positive subgroup. The incidence of residual positive level III lymph nodes were 9.0% (47/521). Multivariate analysis showed that node NB positivity (OR = 2.212, 95% CI: 1.022–4.787, P = 0.044), clinical tumor size >2 cm before NCT (OR = 2.672, 95% CI: 1.170–6.098, P = 0.020), and primary tumor non-response to neoadjuvant chemotherapy (OR = 1.718, 95% CI: 1.232–2.396, P = 0.001) were independent predictors of level III lymph nodes positivity. At median follow-up time of 30 months, the distant disease-free survival (DDFS) rate of level III node positive group was much lower than that of level III negative group (p = 0.011).ConclusionsAbout 9% of node positive T_0–2 breast cancer will have residual positive node in level III region after neoadjuvant chemotherapy. Node positivity proved by NB, large tumor size, and primary tumor non-response to neoadjuvant chemotherapy are independent predictors of level III lymph nodes positivity.     

Accuracy of axillary sentinel lymph node biopsy following neoadjuvant (induction) chemotherapy for carcinoma of the breast

Sentinel lymph node biopsy (SLNB) is widely employed to detect axillary lymph node metastases in breast cancer patients with clinically negative (N0) axillae. One of the few reported contraindications to SLNB is prior treatment with systemic chemotherapy (neoadjuvant/induction chemotherapy). Previous investigators reported difficulty identifying the sentinel node and an unacceptable false-negative rate in this patient cohort. We present one experienced surgeon's experience with SLNB following induction chemotherapy (n = 21). Following treatment with Adriamycin and Cytoxan (AC)-based cyclic chemotherapy, patients underwent SLNB, followed by levels I and II axillary lymph node dissection (ALND). At least one sentinel node was identified in all patients (100%). With respect to metastatic disease, the status of the sentinel node(s) accurately reflected the status of the axilla in 20 of 21 patients (95%). Eleven patients (52%) had axillary metastases identified by ALND. Of this group, SLNB failed to identify metastatic disease in one patient (9%). Previous treatment with induction chemotherapy should not be considered an absolute contraindication to SLNB. An experienced surgeon may utilize the technique in these patients, sparing them the added morbidity of axillary dissection.     

Identification of sentinel lymph nodes in thyroid carcinoma

Sentinel lymph node (SLN) was defined as the first lymph node that the tumor would drain to, within that tumors regional lymphatic basin. In 1998, Kelemen and coworkers have published the first results on SLN lymphonodectomy in thyroid carcinomas. Different methods have been used in a goal of lymphatic mapping (application of vital blue dye and/or radiocolloid). In a period from 2001 to 2003 we have performed SLN biopsy in 64 patients with thyroid tumors. There were 12 cases of thyroid carcinoma. SLN identification rate was 73.44%. We found no false positive or negative results on definitive histopathology. The impact of lymph node metastases in differentiated thyroid carcinoma is still controversial. The management of cervical lymph nodes varies from berry picking to modified radical neck dissection. There is a significant disproportion in percentage of pre and intraoperatively enlarged lymph nodes (27-45%) and histologically confirmed lymph node metastases (80-90%) in papillary thyroid carcinoma. In the current literature the average rate of SLN identification is 91% (66-100%) and when identified, the SLN accurately predicts the disease status of the neck in most patients (80-100%). The SLN biopsy for thyroid carcinoma is good and feasible technique for estimating the cervical lymph node status.     

Feasibility and reliability of sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer patients with positive axillary nodes at initial diagnosis: An up-to-date meta-analysis of 3,578 patients

PurposeNeoadjuvant chemotherapy (NACT) is increasingly adopted in the therapy of breast cancer (BC) patients with positive axillary nodes (cN+), but the reliability and feasibility of sentinel lymph node biopsy (SLNB) following NACT are still controversial. The objective of the present study is to conduct an updated meta-analysis on this issue.MethodsA literature search was performed using PubMed, Cochrane, Embase, and Web of Science to identify papers published from January 1, 2000 to October 22, 2020 to research SLNB after NACT in BC patients. Studies that met the quality standard were enrolled for this meta-analysis.ResultsA total of 3578 participants from 27 trials were included in this meta-analysis. The pooled estimate of the identification rate (IR) for SLNB was 91 %, and the false negative rate (FNR) was 15 %. The pooled negative prediction value (NPV), accuracy, specificity, and sensitivity were 82 %, 89 %, 97 %, and 85 %, respectively. In subgroup analysis, the application of dual mapping could clearly decrease the FNR. The FNR was significantly high in the luminal types, and it declined as more sentinel lymph nodes (SLNs) were removed.ConclusionSLNB following NACT is now technically feasible for BC with cN+. However, it must be emphasized that the FNR is unacceptable high.     

前哨淋巴结活检对乳腺癌新辅助化疗后腋窝状况评估中的价值

目的 研究前哨淋巴结活检在乳腺癌新辅助化疗后的临床应用价值。方法 选择我院2007年9月至2010年11月期间收治的46例Ⅱ、Ⅲ期乳腺癌患者,接受新辅助化疗后超声检查腋窝淋巴结阴性者为研究对象。所有患者前哨淋巴结活检后行乳腺癌改良根治术及标准腋窝淋巴结清扫,所有前哨淋巴结行病理和免疫组化检查,非前哨淋巴结行常规病理检查。结果 前哨淋巴结活检的成功率、假阴性率、灵敏度、特异性、精确性、阳性预测值、阴性预测值分别是93.5%,3.7%,96.3%,100%,97.7%,100%,94.1%。结论 前哨淋巴结活检结合超声可以较准确的评价新辅助化疗后乳腺癌的腋窝淋巴结状态,对于决定患者是否需要行腋窝淋巴结清扫有一定参考价值。     

Intraoperative evaluation of sentinel lymph nodes in invasive lobular carcinoma of the breast

Background

In breast cancer treatment, sentinel lymph node (SLN) evaluation is used to identify patients who may benefit from axillary lymph node dissection (ALND). Intraoperative evaluation (IE) of SLNs facilitates immediate ALND. Controversy exists regarding the accuracy of intraoperative SLN evaluation for patients with invasive lobular carcinoma (ILC) compared to invasive ductal carcinoma (IDC).

Methods

Using breast cancer registry data from January 2003 to March 2008, the intraoperative SLN evaluation of 66 ILC and 810 IDC patients was compared to the final SLN pathology result and to the performance of ALND.

Results

In ILC, the sensitivities of IE for isolated tumor cells (≤.2 mm, N0[i+], n = 9), micrometastases (>.2 mm and ≤ 2.0 mm, N1mi, n = 6), and macrometastases (>2.0 mm, N1a-3a, n = 21) were 0%, 17%, and 71%, respectively. The specificity was 100%. IE identified 16/27 (59%) of SLN-positive (N1mi, N1a-3a) axillae, resulting in synchronous ALND. Delayed ALND for false negative IEs (11/27, 41%) occurred in 7/11 patients (64%). In IDC, the sensitivities of IE for N0(i+) (n = 60), N1mi (n = 75), and N1a-3a (n = 129) metastases were 0%, 7%, and 71%, respectively. The specificity was 99.6%. IE identified 97/204 (48%) of SLN-positive (N1mi, N1a-3a) axillae, resulting in synchronous ALND. Delayed ALND for false negative IEs (107/204, 52%) occurred in 38/107 patients (36%).

Conclusions

Sensitivity and specificity of intraoperative SLN evaluation is very similar in ILC and IDC patients. Intraoperative SLN evaluation facilitated synchronous ALND in concordance with recommended practice guidelines.     

Recurrence rates in breast cancer patients with false-negative intraoperative evaluation of sentinel lymph nodes

Background

Intraoperative identification of sentinel lymph node (SLN) metastases in breast cancer patients results in synchronous axillary lymph node dissection. We examined the effect of false-negative SLN biopsy on breast cancer treatments and recurrence rate.

Methods

Patient and tumor characteristics, intraoperative and final SLN biopsy results, and treatments of patients with and without recurrence were compared.

Results

Recurrence rates for patients with true-positive SLN biopsy (9%) were significantly higher than rates for false-negative SLN biopsy patients (2%). Recurrence rates were significantly higher for patients with primary tumors greater than 2 cm, positive lymph nodes greater than 2 mm, and tumors with negative hormone receptors, and varied with treatment extent.

Conclusions

Patients with greater amounts of disease in the breast and axilla required more treatment and had a higher recurrence rate. False-negative SLN evaluation occurred more commonly in patients with less lymph node metastasis and was not associated with an increased recurrence rate.     

新辅助化疗对乳腺癌腋淋巴结及结外侵犯的影响

目的 旨在观察局部进展期乳腺癌新辅助化疗时腋淋巴结及结外侵犯的临床病理学改变.方法 2002年6月-2009年8月南京大学附属第二医院收治的肿块大于5 cm伴同侧腋淋巴结肿大但不融合的86例患者,以患者是否愿意行新辅助化疗分组,A组患者46例,不愿行新辅助化疗,穿刺确诊后行手术治疗,术后病理证实,腋淋巴结转移40例,转移腋淋巴结结外侵犯17例.B组患者40例,自愿行新辅助化疗,穿刺确诊后平均行3个周期新辅助化疗,再行手术治疗,术后病理证实,腋淋巴结转移26例,转移腋淋巴结结外侵犯6例.结果 A组患者淋巴结转移率为86.9%,转移淋巴结并结外侵犯率为36.9%;B组患者淋巴结转移率为65%,转移淋巴结结外侵犯率为15%,两组病例在淋巴结转移率及转移淋巴结结外侵犯率之间存在显著差异,P<0.05.结论 新辅助化疗对于患者的腋淋巴结转移灶有明显作用,减少了淋巴结转移率及转移淋巴结结外侵犯率.     

Completion axillary lymph node dissection minimizes the likelihood of false negatives for patients with invasive breast carcinoma and cytokeratin positive only sentinel lymph nodes

OBJECTIVE: To document the incidence of metastatic disease in complete axillary lymph node dissections (CALND) of patients with invasive carcinoma after a sentinel lymph node (SLN) biopsy, positive only by immunohistochemical staining for cytokeratin (CK-IHC). METHODS: Sections of all SLNs, negative by routine histology, were immunostained and examined for cytokeratin positive cells. Sections of lymph nodes from CALND specimens were interpreted using routine hematoxylin and eosin (H&E) staining. RESULTS: A total of 409 patients (29.6%) had metastatic disease in at least one sentinel lymph node on H&E examination. Of 971 H&E negative patients, 78 (8.0%) were positive only by CK-IHC. Sixty-two of the CK-IHC positive only patients underwent CALND. Nine of these 62 patients (14.5%) had metastases identified in the CALND specimen. CONCLUSIONS: Because 14.5% of patients with invasive breast cancer and SLNs positive only by CK-IHC were found to have H&E positive lymph nodes on CALND, we conclude first, that CK-IHC should be used to evaluate SLNs, and second, that CALND should be considered when SLNs are positive by CK-IHC only. This approach will result in an absolute reduction of the false negative rate (absolute false negative rate reduced by 2.6% in our series).     

Predictors of positive axillary lymph nodes after sentinel lymph node biopsy in breast cancer.

OBJECTIVE: The purpose of this study was to determine the factors that predict the presence of metastasis in nonsentinel lymph nodes (SLN) when the SLN is positive. METHODS: A prospective database was analyzed and included patients who underwent SLN biopsy for invasive breast cancer from July 1997 to August 2000 (n = 442). One hundred (22.6%) patients had one or more positive SLNs, and were analyzed to determine factors that predicted additional positive axillary nodes. RESULTS: Of the 100 patients with a positive SLN, 40 patients (40%) had additional metastasis in non-SLNs. The only significant variables that predicted non-SLN metastasis were tumor lymphovascular invasion (P = 0.004), extranodal extension (P < 0.001), and increasing size of the metastasis within the SLN (P = 0.011). In analyzing just those patients who had lymphovascular invasion, extranodal extension, and a SLN metastasis > 2mm, 92% were found to have additional positive nodes. CONCLUSIONS: In patients with invasive breast cancer and a positive sentinel lymph node, lymphovascular invasion, extranodal extension, and increasing size of the metastasis all significantly increase the frequency of additional positive nodes.     

Pathological evaluation of sentinel lymph nodes for breast cancer

Recently, sentinel lymph node (SLN) biopsy has been employed to avoid unnecessary lymph node dissection, because SLN negativity for carcinoma metastases may imply an extremely low possibility of non-SLN involvement. Pathological evaluation is essential, but standardized procedures have not yet been determined. Intraoperative consultation, either by frozen section (multiple slices are desirable) or touch imprint cytology, are usually very useful. Their accuracy, however, is variable and depends on the procedures used, but specificity is characteristically 100%, and the missed metastatic focus is always quite minute. After fixation, multiple sections, immunohistochemistry, and their combination will be able to detect small metastatic foci more frequently. The clinical significance of small or submicro- or occult metastases have not yet been clarified, and further investigations are needed. If the SLN is positive for carcinoma metastases, both the procedure for detection and the size of the metastatic focus should be clarified on the pathological reports.     

The potential value of intraoperative imprint cytology of axillary sentinel lymph nodes in breast cancer patients

Axillary sentinel nodes predict the node status and may allow dissection of the axilla on a selective basis. Seventy-two sentinel nodes from 60 patients identified with Patent blue and/or the high radioactivity due to the uptake of 99m-Tc-labeled colloidal albumin were bisected for hematoxylin and eosin-stained touch preparations. The sentinel nodes were submitted in toto for permanent step sections and immunostained for cytokeratins. The imprints had a sensitivity of 83 per cent, a negative predictive value of 86 per cent, and a false negative rate of 17 per cent when the cut surface histology was considered. These corresponding values were 59, 68, and 41 per cent on a patient basis when the whole sentinel node histology was considered as many micrometastases did not appear in the cut surface sampled by the imprints. Although up to two-fifths of patients with tumor cells in the sentinel lymph nodes may be undetected by the method imprint cytology is valuable in the intraoperative assessment of sentinel nodes. This series suggests that 78 per cent of the patients can be adequately selected for a one-step axillary operation on the basis of intraoperative imprints. Results may be improved if the surface sampled is appropriately large and well selected.     

Decreased axillary lymph node retrieval in patients after neoadjuvant chemotherapy

BACKGROUND: The purpose of this study was to assess our clinical impression that fewer lymph nodes are retrieved after level I and II axillary dissection after neoadjuvant chemotherapy and whether there is a positive correlation between the total number of lymph nodes retrieved and the number of diseased lymph nodes. METHODS: Patients included those with stage IIB, IIIA, and IIIB breast cancer of whom 77 had neoadjuvant chemotherapy and 58 had initial surgery only. All had modified radical mastectomy with in continuity level I and II axillary dissection. RESULTS: Patients after neoadjuvant chemotherapy had 14.3 +/- 6.7 lymph nodes detected versus 16.9 +/- 8.8 (mean +/- SD; P <0.057) for those with initial surgery only. The number of positive nodes were 3.7 +/- 4.7 versus 6.6 +/- 8.7 (mean +/- SD; P <0.033) respectively and the number of negative nodes were 10.6 +/- 7.5 versus 10.4 +/- 8 (mean +/- SD; P <0.9). The correlation between the number of positive lymph nodes and the total number of lymph nodes was r = 0.58; P <0.001. CONCLUSIONS: It appears that fewer lymph nodes are retrieved after level I and II axillary dissection after neoadjuvant chemotherapy. The total number of lymph nodes retrieved increases directly with the number of positive lymph nodes in patients not treated with chemotherapy.     

乳腺癌新辅助化疗后腋窝淋巴结的变化

目的评价新辅助化疗对乳腺癌腋窝淋巴结的影响。方法45例Ⅱ、Ⅲ期乳腺癌接受新辅助化疗后手术(新辅助化疗联合手术组),根据体检、B超及钼靶像计数腋窝淋巴结总数和阳性、阴性淋巴结数,与未行新辅助化疗直接手术治疗的79例乳腺癌(直接手术组)比较,观察腋窝淋巴结的变化。结果新辅助化疗联合手术组检出腋窝总淋巴结和阳性淋巴结为(16.9±5.9)枚和(2.5±2.2)枚,显著低于直接手术组的(20.8±8.0)枚和(3.9±3.0)枚(t=-2.856,P=0.005;t=2.790,P=0.006),2组阴性淋巴结分别为(14.4±5.4)枚和(16.7±7.0)枚,无统计学差异(t=-1.904,P=0.055)。新辅助化疗联合手术组40例随访6~19个月,平均10个月;直接手术组67例随访7~21个月,平均12个月,2组各有4例复发。结论乳腺癌经新辅助化疗后行腋窝淋巴结清扫所检出的淋巴结总数和阳性淋巴结数减少。