Intraoperative sentinel lymph node evaluation in patients with node-positive breast cancer status post neoadjuvant systemic therapy - An institutional experience

Recent studies have shown the feasibility and utility of sentinel lymph node (SLN) biopsy in patients with biopsy proven node-positive breast cancer after neoadjuvant chemotherapy. We reviewed our experience in intraoperative SLN evaluation in such cases and its effect on axillary management. A retrospective analysis of breast cancer patients (2015–2018) with a biopsy-proven positive axillary lymph node, who received neoadjuvant systemic therapy and underwent intraoperative SLN assessment was performed. Intraoperative SLN assessment results were compared with final pathology. Its accuracy and effect on axillary management is summarized. We identified 106 patients with positive axillary lymph node and neoadjuvant systemic therapy between the ages of 28 and 75 years who had SLN biopsy and lumpectomy (33) or mastectomy (73). Three or more SLNs were identified in 91 cases (86 %). The previously biopsied lymph node was identified as one of the sentinel lymph nodes in 93 cases (88 %). There is a high concordance rate between frozen section diagnosis and final diagnosis on sentinel lymph nodes. No false positive case and seven false negative frozen section diagnosis cases (diagnosed as negative on frozen section and positive on permanent sections) were identified. False-negative frozen section diagnosis correlated with low-volume nodal disease and obscuring tumor bed changes. Almost half of the positive lymph nodes were converted to negative after neoadjuvant chemotherapy. SLN biopsy with intraoperative frozen section evaluation after neoadjuvant systemic therapy in node-positive patients is an effective way to minimize axillary surgery.     

Update on sentinel node pathology in breast cancer

Pathologic examination of the sentinel lymph nodes (SLNs) in patients with breast cancer has been impacted by the publication of practicing changing trials over the last decade. With evidence from the ACOSOG Z0011 trial to suggest that there is no significant benefit to axillary lymph node dissection (ALND) in early-stage breast cancer patients with up to 2 positive SLNs, the rate of ALND, and in turn, intraoperative evaluation of SLNs has significantly decreased. It is of limited clinical significance to pursue multiple levels and cytokeratin immunohistochemistry to detect occult small metastases, such as isolated tumor cells and micrometastases, in this setting. Patients treated with neoadjuvant therapy, who represent a population with more extensive disease and aggressive tumor biology, were not included in Z0011 and similar trials, and thus, the evidence cannot be extrapolated to them. Recent trials have supported the safety and accuracy of sentinel lymph node biopsy (SLNB) in these patients when clinically node negative at the time of surgery. ALND remains the standard of care for any amount of residual disease in the SLNs and intraoperative evaluation of SLNs is still of value for real time surgical decision making. Given the potential prognostic significance of residual small metastases in treated lymph nodes, as well as the decreased false negative rate with the use of cytokeratin immunohistochemistry (IHC), it may be reasonable to maintain a low threshold for the use of cytokeratin IHC in post-neoadjuvant cases. Further recommendations for patients treated with neoadjuvant therapy await outcomes data from ongoing clinical trials. This review will provide an evidence-based discussion of best practices in SLN evaluation.     

Sentinel lymph node biopsy indications and controversies in breast cancer

Sentinel lymph node biopsy (SLNB) has become the standard of care for early breast cancer. Its use in breast cancer has been evaluated in several randomized controlled trials and validated in multiple prospective studies. Additionally, it has been verified that SLNB has decreased morbidity when compared to axillary lymph node dissection (ALND). The technique used to perform sentinel lymph node mapping was also evaluated in multiple studies and the accuracy rate increases when radiocolloid and blue dye are used in combination. As SLNB became more accepted, contraindications were delineated and are still debated. Patients who have clinically positive lymph nodes or core biopsy-proven positive lymph nodes should not have SLNB, but should have an ALND as their staging procedure. The safety of SLNB in pregnant patients is not fully established. However, patients with multifocal or multicentric breast cancer and patients having neoadjuvant chemotherapy are considered candidates for SLNB. However, the details of which specific neoadjuvant patients should have SLNB are currently being evaluated in a randomized controlled trial. Patients with ductal carcinoma in situ (DCIS) benefit from SLNB when mastectomy is planned and when there is a high clinical suspicion of invasion. With the advent of SLNB, pathologic review of breast cancer lymph nodes has evolved. The significance of occult metastasis in SLNB patients is currently being debated. Additionally, the most controversial subject with regards to SLNB is determining which patients with positive SLNs benefit from further axillary dissection.     

Assessing second echelon lymph nodes during sentinel lymph node biopsy: can we have more accurate axillary treatment for breast cancer patients?

Sentinel lymph node biopsy (SLNB) is the standard treatment for breast cancer patients with clinically negative axilla. For patients with positive sentinel lymph nodes, axillary lymph node dissection (ALND) was required. However, approximately a half of the SLNs-positive patients were found to have clear axillary lymph nodes after ALND, indicating that they had received unnecessary ALND without therapeutic benefit. Therefore, we propose a hypothesis for solution of this clinical problem. We defined the second echelon lymph nodes (SELNs) as those nodes receiving lymphatic drainage directly from the SLNs. For patients with positive-SLNs, SELNs can be biopsy and assessed. If SELNs are negative, no more ALND was needed in these patients even if their SLNs are positive. If our hypothesis were confirmed to be true, we can tailored our axillary treatment to more breast cancer patients, avoiding unnecessary ALND and its complications.     

Intraoperative cytologic evaluation of sentinel lymph nodes in patients with breast carcinoma by scrape preparation

Intraoperative evaluation of sentinel lymph nodes (SLNs) in patients with breast carcinoma allows surgeons to complete axillary lymph node dissection in one procedure if any SLN shows metastasis. The accuracy of intraoperative pathological diagnosis is critical for decision-making. The purpose of this study was to evaluate our rapid intraoperative cytologic diagnosis of SLN through comparing with the final surgical pathologic diagnosis of the corresponding lymph nodes. A total of 454 SLNs from 159 consecutive female patients with a preoperative diagnosis of breast carcinoma over 3-year period were included in this study. After gross examination of each bisected lymph node, a scrape preparation was prepared for each submitted lymph node and was stained by the rapid Papanicolaou method. The intraoperative cytologic diagnosis was compared with the final surgical pathologic diagnoses. The overall sensitivity of intraoperative cytology was 52.5% with specificity of 100%. There were 17 false-negative cases. Of them, six nodes had isolated tumor cells, seven nodes had micrometastasis (0.2-2 mm), and four nodes had macrometastasis (>2 mm). There were no interpretive errors identified. The size of metastasis and tumor grade appeared to be significant factors in detecting metastasis by cytology. In addition, subsequent non-SLN involvement was 9% in patients with micrometastasis versus 50% in patients with macrometastasis (P < 0.05). Our study shows that the intraoperative cytologic evaluation of SLNs in breast carcinoma is a reasonably accurate method. The majority of false-negative cases were due to micrometastasis and isolated tumor cells.     

Lymphangiogenesis in breast cancer is associated with non-sentinel lymph node metastases in sentinel node positive patients

Axillary lymph node dissection (ALND) is not suggested in breast cancer patients with negative sentinel lymph node (SLN) biopsies, and SLN is the only positive node in 40-70% of the remaining cases. To distinguish a subgroup in which ALND would be omitted, we investigated the role of lymphangiogenesis in primary breast cancer as a risk factor for distal lymph node involvements in patients with positive SLNs. 86 patients were included in this study. The frequency of proliferative lymphatic endothelial cells (LECP%) was evaluated in each specimen after immunohistochemical double staining for D2-40 and Ki-67. Larger primary tumor size, increased number of positive SLNs, lymphatic vessel invasion and LECP% were significantly associated with non-SLN metastases in the univariate analysis, but only LECP% retained significance in the multivariate model. A positive correlation between LECP% and lymphatic vessel invasion was also revealed. Our study confirmed the important role of lymphangiogenesis in tumor spread, and suggested that LECP% is a promising predictor for additional axillary lymph node involvements.     

Evaluation of axillary sentinel lymph node biopsy by immunohistochemistry and multilevel sectioning in patients with breast carcinoma

BACKGROUND: Axillary lymph node dissection for evaluation of the presence or absence of metastatic disease is the single most important prognostic factor for patients with newly diagnosed primary breast cancer. Recently, sentinel lymph node (SLN) biopsy is being investigated as an alternative to the evaluation of the entire axilla. We evaluated whether the application of multilevel sectioning and immunohistochemistry in SLNs will increase the accuracy of detection of metastatic deposits. METHODS: Between October 1998 and July 1999, 38 patients with breast carcinoma (25 ductal, 5 lobular, 4 tubular, and 4 mixed ductal and lobular) underwent successful SLN biopsy followed by complete axillary node dissection. Sentinel lymph nodes were localized with a combination of isosulfan blue dye and radionuclide colloid injection. Frozen sections and permanent sections of SLNs were examined. All negative SLNs were examined for micrometastases by 3 additional hematoxylin-eosin (H&E)-stained sections and immunohistochemistry with the cytokeratins AE1/AE3. RESULTS: Sentinel lymph nodes were successfully identified surgically in 38 (93%) of 41 patients. There was a 97% correlation between the results of the frozen sections and the permanent H&E-stained sections. Twelve (32%) of 38 patients showed evidence of metastatic disease in their SLN by routine H&E staining. In 7 (58%) of 12 patients with positive nodes, the sentinel node was the only positive node. The 26 patients with negative SLN examination by H&E were further analyzed for micrometastases; 5 (19%) were found to have metastatic deposits by immunohistochemistry. Of these patients, 2 were also converted to node positive by detection of micrometastatic disease by examination of the additional H&E levels. CONCLUSIONS: Sentinel lymph nodes can be accurately identified in the axilla of breast cancer patients. Evaluation of SLNs provides reliable information representative of the status of the axilla in these patients. Immunohistochemistry and, to a lesser degree, detailed multilevel sectioning are able to further improve our ability to detect micrometastatic disease in SLNs of breast cancer patients.     

Non-sentinel lymph node involvement in patients with breast cancer and sentinel node micrometastasis; too early to abandon axillary clearance

AIMS: It has been suggested that patients with T1-2 breast tumours and sentinel node (SLN) micrometastases, defined as foci of tumour cells smaller than 2 mm, may be spared completion axillary lymph node dissection because of the low incidence of further metastatic disease. To gain insight into the extent of non-sentinel lymph node (n-SLN) involvement, SLNs and complementary axillary clearance specimens in patients with SLN micrometastases were examined. METHODS: A set of 32 patients with SLN micrometastases was selected on the basis of pathology reports and review of SLNs. Five hundred and thirteen n-SLNs from the axillary clearance specimens were serially sectioned and analysed by means of immunohistochemistry for metastatic disease. Lymph node metastases were grouped as macrometastases (> 2 mm), and micrometastases (< 2 mm), and further subdivided as isolated tumour cells (ITCs) or clusters. RESULTS: In 11 of 32 patients, one or more n-SLN was involved. Grade 3 tumours and tumours > 2 cm (T2-3 v T1) were significantly associated with n-SLN micrometastases as clusters (grade: odds ratio (OR), 8.3; 95% confidence interval (CI), 1.4 to 50.0; size: T2-3 tumours v T1: OR, 15; 95% CI, 2.18 to 103.0). However, no subgroup of tumours with regard to size and grade was identified that did not have n-SLN metastases. CONCLUSIONS: In patients with breast cancer and SLN micrometastases, n-SLN involvement is relatively common. The incidence of metastatic clusters in n-SLN is greatly increased in patients with T2-3 tumours and grade 3 tumours. Therefore, axillary lymph node dissection is especially warranted in these patients. However, because n-SLN metastases also occur in T1 and low grade tumours, even these should be subjected to routine axillary dissection to achieve local control.     

Modes of benign mechanical transport of breast epithelial cells to axillary lymph nodes

The status of axillary lymph nodes is a key prognostic indicator available for the management of patients with breast cancer. Sentinel lymph node (SLN) evaluation as a predictor of lymph node status has led to increased use of ancillary methods, principally immunohistochemistry, to increase the sensitivity of the SLN biopsy. So-called "occult" micrometastases detected by such methods have led to speculation that some may have reached the SLNs by benign mechanical transport (BMT) rather than a metastatic process. We review evidence suggesting two potential modes of BMT: lymphatic transport of epithelial cells displaced by biopsy of the primary breast tumor and by breast massage-assisted SLN localization. The biopsy techniques under most scrutiny include fine needle aspiration and large-gauge core biopsy. The evidence implicating breast massage prior to SLN biopsy as a mode of BMT has been supported by statistical analysis; however, no method of distinguishing massage-associated cells in SLNs from true occult micrometastases is available. The significance of small epithelial clusters in SLNs is currently unknown. Thus, deviation from current biopsy and SLN-localizing practices is unwarranted.     

Accuracy of axillary staging using sentinel node biopsy or diagnostic axillary lymph node dissection--a case-control study

We aimed to compare the accuracy of axillary staging in breast cancer between sentinel node biopsy (SNB) and axillary lymph node dissection (ALND). The prevalence of axillary metastases was studied in 166 breast cancer patients with SNB and pair-matched control patients with ALND. The matching factors included age of the patient and grade, histological type and histological size of the tumour. There were 37% of patients with axillary metastases in the SNB group and 31% in the ALND group. Altogether, 57 pairs were discordant in relation to axillary metastases. In 34 discordant pairs the SNB patient and in 23 the ALND patient had axillary metastases, p=ns. Among the 36 discordant pairs with invasive ductal carcinoma (IDC), axillary metastases were detected as often in the SNB and the ALND patients. In the 21 discordant pairs with other histological types, the SNB patient had axillary metastases in 16 pairs and the ALND patient in 5 pairs, p<0.03. SNB seems to be as accurate a method for axillary staging as ALND. However, SNB generated no upstaging effect in IDC, only in other histological tumour types.     

本院5年来乳腺癌前哨啉巴结活检报告

目的探讨乳腺癌前哨淋巴结活检技术的可行性和前哨淋巴结的组织学状况能否准确预告腋淋巴结的状况。方法使用美蓝染色和或^99mTc-SC同位素示踪法对我院收治的108例乳腺癌患者进行前哨淋巴结活检。结果108例患者中有95例成功确定前哨淋巴结，检出率88％，其中关蓝组为87S（S5／98），美蓝与核素联合组全部检出（100S）。40岁以下的妇女检出率明显高于40岁以上的妇女（P〈0．05），而假阴性率有显著性增高。97例浸润性癌（包括导管癌和腺癌）中假阴性率为22％，但当使用免疫组化检查法以后，假阴性率下降至14％。结论前哨淋巴结活检技术在临床是可行的，绝大多数前哨淋巴结可以比较准确地反映其余腋窝淋巴结的组织学特点。美蓝染色和／或^99mTc-SC同位素示踪法结合应用是较好的选择方法。     

Factors affecting metastases to non-sentinel lymph nodes in breast cancer

AIMS: Because sentinel lymph node (SLN) biopsy for breast cancer has become well established, one of the challenges now is to determine which patients require a completion axillary dissection following a positive SLN biopsy. METHODS: A prospective database of patients who underwent SLN biopsy for invasive breast cancer from July 1999 to November 2002 (n = 180) was analysed. Fifty four patients (30%) had one or more positive SLN, and all underwent a completion axillary dissection. This subgroup was further analysed to delineate which factors predicted non-SLN metastasis. RESULTS: Twenty six of the 54 patients with a positive SLN had additional metastases in non-SLNs. Significant variables that predicted non-SLN metastasis included extranodal extension (odds ratio (OR), 17.399; 95% confidence interval (CI), 1.69 to 178.96) and macrometastasis within the SLN (OR, 6.985; 95% CI, 1.291 to 37.785). CONCLUSIONS: In patients with invasive breast cancer and a positive SLN, extranodal extension or macrometastasis within the SLN were both independent predictors of non-SLN involvement.     

Minimal metastatic disease in sentinel lymph nodes in breast carcinoma: some modest proposals to refine criteria for "isolated tumor cells"

Axillary lymph node status is one of the most important prognostic factors in breast carcinoma. The weight of cumulative evidence suggests that the development of the sentinel lymph node (SLN) biopsy procedure has not only allowed for accurate lymph node-staging but has also helped avoid the morbidity of a full axillary dissection in those patients who are unlikely to have metastatic tumor in that location. The detection of metastases in SLNs is facilitated by the, now relatively routine, enhanced histopathologic examination via step-sectioning and immunohistochemistry. In clinical terms, the finding of a metastatic deposit that measures between 0.2 and 2 mm, that is, "micrometastasis" in a SLN is largely noncontroversial; however, the presence of smaller metastatic foci detected either by routine hematoxylin and eosin stain or by cytokeratin immunostain [<0.2 mm, ie, so-called "isolated tumor cells (ITCs)"] has remained problematic since the advent of the SLN biopsy. In this communication, attention is drawn to the broad morphologic range of metastatic disease in SLN that may be placed in the category of so-called ITC. To facilitate the reproducible classification of the various strata of minimal metastasis in sentinel lymph nodes, we recommend the following: (1) the term "isolated tumor cell" (note singular form) be restricted to cases that show the presence of only a single tumor cell. (2) In situations where there are multiple isolated single cells and/or cell cluster(s) present and each cluster measures<0.2 mm, the term "submicroscopic metastasis" be adopted and an actual count of tumor cells present may be given. (3) Restrict the use of the term micrometastasis to cases wherein the largest metastatic focus is larger than 0.2 mm but smaller than 2.0 mm.     

Detection of micrometastases in bone marrow and sentinel lymph nodes of breast cancer patients

Objective: To study the sensitivity and clinical significance of HE-staining,IHC and RT-PCR in detecting breast cancer micrometastases in bone marrow and sentinel lymph nodes (SLNs). Methods:After general anesthesia, all patients underwent bone marrow puncture and sentinel lymph node biopsy (SLNB) by 1% isosulfan blue, and then HE-staining,IHC and RT-PCR were used to detect micrometastases. Results:Of 62 patients with breast cancer whose axillary lymph nodes showed negative HE-staining results, 15 cases presented with positive RT-PCR and 9 cases showed positive IHC results positive in bone marrow micrometastases detection. PT-PCR and IHC showed good uniformity(kappa=0.6945)and there was significant difference in detective rate between these two methods (χ2=4.1667,P=0.0412). In SLN samples, 13 showed positive RT-PCR results, while 7 showed positive IHC results. PT-PCR and IHC showed good uniformity (kappa=0.6483)and significant difference was also found in detective rate between these two methods (χ2=4.1667,P=0.0412). Both bone marrow and SLN samples were RT-PCR positive in 3 cases,which indicated that bone marrow micrometastases did not always accompany SLN micrometastases(χ2=0.067,P=0.796). Conclusion: Even if no axillary lymph node involvement or distant metastases are present in routine preoperative examination, micrometastases can still be detected in bone marrow or SLNs. Because the bone marrow micrometastases and axillary node micrometastses are not present simultaneously, combination test of multiple indicators will detect micrometastases more accurately.     

The role of sentinel lymph node biopsy in the management of breast cancer

Axillary nodes status is the best single predictor of disease outcome in patients with breast cancer; presence ofaxillary node metastasis (ANM) reduces the patient's 5-year survival by 28-40%. However, ANM is seen in only 40% of all breast cancer and furthermore since axillary lymph node dissection (ALND) is associated with significant morbidity, sentinel lymph node biopsy (SLNB) seems to be a good alternative for nodal staging in breast cancer. Pathologically negative sentinel lymph node (SLN) is able to predict the absence of metastasis to the remainder of the regional lymph node basin with a very high degree of certainty. This article presents a systematic detailed review of the existing studies on SLNB in relation to the following parameters: sensitivity and accuracy of the different techniques used; pathologic evaluation of SLN; clinical and pathological factors affecting SLN status and role of SLNB in different clinical situations related to breast cancer management. We have also included brief mention of our experience at UMass from a pathological perspective in this review article.     

In breast cancer patients sentinel lymph node metastasis characteristics predict further axillary involvement

The aim of the study was to correlate various primary tumor characteristics with lymph node status, to examine sentinel lymph node (SLN) metastasis size and non-SLN axillary involvement, to look for a cut-off size/number value possibly predicting additional axillary involvement with more accuracy and to examine the relationship of SLN metastasis size to overall survival. Of 301 patients who underwent SLN biopsy, 75 had positive SLNs. The size of the metastases was measured. For different size categories, association with the prevalence of non-SLN metastases was assessed. Associations between metastasis size and tumor characteristics and overall survival (OS) were studied. The prevalence of axillary lymph node (ALN) involvement was not significantly different between cases with micrometastasis or macrometastasis in SLNs (p?=?0.124). However, for metastases larger than 6, 7, and 8 mm, the prevalence of ALN involvement was significantly higher (p?=?0.046, 0.022, and 0.025). OS was significantly lower in SLN-positive than in SLN-negative cases (p?=?0.0375). Primary tumor size larger than 20 mm was associated with a significantly higher incidence of SLN metastasis (p?<?0.001), and primary tumor size over 26 mm was associated with additional positive non-SLN (p?<?0.001). Higher mitotic index (≥7) in primary tumors was significantly (p?<?0.001) associated with ALN involvement in SLN-positive cases, whereas higher Ki67 labeling index was not significantly correlated with SLN or ALN involvement. Lymphovascular invasion (LVI) in primary tumors was significantly correlated with SLN positivity (p?<?0.001) but not with further ALN involvement or OS. Tumor size and LVI are predictive for SLN metastasis. Mitotic index, primary tumor size, and larger volume SLN involvement are determinants of further ALN involvement. SLN metastasis size over 6 mm is a strong predictor of further axillary involvement. OS is shorter in the presence of positive SLN.     

乳腺癌非前哨淋巴结转移的预测

目的 :预测非前哨淋巴结 (non SLN)转移 ,以筛选出转移局限于前哨淋巴结 (SLN)的乳腺癌患者。方法 :采用99mTc SC作为示踪剂 ,对 95例乳腺癌患者行前哨淋巴结活检 ,对乳腺癌非前哨淋巴结转移进行单因素和多因素分析。结果 :95例患者中成功发现 91例患者有SLN (95 8% ) ,其中 85例患者SLN能准确反映腋窝淋巴结的病理状况 (93 4% )。临床肿块大小(P =0 0 2 8)、肿瘤分级 (P =0 0 40 )和原发灶cyclinD1蛋白 (P =0 0 17)的表达与non SLN转移显著相关。而Logistic多因素分析证实 ,临床肿块大小、肿瘤分级为独立的预测非前哨淋巴结转移的因子。结论 :可根据临床病理学特征 ,筛选出乳腺癌转移只局限于前哨淋巴结的患者 ,也存在免除腋窝淋巴结清扫的可能性     

Axillary staging of breast cancer and the sentinel node

Pathological aspects of axillary nodal staging of breast cancer and in particular sentinel lymph node (SLN) biopsy are reviewed. SLN biopsy seems an almost ideal staging procedure because it has both high accuracy and a low false negative rate. It may also allow a cost effective use of more sensitive methods of metastasis detection. However, the biological relevance of metastases detected only by modern tools remains to be elucidated. This review focuses on standard axillary staging and the histopathological investigation of SLNs, with emphasis on the intraoperative setting. Future trends including ancillary studies, quality control issues, prediction of non-SLN involvement, and suggestions concerning the minimum requirements for the histology of axillary SLNs are also discussed.     

Predictive value of tumor load in breast cancer sentinel lymph nodes for second echelon lymph node metastases.

BACKGROUND: The need for routine axillary lymph node dissection (ALND) in patients with invasive breast cancer and low-volume sentinel node (SN) involvement is questionable. Accurate prediction of second echelon lymph node involvement could identify those patients most likely to benefit from ALND. METHODS: A consecutive series of 317 patients with invasive breast cancer and a tumor positive axillary SN followed by ALND was reviewed. Clinicopathologic features of the primary tumor and the SN were assessed as possible predictors of second echelon lymph node involvement. RESULTS: Second echelon metastases were found in 116/317 cases (36.6%). Frequency of second echelon lymph node involvement in patients with isolated tumor cells (ITC, N=23), micro- (N=101) and macrometastases (N=193) was 13%, 20% and 48%, respectively (p<0.001). Based on the area % of SN occupied by tumor no subgroup of patients could be selected with less than 20% second echelon lymph node involvement. However, none of the patients with SN ITC or micrometastases and a primary tumor size 相似文献   

Intraoperative examination of the sentinel lymph node for breast carcinoma staging.

Intraoperative pathologic examination of the sentinel lymph node (SLN) draining a primary breast carcinoma allows an SLN-positive patient to undergo complete axillary lymphadenectomy as part of the same surgical procedure. However, the optimal technique for rapid SLN assessment has not been determined. We reviewed our results with imprint cytology (IC) and frozen section (FS) examination of SLNs from 278 patients. Compared with H&E-stained paraffin sections, IC and FS had an overall accuracy of 93.2%. The false-reassurance rate (false-negative results/all negative results) was 8.4%. It correctly identified 98% of macrometastases but only 28% of micrometastases. There were no false-positive results. Compared with paraffin-section cytokeratin immunohistochemistry results, the IC-FS false-reassurance rate increased to 25.8%. The false-reassurance rate decreased with smaller primary tumor size (T1 vs T2/3) and ductal type, smaller diameter of the SLN (< or = 2.0 cm), and greater pathologist experience. IC combined with 2-level FS reliably identifies SLN macrometastases but commonly fails to detect SLN micrometastases. If SLN micrometastasis is used to determine the need for further lymphadenectomy, more sensitive intraoperative methods will be needed to avoid a second operation.