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1.  New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients 
BMC Cancer  2008;8:66.
Background
Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.
Methods
We constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.
Results
285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.
Conclusion
We present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets.
doi:10.1186/1471-2407-8-66
PMCID: PMC2311316  PMID: 18315887
2.  Prediction of involvement of sentinel and nonsentinel lymph nodes in a Canadian population with breast cancer 
Canadian Journal of Surgery  2009;52(1):23-30.
Background
We sought to identify criteria for the intraoperative assessment of sentinel lymph node (SLN) involvement in women with early breast cancer. We also sought to determine whether the SLN nomogram developed by the Memorial Sloan-Kettering Cancer Center (MSKCC) to predict nonsentinel lymph node (NSLN) involvement when the SLN is positive would accurately predict NSLN involvement in our patient population.
Methods
We performed 405 SLN biopsies in 397 women between January 1998 and June 2005. We determined factors associated with SLN metastases using univariate and multivariate logistic regression. Ninety women who had 1 positive SLN or more and underwent axillary lymph node dissection (ALND) had complete data for analysis. We applied the MSKCC nomogram retrospectively to this subset of women, and we calculated the probability of NSLN involvement and compared it with the observed rate.
Results
Multifocality and the presence of lymphovascular invasion were predictive of SLN involvement. Ductal carcinoma in situ was negatively associated with SLN involvement. Intraoperative evaluation identified 57 (63%) of the 90 women with involved SLN, of which 26 (29%) had involved NSLN. Application of the MSKCC nomogram to our data set produced an area under the receiver operator characteristic curve of 0.71. The nomogram tended to overestimate the probability of NSLN involvement in our population.
Conclusion
Lymphovascular invasion and multifocality were associated with SLN involvement. Women with small low-grade tumours may not require routine intraoperative evaluation of SLNs. The MSKCC nomogram appears to be most useful as a decision aid in selecting those women with an involved SLN in whom ALND may be omitted.
PMCID: PMC2637641  PMID: 19234648
3.  Micrometastatic Disease and Isolated Tumor Cells as a Predictor for Additional Breast Cancer Axillary Metastatic Burden 
Annals of surgical oncology  2010;17(0 3):303-311.
Background
Our study aims were to investigate breast cancer patients with micrometastases or isolated tumor cells (ITCs) in sentinel lymph nodes (SLNs) to determine the rate of non-SLN metastasis and axillary recurrences, and to compare actual non-SLN metastasis rates with those predicted by the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram.
Methods
We identified 116 stage I to III breast cancer patients who underwent sentinel lymph node biopsy and had micrometastases or ITCs (<2-mm deposits). Patients underwent completion axillary lymph node dissection (ALND) (group 1) or had no further axillary surgery (group 2). P < 0.05 was considered statistically significant.
Results
Of 116 patients with micrometastases or ITCs in SLNs, 55 (47%) underwent completion ALND (group 1), and 61 (53%) had no further axillary surgery (group 2). The rate of non-SLN metastases in group 1 patients was 9 (16%) of 55, which was significantly less than that predicted by the MSKCC nomogram (median 30%, P < 0.001). Patient age, race, tumor histology, tumor grade, estrogen receptor/Her-2neu status, and lymphovascular invasion did not differ significantly between group 1 patients with positive non-SLNs and those with negative non-SLNs (P > 0.05 for each), but patients with positive non-SLNs had larger tumors (P < 0.001). No patient in group 1 experienced an axillary recurrence, while only one patient (1.6%) in group 2 experienced axillary recurrence.
Conclusions
The actual rate of positive non-SLNs for breast cancer patients with SLN micrometastases or ITCs who underwent completion ALND was significantly less than that predicted by the MSKCC nomogram. The rate of axillary recurrence is negligible, regardless of the extent of axillary staging.
doi:10.1245/s10434-010-1255-1
PMCID: PMC3892696  PMID: 20853051
4.  Factors that determine whether a patient receives completion axillary lymph node dissection after a positive sentinel lymph node biopsy for breast cancer in British Columbia 
Canadian Journal of Surgery  2011;54(4):237-242.
Background
Completion axillary lymph node dissection (CALND) is recommended in the setting of positive sentinel lymph node biopsy (SLNB) but is associated with a higher rate of postoperative complications. In this study, the characteristics and outcomes of patients who did and did not have CALND are compared.
Methods
We identified all patients with breast cancer with positive sentinel lymph nodes (SLNs) who did not have concurrent CALND from 2003 to 2006 using a prospectively collected database (British Columbia Cancer Breast Outcomes database) and retrospective chart review. Patient and tumour characteristics were compared between those who received CALND and those who did not.
Results
Among 185 patients with positive SLNs identified by SLNB, 90 had a CALND and 95 had no further surgical therapy. Patients who did not receive CALND had more sentinel nodes removed (p < 0.001), a lower percentage of positive SLNs (p < 0.001) and lower pathologic N stage (p = 0.044) than those who did receive CALND. The size of the breast lesion, size of the largest SLN deposit, estrogen receptor status, grade, lymphovascular invasion, histology and multifocality were not significantly different between groups. Sixty-two percent of women who did not have CALND received radiation to the axilla. Postoperative complication rates (including lymphedema) were higher in the CALND group (21%) compared with the SLNB group (7%). The rates of locoregional recurrence (1% in both groups) and systemic metastases (6% in the CALND group v. 8% in the SLNB group) were similar at 36 months’ follow-up.
Conclusion
Compared with women who had CALND, women who did not receive CALND had on average a lower N stage with 3 or more SLNs removed and less than 50% node positivity. Most of these women received radiation therapy to the axilla and had comparable recurrence rates to those who had CALND.
doi:10.1503/cjs.007810
PMCID: PMC3191897  PMID: 21651836
5.  Use of the dye-guided sentinel lymph node biopsy method alone for breast cancer metastasis to avoid unnecessary axillary lymph node dissection 
For sentinel lymph node biopsy (SLNB), a combination of dye-guided and γ-probe-guided methods is the most commonly used technique. However, the number of institutes in which the γ-probe-guided method is able to be performed is limited, since special equipment is required for the method. In this study, SLNB with the dye-guided method alone was evaluated, and the clinicopathological characteristics were analyzed to identify any factors that were predictive of whether the follow-up axillary lymph node dissection (ALND) was able to be omitted. A total of 374 patients who underwent SLNB between 1999 and 2009 were studied. The SLN identification rate was analyzed, in addition to the false-positive and false-negative rates and the correlation between the clinicopathological characteristics and axillary lymph node metastases. The SLN was identified in 96.8% of cases, and, out of the patients who had SLN metastasis, 63.0% did not exhibit metastasis elsewhere. The sensitivity was 96.4% and the specificity was 100%. The false-negative rate was 3.6%. Univariate analyses revealed significant differences in the lymph vessel invasion (ly) status, nuclear grade (NG), maximum tumor size and the percentage of the area occupied by the tumor cells in the SLN (SLN occupation ratio) between the patients with and without non-SLN metastasis, indicating that these factors may be predictive of axillary lymph node metastasis. Multivariate analysis revealed that ly status was an independent risk factor for non-SLN metastasis. In conclusion, SLN with the dye-guided method alone provided a high detection rate. The study identified a predictive factor for axillary lymph node metastasis that may improve the patients’ quality of life.
doi:10.3892/etm.2013.1445
PMCID: PMC3881064  PMID: 24396425
axillary lymph node dissection; breast cancer; dye-guided method; sentinel lymph node biopsy; prediction of lymph node metastasis
6.  Predictors of Nonsentinel Nodal Involvement to Aid Intraoperative Decision Making in Breast Cancer Patients with Positive Sentinel Lymph Nodes 
ISRN Oncology  2011;2011:539503.
Background. Up to 60% of patients with a positive sentinel lymph node (SLN) have no additional nodal involvement and do not benefit from completion axillary lymph node dissection (ALND). We aim to identify factors predicting for non-SLN involvement and to validate the MSKCC nomogram and Tenon score in our population. Methods. Retrospective review was performed of 110 consecutive patients with positive SLNs who underwent ALND over an 8-year period. Results. Fifty patients (45%) had non-SLN involvement. Non-SLN involvement correlated positively with the number of positive SLNs (P = 0.04), macrometastasis (P = 0.01), and inversely with the total number of SLNs harvested (P = 0.03). The MSKCC nomogram and Tenon score both failed to perform as previously reported. Conclusions. The MSKCC nomogram and Tenon score have limited value in our practice. Instead, we identified three independent predictors, which are more relevant in guiding the intraoperative decision for ALND.
doi:10.5402/2011/539503
PMCID: PMC3199941  PMID: 22091423
7.  Tumor Characteristics Influencing Non-Sentinel Lymph Node Involvement in Clinically Node Negative Patients with Breast Cancer 
Journal of Breast Cancer  2011;14(2):124-128.
Purpose
The negative sentinel lymph node (SLN) biopsy avoids conventional axillary dissection in patients with breast cancer with clinically negative axilla. Despite negative SLN, there is a risk of leaving involved non-SLN behind in the axilla. We investigated the predictive power of tumor characteristics for non-SLN metastasis.
Methods
Lymphatic mapping with blue dye method for SLN biopsy and level 1-2 axillary dissections were performed to establish axillary status in 59 patients with T1 and T2 breast cancer and clinically negative axilla. Tumor's characteristics were histopathologically established to assess their association with non-SLN metastasis.
Results
The axilla was malignant in 23 (39%) patients. The SLN alone was metastatic in 10, both SLN and non-SLN in 9, and non-SLN alone in 4 (7%) patients. The false negative rate for SLN biopsy was 10% in our series. The rate of positive non-SLN was found as 0% in T1a-b, 19% in T1c, and 40% in T2 tumors (p=0.035). Lymphovascular invasion was positive in 14 (61%) patients with axillary metastasis (p<0.001), and in 10 (77%) patients with non-SLN involvement (p<0.001).
Conclusion
We concluded that there was a small risk of involved non-SLN despite negative SLN. Tumor size (near or greater than 2 cm) was significantly associated with non-SLN metastasis. Peritumoral lymphovascular invasion was a positive predictor of the metastatic involvement in non-SLNs.
doi:10.4048/jbc.2011.14.2.124
PMCID: PMC3148535  PMID: 21847407
Axilla; Breast neoplasms; Carcinoma; Ductal; Lymphatic metastasis; Sentinel lymph node
8.  Preoperative Axillary Ultrasound in Breast Cancer: Safely Avoiding Frozen Section of Sentinel Lymph Nodes in Breast Conserving Surgery 
Background
The ACOSOG Z0011 results provided convincing evidence that completion axillary lymph node dissection (CALND) was unnecessary in selected patients with 1–2 positive sentinel lymph nodes (SLNs). We hypothesized that preoperative axillary ultrasound (AUS) with fine needle aspiration is sufficiently sensitive to detect worrisome macrometastasis to preclude need for frozen section pathology of SLNs.
Study Design
A retrospective single institution study, tertiary academic referral center. 1,140 T1-2 breast cancer patients who underwent SLN biopsy ± CALND, from 1/1/07-12/31/10 were reviewed. All patients had negative preoperative AUS ± FNA.
Results
144 (13%) patients were node positive at surgery. Average age, tumor size, histology, ER and PR status were similar comparing 996 SLN negative to 144 (13%) SLN positive patients. Of the SLN positive patients, 25% were premenopausal, 9% were ER negative, and 19% had additional lymph nodes at CALND. Only 19 (2%) patients had SLN metastasis ≥6 mm, 10 (1%) had metastasis >7 mm, and only 1 patient had ≥3 positive SLNs.
Conclusions
The addition of preoperative AUS ± FNA to patients who meet ACOSOG Z0011 eligibility criteria reduced the risk of macrometastasis measuring ≥6 mm to only 2%, very few of whom would be premenopausal, have ER negative tumors, or ≥3 positive SLNs. With the addition of AUS ± FNA, we endorse the conclusions of the ACOSOG Z0011 trial in avoiding CALND, and see marginal gain in frozen section analysis of SLNs.
doi:10.1016/j.jamcollsurg.2013.01.064
PMCID: PMC3691332  PMID: 23628226
9.  High FOXP3+ regulatory T-cell density in the sentinel lymph node is associated with downstream non-sentinel lymph-node metastasis in gastric cancer 
British Journal of Cancer  2011;105(3):413-419.
Background:
We aimed to evaluate the immunologic nature of sentinel lymph nodes (SLNs) in gastric cancer patients and to determine whether it can predict non-SLN metastasis.
Methods:
Sentinel lymph node samples were collected from 64 gastric carcinoma patients who had undergone gastrectomy with SLN biopsy. One representative SLN sample was selected from each patient and was subjected to immunostaining for CD8, CD57, FOXP3, and DC-LAMP. The numbers of marker-positive cells in each sample were counted. The relationships between various immune cell densities and clinicopathologic parameters or metastasis status of SLNs and non-SLNs were sought.
Results:
High FOXP3+ Treg density of the SLN was found to be significantly associated with the presence of metastasis in either SLNs or non-SLNs. DC-LAMP+ cell density of the SLN was the highest at the isolated tumours cell level, and this decreased along with an increase in tumour metastasis in either SLNs or non-SLNs. Univariate and multivariate logistic regression models revealed that high FOXP3+ Treg density of the SLN was an independently significant predictor of non-SLN metastasis.
Conclusions:
This study is the first to indicate an important role of SLNs in metastatic dissemination of gastric cancer. Our findings suggest that Tregs could be a new therapeutic target for regulating the metastasis of gastric cancer.
doi:10.1038/bjc.2011.248
PMCID: PMC3172906  PMID: 21730981
stomach neoplasms; sentinel lymph nodes; regulatory T cells; dendritic cells; tumour immunology
10.  Non-sentinel lymph node involvement in patients with breast cancer and sentinel node micrometastasis; too early to abandon axillary clearance 
Journal of Clinical Pathology  2002;55(12):932-935.
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.
PMCID: PMC1769813  PMID: 12461062
sentinel node; micrometastasis; breast cancer; pathological staging
11.  Value of frozen section and primary tumor factors in determining sentinel lymph node spread in early breast carcinoma 
Introduction
Sentinel lymph node biopsy (SLNB) is the standard of care to assess the metastasis in breast carcinoma. Accuracy of intraoperative frozen section examination to evaluate SLN in detecting metastasis is important as it determines the further management of axilla. Primary tumor characteristics determining the metastasis to the lymph node will help in predicting the probability of spread and to determine the nature of disease. It also helps in refining selection of patients for SLNB. We evaluated all these criteria on Indian patients for the better management.
Materials and methods
Between January 2005 and April 2009, 114 consecutive patients of all age group of both sex, with cytology or biopsy proven carcinoma breast, clinical stage T1/T2 N0 M0 at Manipal Comprehensive Cancer Center, Manipal Hospital, Bangalore were subjected to SLNB and introperative frozen examination. First 75 cases had complete axillary clearance irrespective of SLNB result and subsequently, positive cases underwent axillary lymph node dissection (ALND). Age of the patient and primary tumor characteristics like size, grade, lymphovascular invasion (LVI), perineural invasion, ER/PR status, Her2-neu status and histological sub-types were evaluated for predicting the SLN metastasis. Feasibility of SLNB in previously treated patient is also evaluated.
Results
The age of the patient ranged from 23 to 87 years and its association with SLN spread is not significant. Frozen section examination had accuracy of 97.37% in determining metastatic sentinel node with sensitivity of 96.15% and specificity of 100% with value P < 0.001. SLN remained significant indicator of the status of rest of axilla with value P < 0.001. Primary tumor characteristics like histological subtypes, grade (P = 0.353), ER/PR status (P = 0.839), Her2-neu status (P =0.296) were not significantly associated with SLN metastasis. Size of the primary tumor (P = 0.002), LVI (P < 0.001), perineural invasion (P = 0.084+) were significant factors determining the SLN metastasis. SLNB evaluation had no false negative values in previously treated breast.
Conclusion
SLNB is a valuable method of determining the axillary nodal metastasis. Intraoperative frozen section examination is highly ac-curate in detecting nodal metastasis. Primary tumor characteristics like size, LVI and perineural invasion are significant in predicting SLN metastasis. SLNB remains an important method of predicting axillary metastasis even in previously treated breast carcinomas.
doi:10.1007/s13193-010-0008-8
PMCID: PMC3420992  PMID: 22930615
Sentinel lymph node; Breast carcinoma; Metastasis
12.  Disease Recurrence in Sentinel Node-Positive Breast Cancer Patients Forgoing Axillary Lymph Node Dissection 
Annals of surgical oncology  2012;19(10):3185-3191.
Background
Clinically node-negative breast cancer patients usually undergo sentinel lymph node (SLN) biopsy. When metastasis is identified, completion axillary lymph node dissection (CALND) is recommended. Newer data suggest that CALND may be omitted in some women as it does not improve local control or survival.
Methods
Women with a positive SLN diagnosed between 1999 and 2010 were included in this review and were stratified according to whether they did or did not undergo CALND. Primary endpoints included recurrence and breast cancer-specific mortality. Differences between the groups and in time to recurrence were compared and summarized.
Results
Overall, 276 women were included: 206 (79 %) women who underwent CALND (group 1) and 70 (21 %) women in whom CALND was omitted (group 2). Group 1 patients were younger, had more SLN disease, and received more chemotherapy (P <0.05 for each). The groups did not vary by tumor characteristics (P >0.05 for each). Median follow-up was 69 (range 6–147) and 73 (range 15–134) months for groups 1 and 2, respectively. Five (2 %) women in group 1 and three (4 %) women in group 2 died of breast cancer (P = 0.39). Local–regional or distant recurrence occurred in 20 (10 %) group 1 patients and in 10 (14 %) group 2 patients (P = 0.39). On multivariate analysis, only estrogen receptor negativity and lymphovascular invasion predicted for recurrence.
Conclusions
Omission of CALND in women with SLN disease does not significantly impact in-breast, nodal, or distant recurrence or mortality. Longer-term follow-up is needed to verify that this remains true with time.
doi:10.1245/s10434-012-2547-4
PMCID: PMC4043293  PMID: 22890591
13.  Management of sentinel node re-mapping in patients who have second or recurrent breast cancer and had previous axillary procedures 
Background
In patients with recurrent or second primary ipsilateral breast cancer, axillary staging is the key factor in locoregional control and a strong prognostic characteristic. The efficient evaluation of lymphatic drainage of re-sentinel lymph node biopsies (re-SLNBs) has remained a challenge in the management of ipsilateral primary or recurrent breast cancer patients who are clinically lymph node negative. This study explores whether a SLNB for patients with primary or recurrent breast cancer is possible after previous axillary surgery. It evaluates potential reasons for mapping failure that might be associated with patients in this group.
Methods
Between March 2006 and November 2013, 458 patients were subjected to a breast SLNB. A lymphoscintigraphy procedure was performed on 330 patients for sentinel lymph node (SLN) mapping on the day of surgery. Seven patients with either a second primary cancer in the same breast or recurrent breast cancer were described. Two of these seven patients had axillary lymph node dissection (ALND) during previous treatments and five had SLNB. A dual mapping method was used for all patients. Preoperative lymphoscintigraphy was performed four hours before surgery.
Results
SLNs were successfully remapped in six of seven (85.7%) patients, of whom five (71.43%) had previously undergone SLNB and two (28.57%) previous ALND. Localizations of SLNs were ipsilateral axillary in three patients, ipsilateral internal mammary in one patient, and contralateral axillary in two patients. An altered distribution of lymph nodes was discovered in both patients with previous ALND. In one of the two patients, metastases were found in an aberrant lymph drainage basin at the location of a non-ipsilateral axillary node (contralateral axillary SLN). The second previously ALND patient had an internal mammary SLN. In one patient, mapping was unsuccessful and the SLN was not identified.
Conclusions
Altered lymphatic drainage incidence increases following breast-conserving surgery for an initial breast cancer, and the location of SLNs becomes unpredictable at the time of a second primary or recurrent ipsilateral breast cancer. This leads to the necessity of using a radionuclide (lymphoscintigraphy) for a successful re-mapping procedure. A re-SLNB is precise and beneficial even though there are few patients. A lymphoscintigraphy can identify SLNs at their new unpredicted location.
doi:10.1186/1477-7819-12-205
PMCID: PMC4108238  PMID: 25016393
14.  Microscopic Tumor Burden in Sentinel Lymph Nodes Predicts Synchronous Nonsentinel Lymph Node Involvement in Patients With Melanoma 
Journal of Clinical Oncology  2008;26(26):4296-4303.
Purpose
We and others have demonstrated that additional positive lymph nodes (LNs) are identified in only 8% to 33% of patients with melanoma who have positive sentinel LNs (SLNs) and undergo complete therapeutic LN dissection (cTLND). We sought to determine predictors of additional regional LN involvement in patients with positive SLNs.
Patients and Methods
Patients with clinically node-negative melanoma who underwent SLN biopsy (1991 to 2003) and had positive SLNs were identified. Clinicopathologic factors, including extent of microscopic disease within SLNs, were evaluated as potential predictors of positive non-SLNs.
Results
Overall, 359 (16.3%) of the 2,203 patients identified had a positive SLN. Positive non-SLNs were identified in 48 (14.0%) of the 343 patients with positive SLNs who underwent cTLND. On univariate analysis, several measures of SLN microscopic tumor burden, one versus three or more SLNs harvested, tumor thickness more than 2 mm, age older than 50 years, and Clark level higher than III were predictive of positive non-SLNs; primary tumor ulceration and number of positive SLNs had no apparent impact. On multivariable logistic regression analysis, measures of SLN microscopic tumor burden were the most significant independent predictors of positive non-SLNs; tumor thickness more than 2 mm and number of SLNs harvested also predicted additional disease. A model was developed that stratified patients according to their risk for non-SLN involvement.
Conclusion
In melanoma patients with positive SLNs, SLN tumor burden, primary tumor thickness, and number of SLNs harvested may be useful in identifying a group at low risk for positive non-SLNs and be spared the potential morbidity of a cTLND.
doi:10.1200/JCO.2007.15.4179
PMCID: PMC2653121  PMID: 18606982
15.  A New and Simple Predictive Formula for Non-Sentinel Lymph Node Metastasis in Breast Cancer Patients with Positive Sentinel Lymph Nodes, and Validation of 3 Different Nomograms in Turkish Breast Cancer Patients 
Breast Care  2012;7(5):397-402.
Background
Nomogram accuracies for predicting non-sentinel lymph node (SLN) involvement vary between different patient populations. Our aim is to put these nomograms to test on our patient population and determine our individual predictive parameters affecting SLN and non-SLN involvement.
Patients and Methods
Data from 932 patients was analyzed. Nomogram values were calculated for each patient utilizing MSKCC, Tenon, and MHDF models. Moreover, using our own patient- and tumor-depended parameters, we established a unique predictivity formula for SLN and non-SLN involvement.
Results
The calculated area under the curve (AUC) values for MSKCC, Tenon, and MHDF models were 0.727 (95% confidence interval (CI) 0.64–0.8), 0.665 (95% CI 0.59–0.73), and 0.696 (95% CI 0.59–0.79), respectively. Cerb-2 positivity (p = 0.004) and size of the metastasis in the lymph node (p = 0.006) were found to correlate with non-SLN involvement in our study group. The AUC value of the predictivity formula established using these parameters was 0.722 (95% CI 0.63–0.81).
Conclusion
The most accurate nomogram for our patient group was the MSKCC nomogram. Our unique predictivity formula proved to be as equally effective and competent as the MSKCC nomogram. However, similar to other nomograms, our predictivity formula requires future validation studies.
doi:10.1159/000338844
PMCID: PMC3518942  PMID: 24647780
Sentinel lymph node biopsy; MSKCC nomogram; Tenon score; Turkish nomogram; Non-sentinel lymph node metastasis
16.  Molecular Subtype Classification Is a Determinant of Non-Sentinel Lymph Node Metastasis in Breast Cancer Patients with Positive Sentinel Lymph Nodes 
PLoS ONE  2012;7(4):e35881.
Background
Previous studies suggested that the molecular subtypes were strongly associated with sentinel lymph node (SLN) status. The purpose of this study was to determine whether molecular subtype classification was associated with non-sentinel lymph nodes (NSLN) metastasis in patients with a positive SLN.
Methodology and Principal Findings
Between January 2001 and March 2011, a total of 130 patients with a positive SLN were recruited. All these patients underwent a complete axillary lymph node dissection. The univariate and multivariate analyses of NSLN metastasis were performed. In univariate and multivariate analyses, large tumor size, macrometastasis and high tumor grade were all significant risk factors of NSLN metastasis in patients with a positive SLN. In univariate analysis, luminal B subgroup showed higher rate of NSLN metastasis than other subgroup (P = 0.027). When other variables were adjusted in multivariate analysis, the molecular subtype classification was a determinant of NSLN metastasis. Relative to triple negative subgroup, both luminal A (P = 0.047) and luminal B (P = 0.010) subgroups showed a higher risk of NSLN metastasis. Otherwise, HER2 over-expression subgroup did not have a higher risk than triple negative subgroup (P = 0.183). The area under the curve (AUC) value was 0.8095 for the Cambridge model. When molecular subtype classification was added to the Cambridge model, the AUC value was 0.8475.
Conclusions
Except for other factors, molecular subtype classification was a determinant of NSLN metastasis in patients with a positive SLN. The predictive accuracy of mathematical models including molecular subtype should be determined in the future.
doi:10.1371/journal.pone.0035881
PMCID: PMC3338552  PMID: 22563412
17.  Advantages of one step nucleic acid amplification (OSNA) whole node assay in sentinel lymph node (SLN) analysis in breast cancer 
SpringerPlus  2013;2:542.
Background
The purpose of this study is to present our first results of sentinel node analysis (SLN) by one step nucleic acid amplification (OSNA) in routine clinical practice in our centre and compare them with the results of classic histopathological analysis in a historical cohort from our same institution.
Methods
407 patients (total study population) with early breast cancer and no clinical nodal involvement underwent SLN biopsy in our institution. The SLN was analysed by OSNA in 164 biopsies. OSNA results were compared with the conventional histopathology study of 244 patients who had undergone SLN biopsy previously. The characteristics of the patients in both groups were evaluated and a comparison was made of the rate of metastases detected by both methods and of the surgical procedures needed in each group. We also investigated the state of non-sentinel lymph nodes if micrometastases where found in SLN.
Results
SLN biopsy result was considered as positive in 45 patients (28%) in the OSNA group and in 58 in the historical group (24%). There was no difference in the rate of macrometastases (16,5% for OSNA, 20% for HE) but we found differences in the rate of micrometastases (11% for OSNA and 3,6% for HE p = 0.0007). Axillary lymphadenectomy (ALND) was performed in 43/45 cases in the OSNA group and in 51/58 of the historical group. In all patients diagnosed by OSNA, ALND was performed during the initial surgical procedure. In the historical cohort ALND was performed during the initial surgical procedure in 41 patients and in a second surgical procedure in 10 patients. Patients from both groups with micrometastases in the SLN had no metastases in other nodes when the ALND was performed.
Conclusions
OSNA analysis allows the detection of SLN metastases as precisely as conventional pathology with an increased detection of micrometastases. The OSNA method can reduce the need of a deferred lymphadenectomy.
doi:10.1186/2193-1801-2-542
PMCID: PMC3824711  PMID: 24255842
Sentinel lymph node biopsy; Breast cancer; Molecular analysis; Micrometastases
18.  Multiparameter flow cytometry as a tool for the detection of micrometastatic tumour cells in the sentinel lymph node procedure of patients with breast cancer 
Journal of Clinical Pathology  2002;55(5):359-366.
Aim: To investigate whether multiparameter flow cytometry (MP-FCM) can be used for the detection of micrometastasis in sentinel lymph nodes (SLNs) in breast cancer.
Methods: Formalin fixed, paraffin wax embedded sentinel lymph nodes (n = 238) from 98 patients were analysed. For each lymph node, sections for haematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) for cytokeratin (MNF116) were cut at three levels with a distance of 500 μm. The intervening material was used for MP-FCM. Cells were immunostained with MNF116, followed by an incubation with fluorescein isothiocyanate (FITC) labelled goat antimouse immunoglobulin. DNA was stained using propidium iodide. From each lymph node 100 000 cells were analysed on the flow cytometer.
Results: Thirty eight of the 98 patients with breast carcinoma showed evidence of metastatic disease in the SLN by one ore more of the three methods. In 37 of 38 cases where metastatic cells were seen in the routine H&E and/or IHC, more than 1% cytokeratin positive cells were detected by MP-FCM. In 24 patients, metastatic foci were more than 2 mm (macrometastasis) and in 14 these foci were smaller than 2 mm (micrometastasis). In three of these 14 cases, MP-FCM revealed positive SLNs, although this was not seen at first glance in the H&E or IHC sections. After revision of the slides, one of these three remained negative. However, MP-FCM analysis of the cytokeratin positive cells showed an aneuploid DNA peak, which was almost identical to that of the primary breast tumour. Duplicate measurements, done in 41 cases, showed a 99% reproducibility. In five of 14 patients with micrometastasis, one or two metastatic foci were found in the non-SLN. However, in 15 of 24 macrometastases multiple non-SLNs were found to have metastatic tumour. All micrometastases except for the remaining negative one mentioned above showed only diploid tumour cells, despite the fact that their primary tumours contained both diploid and aneuploid tumour cells. In primary tumours with more than 60% aneuploid cells, predominantly aneuploid macrometastasis were found, whereas diploid primary tumours only showed diploid micrometastases or macrometastases in their SLN. Aneuploid SLN macrometastases were associated with non-SLN metastases in five of seven patients, whereas diploid cases showed additional non-SLN metastases in only seven of 16 patients.
Conclusion: In all cases, MP-FCM was sufficient to detect micrometastatic tumour cells in a large volume of lymph node tissue from SLNs. In some cases it was superior to H&E and IHC staining. Approximately 30% of SLN micrometastases are accompanied by additional non-SLN metastases. The size of the aneuploid fraction (> 60%) in the primary tumour may influence the risk of having both SLN and non-SLN metastases.
PMCID: PMC1769646  PMID: 11986342
breast cancer; sentinel node; flow cytometry; double staining
19.  Sentinel Lymph Node Biopsy in the Management of Early-Stage Cervical Carcinoma 
Gynecologic oncology  2011;120(3):347-352.
Objectives
We aimed to determine the sentinel lymph node detection rates, accuracy in predicting the status of lymph node metastasis, and if pathologic ultrastaging improves the detection of micrometastases and isolated tumor cells at the time of primary surgery for cervical cancer.
Methods
A prospective, non-randomized study of women with early-stage (FIGO stage IA1 with lymphovascular space involvement – IIA) cervical carcinoma was conducted from June 2003 to August 2009. All patients underwent an intraoperative intracervical blue dye injection. Patients who underwent a preoperative lymphoscintigraphy received a 99m Tc sulfur colloid injection in addition. All patients underwent sentinel lymph node (SLN) identification followed by a complete pelvic node and parametrial dissection. SLN were evaluated using our institutional protocol that included pathologic ultrastaging.
Results
SLN mapping was successful in 77 (95%) of 81 patients. A total of 316 SLN were identified, with a median of 3 SLN per patient (range, 0-10 SLN). The majority (85%) of SLN were located at three main sites: the external iliac (35%); internal iliac (30%); and obturator (20%). Positive lymph nodes (LN) were identified in 26 (32%) patients, including 21 patients with positive SLN. Fifteen of 21 patients (71%) had SLN metastasis detected on routine processing. SLN ultrastaging detected metastasis in an additional 6/21 patients (29%). Two patients had grossly positive LN at exploration, and mapping was abandoned. Three of 26 (12%) patients had successful SLN mapping; however, the SLN failed to identify the metastatic LN. Of these 3 false negative cases, 2 patients had a metastatic parametrial node as the only positive LN with multiple negative pelvic nodes including negative SLN. One patient with stage IA1 disease and lymphovascular invasion had unilateral SLN mapping and a metastatic common iliac LN identified on completion lymphadenectomy of the contralateral side that did not map. The 4 (5%) patients with unsuccessful mapping included 1 who had grossly positive nodes identified at the time of laparotomy; the remaining 3 occurred during each surgeon's initial SLN mapping learning phase.
Conclusion
SLN mapping in early-stage cervical carcinoma yields high detection rates. Ultrastaging improves micrometastasis detection. Parametrectomy and side-specific lymphadenectomy (in cases of failed mapping) remain important components of the surgical management of select cases.
doi:10.1016/j.ygyno.2010.12.334
PMCID: PMC3951119  PMID: 21216450
Sentinel lymph nodes; micrometastasis; cervical cancer
20.  Sentinel lymph node biopsy: technique validation at the Setúbal Medical Centre, Portugal 
ecancermedicalscience  2009;3:124.
Aims:
To evaluate the accuracy of sentinel lymph node biopsy in breast cancer patients at this institution, using combined technetium-99m (99mTc) sulphur colloid and patent blue vital dye.
Methods:
From March 2007 to July 2008, 50 patients with a tumour of less than 3 cm and with clinically negative axillary lymph nodes underwent sentinel lymph node biopsy (SLNB), followed by axillary lymph node dissection (ALND). Sub-areolar 99mTc sulphur colloid injection was performed the day before surgery, and patent blue vital dye was also injected sub-areolarly at least 5 minutes before surgery. Sentinel lymph node was identified during the surgical procedure, using a gamma probe and direct vision. All sentinel nodes underwent frozen section analysis. Later haematoxylin and eosin staining and immunohistochemical analysis were performed. Finally, SLNB was compared with standard ALND for its ability to accurately reflect the final pathological status of the axillary nodes.
Results:
The sentinel lymph node (SLN) was identified in 48 of 50 patients (96%). The number of sentinel lymph nodes ranged from one to four (mean 1.48) and non-sentinel nodes ranged from seven to 27 (mean 14.33). Of the 48 patients with successfully identified SLNs, 29.17% (14/48) were histologically positive. Sensivity of the SLN to predict axilla was 93.75%; accuracy was 97.96%. The SLN was falsely negative in one patient—6.25% (1/16).
Conclusions:
The SLNB represents a major advance in the surgical treatment of breast cancer as a minimally invasive procedure predicting the axillary lymph node status. This validation study demonstrates the accuracy of the SLNB and its reasonable false negative rate when performed in our institute. It can now be used as the standard method of staging in patients with early breast cancer at this institution.
doi:10.3332/ecancer.2008.124
PMCID: PMC3224010  PMID: 22275996
21.  Histologic evaluation of sentinel and non-sentinel axillary lymph nodes in breast cancer by multilevel sectioning and predictors of non-sentinel metastasis 
Gland Surgery  2014;3(1):2-13.
Sentinel lymph node (SLN) provides accurate nodal staging for breast cancer. This technique has been introduced in Siriraj Hospital since 1998. The goal of this study is to assess its accuracy in predicting the state of the axilla, and compare the results of standard examination and multilevel sectioning. A retrospective analysis of 195 breast cancer patients who underwent both SLN biopsy (using dye alone as the lymphatic mapping) and axillary node dissection during 1998-2002 were analyzed. All slides including SLNs and the non-SLNs (NSLNs) were reviewed and multilevel study was performed on all SLNs and NSLNs [four levels of hematoxylin-eosin (HE) at 200 µm interval and keratin stains on the first and fourth levels]. Of 195 patients, 30% of cases were SLN-positive (32 NSLN-positive and 27 NSLN-negative). Additional study could detect positive axillary nodes 10.8% (4 SLN-positive and 5 NSLN-positive) more than standard HE stain. The false negative rate increased from 20.3% to 24.1%. The concordance between SLN and NSLN statuses was 89.7%. The sensitivity was 75.9%. By multivariate analysis, the significant predictors for axillary node metastasis were tumor size of more than 2.2 cm, histologic type of invasive ductal carcinoma (IDC), not otherwise specified (NOS) and lymphovascular invasion (LVI). By univariable analysis, the significant predictors of NSLN metastasis after positive-SLN were outer location of the tumor, LVI and perinodal extension. In conclusion, use of multilevel and immunohistochemistry increased detection of positive-SLNs. Caution should be kept in accepting SLN biopsy using peritumoral dye technique alone as the procedure for staging due to a high false-negative rate. The concordance rate of 89.7% confirmed the reliability of SLN. Outer location of tumor, LVI and perinodal extension is significant predictors of positive-NSLN after positive-SLN.
doi:10.3978/j.issn.2227-684X.2014.02.01
PMCID: PMC4115770  PMID: 25083488
Breast cancer; immunohistochemistry study; mutilevel study; non-sentinel lymph node (NSLN); sentinel lymph node (SLN)
22.  Factors affecting metastases to non-sentinel lymph nodes in breast cancer 
Journal of Clinical Pathology  2004;57(1):73-76.
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.
PMCID: PMC1770170  PMID: 14693840
metastasis; breast cancer; sentinel node
23.  Whole sentinel lymph node analysis by a molecular assay predicts axillary node status in breast cancer 
British Journal of Cancer  2012;107(8):1239-1243.
Background:
The one-step nucleic acid amplification (OSNA) assay is a rapid procedure for the detection of lymph node (LN) metastases using molecular biological techniques. The aim of this study was to assess the reliability of the whole sentinel lymph node (SLN) analysis by the OSNA assay as a predictor of non-SLN metastases.
Methods:
Consecutive 742 patients with breast cancer were enroled in the study. The association of non-SLN or ⩾4 LN metastases with clinicopathological variables was investigated using multivariate logistic analysis.
Results:
In total, 130 patients with a positive SLN who underwent complete axillary LN dissection were investigated. The frequency of non-SLN metastases in patients who were OSNA+ and ++ was 19.3% and 53.4%, respectively, and that in patients with ⩾4 LN metastases who were OSNA+ and ++ was 7.0% and 27.4%, respectively. The cytokeratin 19 (CK19) mRNA copy number (⩾5.0 × 103; OSNA++) in the SLN was the most significant predictors of non-SLN metastases (P=0.003). The CK19 mRNA copy number (⩾1.0 × 105) in the SLN was the only independent predictor of ⩾4 LN metastases (P=0.014).
Conclusion:
Whole SLN analysis using the OSNA assay could become a valuable method for predicting non-SLN and ⩾4 LN metastases.
doi:10.1038/bjc.2012.387
PMCID: PMC3494436  PMID: 22929881
breast cancer; whole sentinel lymph node; one-step nucleic amplification assay; non-sentinel lymph node
24.  Axillary lymph node dissection for sentinel lymph node micrometastases may be safely omitted in early-stage breast cancer patients: long-term outcomes of a prospective study 
Objectives
To evaluate the long-term disease-free and overall survival of patients with sentinel lymph node (SLN) micrometastases, in whom a completion axillary lymph node dissection (ALND) was systematically omitted.
Background
The use of step sectioning and immunohistochemistry for SLN analysis results in a more accurate histopathologic examination and a higher detection rate of micrometastases. However, the clinical relevance and therapeutic implications of SLN micrometastases remain a matter of debate.
Methods
In this prospective study, 236 SLN biopsies were performed in 234 consecutive early-stage breast cancer patients (T1, T2 ≤ 3 cm, cN0 M0) between 1998 and 2002. The SLN were examined by step sectioning and stained with hematoxylin and eosin and immunohistochemistry. None of the patients with negative SLN or SLN micrometastases (International Union Against Cancer classification, >0.2 to ≤ 2 mm) underwent a completion ALND or radiation to the axilla. Long-term overall and disease-free survivals were compared between patients with negative SLN and those with SLN micrometastases by log rank tests.
Results
The SLN was negative in 55% of patients (123 of 224). SLN micrometastases were detected in 27 patients (27 of 224, 12%). After a median followup of 77 months (range, 24–106 months), neither locoregional recurrences nor distant metastases occurred in any of the 27 patients with SLN micrometastases. There were no statistically significant differences for overall (P = 0.656), locoregional (P = 0.174), and axillary and distant disease-free survival (P = 0.15) between patients with negative SLN and SLN micrometastases.
Conclusions
This analysis of unselected patients provides evidence that a completion level I and II ALND may be safely omitted in early-stage breast cancer patients with SLN micrometastases.
doi:10.1007/s13193-010-0013-y
PMCID: PMC3420993  PMID: 22930620
25.  Sentinel lymph node biopsy is unsuitable for routine practice in younger female patients with unilateral low-risk papillary thyroid carcinoma 
BMC Cancer  2011;11:386.
Background
Sentinel lymph node (SLN) biopsy has been used to assess patients with papillary thyroid carcinoma (PTC). To achieve its full potential the rate of SLN identification must be as close to 100 percent as possible. In the present study we compared the combination of preoperative lymphoscintigraphy scanning by sulfur colloid labeled with 99 m Technetium, gamma-probe guided surgery, and methylene blue with methylene blue, alone, for sentinel node identification in younger women with unilateral low-risk PTC.
Methods
From January 2004 to January 2007, 90 female patients, ages 23 to 44 (mean = 35), with unilateral low-risk PTC (T1-2N0M0) were prospectively studied. Mean tumor size was 1.3 cm (range, 0.8-3.7 cm). All patients underwent unilateral modified neck dissection. Prior to surgery, patients had, by random assignment, identification and biopsy of SLNs by methylene blue, alone (Group 1), or by sulfur colloid labeled with 99 m Technetium, gamma-probe guided surgery and methylene blue (Group 2).
Results
In the methylene blue group, SLNs were identified in 39 of 45 patients (86.7%). Of the 39 patients, 28 (71.8%) had positive cervical lymph nodes (pN+), and 21 patients (53.8%) had pSLN+. In 7 of the 28 pN+ patients (25%), metastases were also detected in non-SLN, thus giving a false-negative rate (FNR of 38.9% (7/18), a negative predictive value (NPV) of 61.1% (11/18), and an accuracy of 82.1% (32/39). In the combined technique group, the identification rate (IR) of SLN was 100% (45/45). Of the 45 patients, 27 (60.0%) had pN+, 24 (53.3%) had pSLN+. There was a FNR of 14.3% (3/21), a NPV of 85.7% (18/21), and an accuracy of 93.3% (42/45). The combined techniques group was significantly superior to the methylene blue group in IR (p = 0.035). There were no significant differences between two groups in sensitivity, specificity, NPV, or accuracy. Location of pN+ (55 patients) in 84 patients was: level I and V, no patients; level II, 1 patient (1.2%); level III, 6 patients (7.2%); level III and IV, 8 patients (9.5%); level IV, alone, 8 patients (9.5%); level VI, 32 patients (38.1%). In all 90 patients, IR of SLN was 93.3%, FNR, 25.6%, NPV, 74.4%, and accuracy rate, 88.1 percent.
Conclusions
Compared to a single technique, there was a significantly higher SLN identification rate for the combined technique in younger female with ipsilateral, low-risk PTC (T1-2N0M0). Thus, a combined SLN biopsy technique seems to more accurately stage lymph nodes, with better identification of SLN located out of the central compartment. Regardless of the procedure used, the high FNR renders the current SLN techniques unsuitable for routine practice. Based on these results, prophylactic node dissection of level VI might be considered because 38.1% of our patients had such node metastases.
doi:10.1186/1471-2407-11-386
PMCID: PMC3224365  PMID: 21888655

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