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10.1245/s10434-006-9232-4
Annals of Surgical Oncology 14:621-626 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Value of the Sentinel Lymph Node Procedure in Patients With Large Size Breast Cancer

Loic Lelievre, MD1, Gilles Houvenaeghel, MD1, Max Buttarelli, MD1, Isabelle Brenot-Rossi, MD2, Laetitia Huiart, MD3, Agnes Tallet, MD4, Carole Tarpin, MD5 and Jocelyne Jacquemier, MD6

1 Department of Surgery, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France
2 Department of Nuclear Medicine, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France
3 Department of Oncogenetics, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France
4 Department of Radiation Oncology, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France
5 Department of Medical Oncology, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France
6 Department of Pathology, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, Marseilles, France

Correspondence: Address correspondence and reprint requests to: Loic Lelievre, MD; Département de Chirurgie, Chirurgie Oncologique 2, Institut Paoli-Calmettes, 232 Bd Sainte Marguerite, 13009 Marseille, France; E-mail: lelievrel{at}marseille.fnclcc.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Widely used in routine for small breast cancers, the sentinel lymph node (SN) biopsy is still discussed in tumors ≥ 3 cm.

Methods: From 2000 to 2005, 152 patients with invasive breast tumor pT ≥ 3 cm had a SN biopsy systematically followed by complete level I/II axillary dissection. Surgery was always the first stage of the treatment. Detection was done after injection of radioisotope followed by a lymphoscintigraphy and injection of Patent Blue. The SN procedure systematically included palpation of the axilla with removal of any enlarged (>1 cm) and/or abnormally firm node even if neither blue nor radioactive. The sentinel lymph node status was compared with the final axillary status.

Results: Tumor size ranged from 30 to 200 mm (median 42 mm). Lymphoscintigraphy was positive in 98% of the cases. At least one labeled sentinel node was retrieved in 97.4% of the patients. The median number of SN cleared out was 2 (range 1–9). The false negative risk was 4% (4/99). The false negative risk was not related to the tumor size and not related to the number of SN removed.

Conclusions: This study shows that the SN procedure is feasible in patients with breast tumors ≥ 3 cm with an acceptable false negative risk <5%, similar to false negatives reported for smaller tumors.

Key Words: Breast carcinoma • Large breast cancer • Sentinel lymph node biopsy • Lymphoscintigraphy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The sentinel node (SN) biopsy has been widely accepted in early breast cancer (T0/T1) with no evidence of lymph node involvement (N0).1,2 Consensus conferences have recommended each surgeon should perform at least 30 procedures followed by level I/II axillary lymph node dissection (ALND) with a detection rate > 90% and a false negative rate <5% before using the technique in routine (i.e. with no complementary ALND).3 The value of the sentinel lymph node biopsy has been established in numerous studies,4 including a randomized mono-centric study.5 The main benefits of the procedure include a better pathological assessment of the lymphatic involvement due to the small number of nodes being analyzed and a decreased morbidity in case of no ALND.5–7 10 to 20% of invasive breast tumors are > T1 at diagnosis.8 In these tumors, the lymphatic spread can be estimated at approximately 50% (pT2) up to 80% (pT3).9 Hence a substantial amount of patients with large breast cancers could benefit from the SN biopsy.

The aim of this study was to evaluate the reliability of the sentinel node biopsy in large breast tumors ≥ 3 cm.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
From March 1999 to October 2005, 1022 patients with needle biopsy-proven non inflammatory primary invasive carcinoma or large ductal carcinoma in situ of the breast TNM classification T0, T1, T2 ≤ 3cm, N0, Mx had a sentinel lymph node procedure at the time of the surgical treatment. Surgical treatment was the first level of therapeutics. An additional ALND was systematically carried out in the 152 patients with pathologically confirmed invasive tumor ≥ 3 cm, whatever the SN status. This latter subset of patients represents the study group; all histological invasive carcinoma subtypes were allowed.

A re-intervention for complementary ALND was performed if the tumor size ≥ 3 cm could not be determined intra-operatively.

This standard of care was in accordance with accepted recommendations on the use of the sentinel lymph node procedure in breast cancer3 and has been approved by our institutional breast committee.

Patients were informed of the protocol and an individual consent was obtained. Patient characteristics and tumor characteristics (location, TNM classification, pathological findings) were prospectively recorded and treated in accordance with the French legislation (Commission Nationale Informatique et Liberté).

Pre-Operative Lymphoscintigraphy
Lymphoscintigraphy was performed the day before surgery by intradermal and intraparenchymal injection of 37 MBq (1 mCi) 99mTc-sulfur colloid (Nanocis; Schering) in 0.4 mL physiologic saline, divided in 4 equal doses. The injections were administered above and around the tumor or biopsy site at a distance of <1 cm. After injection of the radiolabeled colloid, the breast was massaged gently for approximately 5 min to improve the lymphatic drainage. Early planar views were obtained over 10 min to identify dominant lymphatic channels and delayed images were acquired 2–4 h after tracer injection. Static anterior and lateral views were obtained during a 5-min period using a single-head gamma camera (SP6 Elscint; General Electric) with a low-energy high-resolution collimator. A second injection of radiocolloid was administered if no lymphatic node was visualized 2h after the first injection. A skin mark was done on the SN projection and the location was confirmed using of a hand-held {gamma}-probe (Neoprobe 2000; MDS Nordion). A diagram showing the location of the SN(s) was sent to the surgeon.

Intra-operative SN Detection
After induction of general anesthesia, 2 mL of Patent Blue dye (Bleu Patenté V 2.5% sodique, Guerbet, Roissy, France) were injected into the peritumoral (up to 2005) or subareolar site (from January 2005 onwards, 18 patients of the study group). A 5-mn gentle breast massage was then performed. After removal of the breast tumor, the SN detection was carried out with a hand-held {gamma}-probe (Neoprobe 2000; MDS Nordion) and the visual guidance of the blue dye. Exploration only included the ipsilateral axillary basin. All the blue nodes were removed as well as the radioactive nodes counting at least 10-fold above the background radiation levels. Identified as SNs, these nodes were sent individually for histological evaluation with information concerning blue dye uptake and ex-vivo radioactivity count. Finally, palpation of the open axilla was systematically performed as part of the procedure so as to detect and remove enlarged (>1 cm) and/or abnormally firm tracer negative nodes.

Complete Axillary Lymph Node Dissection (ALND)
Level I/II ALND was systematically performed in patients whose tumor measured ≥ 3 cm. A re-intervention for ALND was performed in case of tumor size intra-operatively <3 cm and ≥ 3 cm at final examination.

Pathologic Processing
Tumor size and margins were evaluated intra-operatively after frozen sectioning. SNs were analysed by intra-operative imprint cytology in all cases and frozen section only in case of doubt and long axis ≥ 5 mm. Further SN analysis included serial sectioning of the whole node after formalin fixation and paraffin embedding. Every section of 150 µm (approximately 6) was stained with hematoxylin–eosin, with the adjacent section stained with anticyto-keratin antibodies (KL1; Immunotech France) for the detection of micrometastases (≤2 mm) and isolated tumor cells (≤ 0.2 mm). From 2003, ten 200 µm-wide interval sections were performed. Standard hematoxylin–eosin staining was used to analyze the non-sentinel nodes (NSN). Tumor size and surgical margins were definitely assessed after formalin fixation and paraffin embedding.

Analysis
For each patient, age and tumor characteristics (location, TNM stage, histology, pT, grade, lympho-vascular invasion, hormonal receptivity, SN status and NSN status ) were prospectively recorded.

Relative risks are presented with their 95% confidence interval (CI). Factors influencing the false negative risk have been studied by univariate analysis performed by the Fisher’s exact test and the Mann-Whitney’ test, a P value of 0.05 considered significant. Calculations were performed using SPSS software version 13 for Windows (SPSS, Inc.).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
During the study period, 152 patients with tumor pT ≥ 3 cm (T2 ≤ 3 cm at clinical examination, N0) underwent the procedure (study group). The characteristics of patients, tumors, and SN detection are summarized in Table 1Go.


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  		TABLE 1. Characteristics of the 152 study patients
 
Intra-operative Detection
Intra-operative detection of blue and/or radio-labeled sentinel node(s) has been successful in 148 patients (97.4%) (Table 1Go).

This detection was 78.9% with the blue dye only (120/152 patients), 96.7% with the isotopic method (146/151), and 97.4% with the combined method (147/151).

False negatives (Tables 2Go and 3Go)
An axillary node involvement has been observed in 102 patients (67.1%), of whom 99 had labeled SN retrieved. No hot or blue stained metastatic node was found in 10 of them. Hence the false negative risk of the isotopic/blue dye method was 10.1% (10/99, 95% CI [4.2;16]). However, 6 of these patients had enlarged (> 1 cm) and/or firm metastatic node(s) found at axillary palpation after removal of all the blue and/or hot nodes, so the false negative risk of the entire procedure including palpation of the axilla was 4% (4/99, 95% CI [1.11;10.02]). The number of SN removed has no effect on false negatives: the risk was 3.1% (2/64) in the 104 patients with ≥ 2 SN removed and 3.5% (1/28) in the 44 patients with ≥ 3 SN removed.


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  		TABLE 2. Accuracy of the SN procedure
 

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  		TABLE 3. False negatives of the marking methods (isotopic method and blue dye)
 
Tumor size did not appear as a risk factor for false negatives. In the subset of patients with tumors between 30 and 40 mm, the false negative risk of the entire procedure was 3.7% (2/54). This risk was 4.4% (3/67) in patients with tumors measuring 30 to 50 mm, and 2.7% (1/36) in patients with tumors >50 mm.

When comparing false negatives (FN) of the marking technique (cases with no blue and/or radioactive node retrieved, n = 10) with true positives (TP), no significant difference has been found as to the hormonal status (RH+: 9/10 versus 75/89, P = 1.00), the lympho-vascular space invasion (LVSI: 4/10 versus 35/89, P = 1.0), the tumor grade (grade 2–3: 8/10 versus 71/89, P = 1.00), or the tumor location (upper outer quadrant: 4/10 versus 39/89, P = 1.00). The histological sub-type did not significantly affect the risk (lobular : 4/10 versus 15/87 respectively, P = 0.10). In addition, the mean pT size was not significantly different with a mean tumor size of 41.3 mm (SD 12.17) in the FN group versus 52 mm (SD 27.65) in the TP group (P = 0.354).

Non-sentinel Lymph Node Involvement
We observed 89 procedures with metastatic blue and/or radio-labeled SN(s), including one i+ SN. At least one positive non-sentinel node (NSN) was retrieved at complementary axillary lymph node dissection (ALND) in 39.8% of these patients. In 13.6% of the cases, only one non-sentinel node was involved. The SN metastatic spread was mi+ or i+ in 28 cases, of whom 20 had no non-sentinel node involvement (71.4%), 4 had one positive non-sentinel node (14.2%), one patient had 2 NSN+, one patient 3 NSN+, one patient 4 NSN+, and one patient had 5 NSN+.

Intra-operative Pathological Examination
Intra-operative pathological examination of the surgical specimen accurately predicted the tumor size in 22.5% of the cases. The error was ≤ 10 mm in 49% of the cases.

The sensitivity, specificity, positive and negative predictive values, and the precision of the intra-operative examination of the labeled SNs to predict their involvement were respectively: 46.5%, 96.6%, 95.3%, 55.2%, and 66.8%. The SN was falsely positive at intra-operative exam in two patients, and in one case, positive NSN were retrieved at completion ALND (false negative procedure).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We observed a labeled SN detection rate and an overall risk of false negatives of 97.4% and 4%, respectively. This is consistent with the detection and false negative rates reported by Bedrosian et al. in 56 patients with tumors ≥ 30 mm, respectively 98% and 3%.10 Similar results are achieved with smaller tumors for which the technique is used in routine.11 As the risk of nodal involvement increases in relation to the pT stage, approximately 50% for pT2 and 80% for pT3 tumors,9 palpation of the open axilla must be part of the procedure to remove any suspicious unmarked nodes. Actually, it has been shown that a massive node involvement can block the route of the tracers to the sentinel node and re-direct them to second echelon nodes.12 Thus, true sentinel nodes may appear tracer negative but abnormally firm or enlarged (>1 cm) at palpation.

We observed no significant difference in clinico-pathological factors (tumor location, histological sub-type, grade, lympho-vascular space involvement, hormonal status) between false negatives of the marking method versus true positives. However our sample size was limited. Few studies report comparison between false negatives (FN) and true positives (TP). Martin RC 2nd et al. recently reported a large multicenter study of 3870 successful SN procedures in T1-T2 N0 patients with 1243 TP and 106 FN.13 These authors found no significant difference as to the histological sub-type between TP and FN, but in multivariate analysis, a number of SNs removed ≥ 2 was associated with less FN results (P < 0.0001), as well as a tumor size ≥ 2.5 cm (P < 0.0066) which is in contradiction with several previous reports.14,15 They suggest that the risk of FN is likely to decrease if the axillary involvement increases. Further studies of factors influencing the risk of FN are needed.

One can argue that benefits of the SN biopsy are limited to small tumors, up to 40 mm,16 for which the risk of node involvement is low, and for which the discovery of a positive node can alter therapy decisions.

On the other hand, the morbidity of ALND is high, whatever the tumor size, with arm swelling in 10 to 15% of the patients, decreased sensation in up to 81%, pain in 30%, numbness in 35 to 70%, stiffness, weakness, and reduced mobility of the arm in 8 to 27% of the cases.17,18 If no ALND after SN biopsy, this morbidity is significantly decreased.5,6 In addition, there is no good correlation between size estimation by clinical examination, mammography and breast ultrasound and pathological pT, especially in case of lobular invasive carcinoma.19 Moreover, our study shows the lack of accuracy of frozen sectioning to evaluate the tumor size intraoperatively. The SN biopsy in routine in large tumors would avoid the re-interventions for complementary level I/II ALND when the decision is only based on the tumor size exceeding the threshold set up by the team.

In this series of patients with tumor pT ≥ 3 cm, the risk of NSN involvement in case of micrometastatic SN (mi+ or i+) was 29.6%. This is consistent with prior studies (18 to 37.5%).4,10,20,21 However, we observed a lesser NSN involvement in case of macrometastatic SN than previously reported, 44.2% (27/61) versus 83.4% to 95.5%.10,21 One explanation could be that their number of patients was smaller.

Imprint/scraping cytology and frozen sectioning for intra-operative examination of the SNs seem equivalent, with accuracy and false negative risk of 79 to 98% and 9 to 52%, respectively for frozen sectioning, and from 77 to 99% and 5 to 70%, respectively, for imprint/scraping cytology.4 The accuracy of intra-operative examination that we observed in this current study is lower (66.8%). In any case, the sensitivity to detect micrometastases remains low.22

The use of the SN biopsy in large tumors can be of interest if the option of neo-adjuvant treatment has been chosen. The best sequence should be to perform the SN biopsy before initiating the treatment so as to discuss the possibility of breast conservation in case of negative SN, to confirm the option of neo-adjuvant therapy in case of positive SN, or to introduce another major prognostic factor. If limited to the SN biopsy, the exploration of the nodal spread should not delay the neo-adjuvant treatment. The role of SN biopsy after neoadjuvant therapy appears of lesser interest as the risk of false negatives is high, 11 to 17%,23–25 and the fact that true negative nodes cannot be differentiated from positive nodes sterilized by the neo-adjuvant treatment.

The SN biopsy does not seem efficient to explore the axillary involvement after chemotherapy in inflammatory carcinomas as false negatives up to 40% (2/5) have been reported.26

In conclusion, other studies are needed to confirm the reproducibility of these results, especially in tumors ≥3 cm at clinical examination. We recommend a learning period for these large tumors before the use of the technique in routine. The SN procedure would avoid the morbidity of ALND like in early breast cancers and allow a better evaluation of the nodal involvement thanks to the few nodes being analyzed. In addition, the SN biopsy could be part of the pre-treatment evaluation before neo-adjuvant therapy.

Received for publication September 1, 2006. Accepted for publication September 1, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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