| Japanese Journal of Clinical Oncology | Pages |
Sentinel Node Biopsy Guided by Indocyanin Green Dye in Breast Cancer Patients
Introduction
Patients And Methods
Patients
Methods
Results
Discussion
Acknowledgments
References
Sentinel Node Biopsy Guided by Indocyanin Green Dye in Breast Cancer Patients
Background: We aimed to evaluate whether dye-guided sentinel node biopsy is a useful indicator of axillary node involvement in breast cancer patients and whether clinicopathological features affect its success in identifying sentinel nodes. Methods: Sentinel node biopsy was performed in patients with stage I or II breast cancer using an indocyanin green dye-guided method. Results: We could identify sentinel nodes in 127 (73.8%) of 172 patients. The mean number of sentinel nodes per patient was 1.7 (range, 1-8) and the mean node size was 9.3 mm (range, 3.0-28.0 mm). Of the 127 patients, 40 (31.5%) also had axillary node involvement. In 16 (40.0%) of these, the sentinel node was the only node involved. There was concordance between sentinel node and axillary node status in 122 (96.1%) of the 127 patients. Success in identifying sentinel nodes was not affected by tumor size, operative procedure, histological type of tumor or tumor location; however, the success rate was significantly lower in patients with axillary node involvement (65.7 vs 79.0% in axillary node-negative patients, p = 0.039) and the presence or absence of lymphatic or vascular invasion in the tumor (63.8 vs 78.9% in patients without lymphatic or vascular invasion, p = 0.043). Sentinel nodes could also be identified significantly more frequently in patients under 50 years old (83.3%) than in those over 50 years old (64.8%, p = 0.009). Conclusions: Sentinel node biopsy guided by indocyanin green dye is an easy technique with an acceptable success rate in detecting sentinel nodes and predicting axillary nodal status. Axillary node status, the presence or absence of lymphatic or vascular invasion in the tumor and patient age affect its success in identifying sentinel nodes.
Key words: sentinel node - breast cancer - axillary lymph node dissection - staging
INTRODUCTION
Axillary lymph node status is still the most important prognostic factor in breast cancer and is a primary determinant for the use of systemic adjuvant therapy. Because there is no non-surgical alternative for staging, complete axillary lymphadenectomy remains the `gold standard' despite carrying a high risk of morbidity (1-3).
Sentinel node biopsy (SNB) was initially developed to identify regional lymphatic metastases from a primary cutaneous melanoma (4). This technique is based on the concept that the sentinel node is the first axillary lymph node draining the lymph from a primary tumor. Giuliano et al. (5) extended this technique to breast cancer using a blue dye injected at the breast tumor site and demonstrated that it was both feasible and practical. In their initial trial of intraoperative lymphatic mapping and sentinel lymphadenectomy, sentinel nodes were detected in only 114 (65.5%) of the 174 patients; however, the sentinel node status accurately predicted the axillary status of 109 (95.6%) of these patients. In a subsequent study, sentinel nodes were identified in 100 (93.5%) of 107 patients using a dye-guided method alone (6). The authors pointed out that there was a definite learning curve, as the rate of detection of sentinel nodes increased with the surgeon's experience. They also stressed that the timing of the dye injection and the positioning of the injection needle are important in ensuring successful detection of sentinel nodes.
The aim of this study was to investigate whether dye-guided SNB is a useful indicator of axillary node involvement in breast cancer patients and whether there are any associations between various clinicopathological features and the success of a dye-guided method in identifying sentinel nodes in such patients.
PATIENTS AND METHODS
Patients
The subjects were patients with stage I or II breast cancer according to UICC criteria and were studied between December 1997 and October 1998. All patients were diagnosed as having breast cancer by fine-needle aspiration biopsy. Women with multiple primary tumors, non-palpable breast cancer, prior excisional biopsy or axillary surgery or pregnancy were excluded. Informed consent was obtained from all patients.
Methods
SNB was performed as described by Giuliano et al. (5) with minor modifications. In brief, 5 ml of indocyanin green (Diagnogreen 0.5%; Daiichi Pharmaceutical, Nihonbashi, Tokyo) was injected into the breast parenchyma surrounding the primary tumor. In order to identify stained lymph nodes, a transverse incision was made just below the hair-bearing region of the axilla 10 min after dye injection. In patients who subsequently underwent breast conserving surgery, axillary dissection and partial excision of the breast were carried out through a separate incision. In patients who required a mastectomy, the standard skin incision was made and skin flaps were dissected before SNB. Blunt dissection was then performed until a green-stained lymphatic tract or sentinel node was identified. The dye-filled tract was dissected to the first green lymph node. After SNB, axillary lymph node dissection (ALND) was carried out in all subjects. Sentinel node and complete ALND specimens were examined separately and the incidence of metastases was compared. Sentinel nodes were serially sectioned at 2 mm intervals. One level of non-sentinel nodes was examined. All sections were paraffin-embedded and stained with hematoxylin and eosin.
Clinicopathological features, such as patient age, tumor size, axillary lymph node status, the presence or absence of lymphatic or vascular invasion in the tumor, operative procedure, histological type of tumor according to the histological classification of the World Health Organization and tumor location, were recorded and used to determine whether there were any significant associations with the success of SNB in identifying sentinel nodes.
Fisher's exact test was used to evaluate the significance of any relationships between clinicopathological features and the success of SNB in identifying sentinel nodes. Differences were considered to be significant when p < 0.05.
RESULTS
One hundred and seventy-two consecutive women with operable T1/T2 primary breast cancer took part in this study. Their median age was 51 years (range 28-75 years). The median pathological tumor size was 2.1 cm (range 0.5-5.0 cm). Ninety-six women (55.8%) had T1 lesions and 76 (44.2%) had T2 lesions. Breast-conserving surgery was performed in 69.2% of the patients.
Sentinel nodes were successfully identified in 127 (73.8%) of the 172 patients. The mean number of sentinel nodes per patient was 1.7 (range, 1-8) and the mean node size was 9.3 mm (range, 3.0-28.0 mm). Of the 127 patients with sentinel nodes, 40 (31.5%) had a tumor-positive SNB specimen. In 16 (40.0%) of these 40 patients, the sentinel node was the only node involved (Table 1). Of the 87 patients who had negative sentinel nodes, all axillary nodes were negative in 82 cases (95.0%). The remaining five patients with disease-free sentinel nodes were tumor-positive in other axillary nodes. Thus, in patients with negative sentinel nodes, the negative predictive value was 94.3% (82/87) and there was concordance between sentinel node and axillary node status in 122 (96.1%) of the 127 patients. The false-negative rate was 11.1% (5/45).
Table 1. Sentinel node status versus non-sentinel node status
| Sentinel nodes | Non-sentinel nodes | ||
| Positive | Negative | Total | |
| Positive | 24 | 16 | 40 |
| Negative | 5 | 82 | 87 |
| Total | 29 | 98 | 127 |
Table 2 shows the clinicopathological features and success rate of SNB in identifying sentinel nodes. Tumor size, operative procedure and histological type of tumor did not affect the successful identification of sentinel nodes. However, the success rate was significantly (p = 0.039) higher in patients without (79.0%) than with axillary node involvement (65.7%). The success rate was also significantly associated with the presence or absence of lymphatic or vascular invasion in the tumor (p = 0.043) and patient age (p = 0.009). The sentinel node detection rate was higher in patients without (78.9%) than with lymphatic or vascular invasion in the tumor (63.8%). The sentinel node detection rate was higher (83.3%) in patients under 50 years old than in those over 50 years old (64.8%).
Table 2. Clinicopathological features and success rate of identifying sentinel nodes
| Clinicopathological features | No. of cases examined | No. of sentinel node indentified cases | Success rate (%) | p Value |
| Age | ||||
| [ge]50 years old | 88 (51.2%) | 57 | 64.8 | 0.009 |
| <50 years old | 84 (48.8%) | 70 | 83.3 | |
| Lymph node status | ||||
| Positive | 67 (39.0%) | 44 | 65.7 | 0.039 |
| Negative | 105 (61.0%) | 83 | 79.0 | |
| Lymphatic or vascular | ||||
| invasion | ||||
| Positive | 58 (33.7%) | 37 | 63.8 | 0.043 |
| Negative | 114 (66.3%) | 90 | 78.9 | |
| Size | ||||
| >2 cm | 76 (44.2%) | 54 | 71.1 | >0.05 |
| <2 cm | 96 (55.8%) | 73 | 76.0 | |
| Operative procedure | ||||
| Conservation | 119 (69.2%) | 92 | 77.3 | >0.05 |
| Mastectomy | 53 (30.8%) | 35 | 66.0 | |
| Histological type of tumor | ||||
| Intraductal carcinoma | 27 (15.7%) | 23 | 85.2 | >0.05 |
| Invasive ductal carcinoma | 135 (78.5%) | 97 | 71.9 | |
| Others | 10 (5.8%) | 7 | 70.0 |
Table 3 shows the tumor location according to the breast quadrant and success in identifying sentinel nodes. Success rates in identifying sentinel nodes were 72.2% (104/144) for tumors in the upper quadrants and 83.3% (20/24) for those in the lower quadrants. This difference was not significant. Success rates were 74.8% (92/123) for tumors in the outer quadrants and 71.1% (32/45) for those in the inner quadrants. Again, the difference was not significant.
Table 3. Tumor location and success rate of identifying sentinel nodes
| Quadrant of breast | No. of cases examined | No. of sentinel node identified cases | Success rate(%) |
| Upper outer | 107 | 79 | 73.8 |
| Upper inner | 37 | 25 | 67.6 |
| Lower outer | 16 | 13 | 81.3 |
| Lower inner | 8 | 7 | 87.5 |
| Central | 4 | 3 | 75.0 |
DISCUSSION
The sentinel node is defined as the first node in the regional lymphatic basin that drains a primary tumor. Krag et al. (7) were the first to report gamma probe-guided sentinel lymphadenectomy. They were able to identify sentinel nodes in 18 (82%) of 22 patients and the sentinel node accurately reflected the tumor stage in the axilla in all cases. Giuliano et al. (5) then reported dye-guided lymphatic mapping. They identified sentinel nodes in 114 (65.5%) of 174 patients, but stressed that both the timing of the dye injection and the positioning of the injection needle may influence the rate of detection of sentinel nodes. In their study, sentinel nodes predicted the axillary status in 109 (95.6%) cases. Here we present the results of SNB using indocyanin green dye in 172 patients. Indocyanin green is a popular diagnostic reagent and is readily available. It rarely produces side effects and we observed no allergic reactions during the study. Sentinel nodes were found in 73.8% of patients and the tumor status of the sentinel nodes accurately predicted axillary node status in 96.1%. These results are similar to those in initial reports by Giuliano et al., suggesting that indocyanin green is useful in identifying sentinel nodes.
Veronesi et al. (8) reported the results of SNB guided by scintigraphic images and a gamma probe. A sentinel node was identified in 371 (98.7%) of 376 patients and axillary lymph node status was predicted with success in 359 (96.8%). The authors stated that using the lymphoscintigraphic technique made it easy to locate nodes and therefore dissection was quick and consistently successful. Albertini et al. (9) reported successful lymphatic mapping in 57 (92%) of 62 patients using a combination of a dye and a gamma probe, with 100% correct prediction of staging. They claimed that the addition of a radiocolloid increased the rate of identification from 73 to 92%. Cox et al. (10) also concluded that the use of these two techniques in combination yielded greater success in lymphatic mapping. They found that SNB using dye alone allowed the identification in approximately 70-80% of patients and that adding a radiocolloid improved the detection rate. It is therefore certain that the combination of dye and radiocolloid will become more commonly used in SNB.
A critical issue in the present study is the high false-negative rate of 11% for SNB using dye only. There are several reasons for these false-negative results. One may be that some of the sentinel nodes are missed. Krag et al. (11) reported that 3% of the positive sentinel nodes in their series of patients were in non-axillary locations and that such nodes could not be identified with dye alone. They also commented that it was difficult to determine whether or not multiple sentinel nodes were present when using dye only. The addition of radiocolloid has been found to increase the mean number of sentinel nodes located, compared with dye alone (9) and several studies have indicated a low false-negative rate when a combination of dye and radiocolloid (9,10). A combined procedure should also be useful in decreasing the false-negative rate for SNB.
Barnwell et al. (12) reported that sentinel nodes were difficult to identify in patients with inner-quadrant tumors. In this study, we successfully identified sentinel nodes regardless of tumor size, operative procedure, histological type of tumor or tumor location. On the other hand, the success rate was significantly lower in patients with axillary node involvement. The presence of tumor in the lymph nodes may interfere with their ability to take up the dye. Furthermore, another reason for false-negative results may be a change in lymphatic flow by tumor cell embolism in the lymphatics. Patient age also influenced our success in identifying sentinel nodes. Krag et al. (11) also reported that failure to identify sentinel nodes was more common in patients aged 50 years or older, probably because the capacity of lymph nodes to retain radiocolloid may be lower, as lymph nodes are replaced by fat in older people. Indocyanin green dye may possess the same characteristics as radiocolloid in this respect.
In summary, we identified sentinel nodes in 127 (73.8%) of 172 patients using indocyanin green dye alone and found concordance between the sentinel node and axillary node status 122 (96.1%) of these 127 patients. These results suggest that sentinel node biopsy guided by indocyanin green dye is a simple technique with an acceptable success rate in predicting axillary node status. Axillary node status, the presence or absence of lymphatic or vascular invasion in the tumor and patient age affected the success rate of this technique in identifying sentinel nodes.
Acknowledgments
This study was presented at and received an award for excellence at the 25th Meeting of the Japanese Society for Cancer and Lymph Node Research. This study was supported in part by a grant-in-aid from the Ministry of Health and Welfare of Japan (No. 10-3).
References
Received July 5, 1999; accepted September 6, 1999
For reprints and all correspondence: Kazuyoshi Motomura, Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan
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