© 2004 Foundation for Promotion of Cancer Research
Prognosis of Breast Cancer Patients Treated with Sentinel Node Biopsy in Japan
1 Breast Surgery Division and 2 Radiology Division, National Cancer Center Hospital East, 3 Pathology Division, National Cancer Center Research Institute East, Kashiwa, Chiba, and 4 Head and Neck Surgery Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
For reprints and all correspondence: Shigeru Imoto, Breast Surgery Division, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: simoto{at}east.ncc.go.jp
Received April 16, 2004; accepted May 20, 2004
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Sentinel node biopsy predicts accurate pathological nodal staging. The survival of node-negative breast cancer patients should be evaluated between the patients treated with sentinel node biopsy alone and those treated with axillary lymph node dissection.
Methods: Ninety-seven patients with negative axillary nodes underwent sentinel node biopsy immediately followed by axillary lymph node dissection between January 1998 and June 1999 (the ALND group). Since then, if sentinel lymph nodes were negative on the frozen-section diagnosis, 112 patients underwent sentinel node biopsy alone without axillary lymph node dissection between July 1999 and December 2000 (the SNB group). We retrospectively observed the outcome of the two study groups.
Results: Median follow-up was 52 months in all patients. Relapse-free survival rates at 3 years in the ALND and SNB groups were 94% and 93%, respectively. Five of the 112 patients in the SNB group had overt axillary metastases. Three of them with axillary metastases alone were treated with delayed axillary lymph node dissection. These three patients have been free of other events for 3 years after local salvage treatment.
Conclusions: Sentinel node biopsy will emerge as a standard method to diagnose axillary nodal staging for clinically node-negative breast cancer patients.
Key Words: breast cancer • sentinel node biopsy • axillary lymph node dissection • prognosis
Abbreviations: ALND, axillary lymph node dissection • CT, chemotherapy • ER, estrogen receptor • HE, hematoxylin–eosin • IDC, invasive ductal carcinoma • IHC, immunohistochemistry • ILC, invasive lobular carcinoma • NIDC, non-invasive ductal carcinoma • Ps, parasternal • PR, progesterone receptor • SLNs, sentinel lymph nodes • SNB, sentinel node biopsy • Sc, supraclavicular • TAM, tamoxifen • 99mTc, technetium 99m-labeled • UFT, Uracil plus Tegafur
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Axillary lymph node dissection (ALND) remains the standard care in the treatment of early and advanced breast cancer patients (1). ALND can control loco-regional recurrence. The information of pathological nodal status influences the decision-making process regarding adjuvant chemo-hormonal therapy and radiation therapy. The survival of node-positive breast cancer patients may be improved by ALND. However, most patients undergoing ALND suffer from arm morbidity, especially lymphedema. It is unnecessary for node-negative breast cancer patients to undergo ALND. The hypothesis regarding the sentinel lymph nodes (SLNs), which drain the lymphatic vessels from the tumor directly, is unique and simple. Because negative SLNs imply no axillary metastases, unnecessary ALND should be avoided in breast cancer patients with negative SLNs. Since Krag et al. (2) attempted a gamma probe-guided sentinel node biopsy (SNB) in 1993, a large number of feasibility studies have been reported (3). We performed a feasibility study on SNB immediately followed by ALND in 203 cases of stage 0-IIIB-breast cancer between January 1998 and June 1999 (4–6). Subsequently, an observational study for patients with clinically node-negative breast cancer has been in progress. To evaluate the clinical benefit of SNB, we observed the outcome of breast cancer patients who underwent SNB followed by ALND and those treated with SNB alone.
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SUBJECTS AND METHODS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT SELECTION
Three hundred and ninety-one cases were recorded from the SNB database at the National Cancer Center Hospital East from January 1998 to December 2000. The first 203 cases of a feasibility study were recorded between January 1998 and June 1999 and the last 188 cases of an observational study between July 1999 and December 2000. The following cases were excluded from this study: 115 cases with positive SLNs and/or positive non-SLNs, 36 cases with tumors more than 5 cm in diameter, or at stage IIB or beyond, 21 cases of synchronous or metachronous bilateral breast cancer, four cases of double cancer, five cases of benign breast disease at the final pathological diagnosis and one case with SNB failure during the observational study. In our observational study, patients were provided with a thorough explanation regarding lymphatic mapping and SNB, the clinical benefit of SNB, risk of axillary recurrence and arm morbidity after ALND. A written consent was obtained from all patients.
Finally, 97 patients with histologically node-negative breast cancer treated with SNB followed by ALND during the feasibility study (the ALND group) and 112 patients treated with sentinel node biopsy alone during the observational study (the SNB group) were analyzed in the study.
LYMPHATIC MAPPING AND SENTINEL NODE BIOPSY
The feasibility study was approved by the ethics committee of the National Cancer Center Hospital. Our initial experience of SNB in breast cancer was reported using a vital blue dye, indigocarmine (Daiichi Pharmaceutical, Tokyo, Japan) (4). We also investigated radiopharmaceuticals available in Japan to evaluate mammary lymphoscintigraphy (7). We found that technetium 99m-labeled (99mTc)-human serum albumin or 99mTc-tin colloid (Nihon Medi-Physics, Tokyo, Japan) were feasible and reliable for lymphatic mapping of SLNs. Finally, we attempted a combined method using indigocarmine and the double-tracer, a cocktail of 99mTc-human serum albumin and 99mTc-tin colloid.
The day before the surgery, lymphatic mapping was performed using the double-tracer. The double-tracer consisted of 20 to 30 MBq of 99mTc-human serum albumin and 99mTc-tin colloid in each. Approximately 50 MBq of this tracer was injected subcutaneously at one or two sites around the breast tumor or the scar after tumor biopsy. At the delayed image of lymphoscintigraphy, skin marking was made under scintillation scan to identify SLNs as hot spots. In the operation theater, indigocarmine was injected subcutaneously in a dose of 5 ml at two or three sites around the tumor or the scar after tumor biopsy under general anesthesia and the breast was massaged gently. We tried to first identify blue-stained SLNs, and then searched for radioactive SLNs using a gamma-probe (Navigator USSC, USA). Blue-stained or radioactive nodes were examined as SLNs.
PATHOLOGICAL EXAMINATION
Several of the largest SLN slices were examined on intra-operative immediate frozen sections and paraffin-embedded permanent sections with hematoxylin–eosin (HE) staining. The histological concordance between frozen and permanent sections of SLN has been previously reported to be 96% (5). However, detailed analysis of SLNs using serial sectioning and immunohistochemistry (IHC) was not attempted in this series. Pathological diagnosis was made on the basis of primary tumors on paraffin-embedded HE-stained sections. The histologic grade was determined on the basis of the number of mitoses and architectural and cytological atypia by the Bloom and Richardson grading system with modifications (8). Estrogen receptor (ER) and progesterone receptor (PR) in the cytosol fractions were determined by enzyme immunoassay (Otsuka Assay Laboratory, Tokushima, Japan). The higher limit cutoff values in the ER and PR assay were set at 13 and 10 fmol/mg protein, respectively.
ADJUVANT THERAPY AND FOLLOW-UP
Adjuvant chemo-hormonal therapy and radiation therapy were administered for node-negative high-risk breast cancer patients (1). Adjuvant chemotherapy consisted of 100 mg of cyclophosphamide administered orally on day 1 through 14, 40 mg of methotrexate per square meter administered intravenously on days 1 and 8, and 500 mg of 5-fluorouracil per square meter administered intravenously on days 1 and 8 (CMF) every 4 weeks for six courses. Eleven patients in the ALND group preferred to take 400 mg of Uracil plus Tegafur (UFT) administered orally for 2 years. ER-positive and/or PR-positive breast cancer patients were recommended a course of tamoxifen 20 mg administered orally for 5 years. Most patients who underwent partial mastectomy received a 50- or 60-Gy dose of radiation therapy to the conserved breast. Physical examination was performed every 3 months for the first 2 years and every 6 months for the next 3 years. Chest X-ray and mammography were examined biannually, and liver ultrasound and bone scan were examined annually.
STATISTICAL ANALYSIS
The correlation between patient characteristics and SNB was determined using the chi-square test, Fisher's exact probability test or Student's t-test. The relapse-free survival curves were constructed using the Kaplan–Meier product-limit method and the statistical difference was analyzed by the log-rank test. A P value less than 0.05 was considered significant. To evaluate the clinico-pathological prognostic factors, univariate and multivariate analyses were performed using Cox proportional hazard model by StatView (SAS Institute Inc, NC, USA).
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RESULTS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT AND TUMOR CHARACTERISTICS
Patient and tumor characteristics are summarized in Table 1. As the ALND group included patients with relatively large tumors of stage IIA breast cancer, tumor size was significantly smaller in the SNB group. The clinical stage and the type of breast surgery were also different in the two study groups. Eighteen patients in the ALND group failed in SNB; however, ALND following SNB was completed. The mean number of lymph nodes examined in the ALND group was 20. The mean numbers of SLNs identified were 2.1 and 1.9 in the ALND and SNB groups, respectively. When the radioactive parasternal nodes were clearly visualized on the lymphoscintiscan, parasternal SNB was performed through the second or third intercostal approach. Five patients in the SNB group, but none in the ALND group, underwent parasternal SNB. Parasternal SLNs were identified in 3 patients (60%) and proved histologically negative. Tumor characteristics (histologic grade, histologic subtype, lympho-vascular invasion and hormonal receptor status), postoperative breast irradiation and adjuvant chemo-hormonal therapy were not different in the two study groups.
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RELAPSE-FREE SURVIVAL
As of December 2003, of all the patients, 18 (9%) had reported a relapse (Table 2). In the ALND group, five patients had loco-regional recurrence and five had distant metastases. In the SNB group, five patients had loco-regional recurrence and three had distant metastases. Five (4%) of the 112 patients in the SNB group had overt axillary metastases. Axillary recurrence was suspected by physical examination, and subsequently, most cases were examined by ultrasound. Final diagnosis was confirmed by aspiration biopsy cytology. The relapse time since SNB ranged from 3 to 22 months. They were all postmenopausal women. Their age ranged from 52 to 78 years. They had one to four negative SLNs. Tumor size ranged from 2.4 to 4.3 cm. Three patients underwent total mastectomy with SNB. The remaining two patients underwent partial mastectomy with SNB, followed by breast irradiation. A high histologic grade was observed in five cases, lympho-vascular invasion in four and negative hormonal receptor status in two. However, four patients refused to receive adjuvant chemo-hormonal therapy. Three patients without other metastatic sites underwent delayed ALND. One node was involved in two of these three patients, and two nodes were involved in the other patient. They have been free from other events for 3 years after salvage surgery.
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Median follow-up was 52 months in all patients. The relapse-free survival rates at 3 years in the ALND and SNB groups were 94% and 93%, respectively (P = 0.78 by the log-rank test, Fig. 1). The univariate analysis revealed significant prognostic factors: clinical stage IIA, tumor larger than 2 cm in diameter, high histologic grade (grade 3), lympho-vascular invasion and negative hormonal receptor status. However, the high histologic grade and lympho-vascular invasion continued to be statistically significant on multivariate analysis after adjusting for these prognostic factors. The hazard ratio (95% confidence interval; P value) was 3.64 (1.35–9.81; 0.011) for high histologic grade, and 4.06 (1.32–12.5; 0.014) for lympho-vascular invasion.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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In the 56 cases of our final feasibility study of SNB with a combined method of dye and tracer, the identification rate, accuracy and sensitivity of SLNs were 96%, 98% and 96%, respectively (6). Subsequently, we initiated an observational study for patients with clinically negative axillary nodes. Axillary recurrence rate in the SNB group was estimated at 5% or less. The relapse-free survival rate at 3 years after surgery was not different between the two study groups (94% vs 93%). ALND had no survival benefit in node-negative breast cancer as reported in the National Surgical Adjuvant Breast Project trial B04 (9). However, five patients (4%) with negative SLNs had overt axillary metastases in the SNB group. They had high-risk breast cancer. Most of them opted for observation without adjuvant chemo-hormonal therapy. Three patients without distant metastases underwent salvage ALND.
Axillary metastases could have occurred in the SNB group owing to several reasons. First, lymphatic mapping requires an optimal tracer and dye. The tracer, 99mTc-sulfur colloid and 99mTc-colloidal albumin, are commonly used in Western countries, but are not available in Japan. The particles of 99mTc-sulfur colloid and 99mTc-colloidal albumin are appropriate in size for mammary lymphatic mapping (10 to 200 nm). On the other hand, 99mTc-human serum albumin has a very small particle size (5 nm or less), while 99mTc-tin colloid has a very large particle size (500 nm or more) (7). A small particle can permeate the lymphatic vessels rapidly, but goes through the SLN to the secondary nodes (echelon nodes). In some cases, echelon nodes might be misdiagnosed as SLNs. A large particle can be retained in an SLN, but it is too large to migrate through the lymphatic vessels. Hot spots such as SLNs are not visualized under scintillation scan. We found that the double-tracer consisting of 99mTc-human serum albumin and 99mTc-tin colloid had particles of approximately 100 nm in diameter (unpublished data). In the SNB group, hot spots on the lymphoscintigram were visualized in 86 of the 92 patients (93%). However, an unstable particle condition of the double-tracer might result in false lymphatic mapping.
Second, large tumors with a diameter of 3 cm or more may lead to mapping failure. A multicenter validation study of SNB in Japan demonstrated that the accuracy of SNB was 100% in patients with tumors less than 1.6 cm in diameter, in spite of differences in the SNB technique (10). The mean diameter in five cases of axillary metastases was 3.4 cm. Large tumors may have multiple lymphatic channels to the axillary nodes and more than one SLN. Incomplete lymphatic mapping and SNB might leave positive SLNs in the axilla.
Third, the pathological work-up of SLNs in breast cancer is essential for accurate nodal staging. The European Working Group for Breast Screening Pathology reviewed published data to evaluate the accuracy of SLNs (11). They reported that 9–47% of the patients with negative SLNs diagnosed with HE-stained sections were upstaged on the basis of the additional assessment of SLNs with serial sectioning and cytokeratin IHC staining. About 18% of the patients with micrometastasis or isolated tumor cells in SLNs might be associated with further non-SLN metastases. Our routine pathological examination of SLNs was based on the HE-stained frozen- and permanent-sections at one-level. The histological concordance between frozen- and permanent-sections of SLNs was 96% (5). However, micrometastasis in SLNs might be overlooked in some cases with positive non-SLNs in the SNB group. The recent prospective studies demonstrated excellent results regarding local control after SNB alone in clinically node-negative T1 or T2 breast cancer (12–14). The pathological examination of SLNs was carried out with frozen- or paraffin-embedded sections cut at 40–250 micrometer intervals with HE and cytokeratin IHC staining. In the three observational studies, the median follow-up ranged from 22 months to 46 months. No axillary metastases had occurred in a total of 469 breast cancer patients with negative SLNs. In any event, a more detailed pathological work-up should be performed. Presently, we are investigating a retrospective pathological analysis of SLNs in the two study groups.
Our study had a limitation regarding the comparison of the prognosis between the two groups. This is a non-randomized retrospective study for patients with clinically node-negative breast cancer. There were differences in patient characteristics and SNB technique between the two groups. In addition, the follow-up period was shorter in the SNB group than in the ALND group. However, axilla surgery had little impact on the prognosis of histologically sentinel node-negative and/or axillary node-negative breast cancer patients.
Veronesi et al. (14) first reported no survival benefit in patients with clinically node-negative T1 breast cancer when SNB was compared with ALND in a randomized trial. He reported that 50 (83%) of the 60 patients with micrometastatic SLNs had no other nodal metastases in the axilla. The clinical issue thus remains unresolved as to whether additional ALND should be performed in breast cancer patients with micrometastatic SLNs. Braun et al. (15) demonstrated that bone marrow micrometastasis was an independent prognostic factor in node-negative breast cancer, but the presence of IHC-positive cancer cells in lymph nodes was not. The prognostic importance of micrometastasis in SLNs and bone marrow remains uncertain. In order to answer this question, several randomized clinical trials comparing SNB with ALND are underway in Western countries.
In conclusion, a detailed assessment of SLNs and optimal lymphatic mapping is required to decrease the risk of overt axillary metastases in the SNB group. However, the short-term relapse-free survival rate was similar in the SNB and ALND groups. Our results suggest that SNB will emerge as a standard method to diagnose axillary nodal staging for clinically node-negative breast cancer patients.
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Acknowledgments |
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This study was supported in part by a Grant for Scientific Research Expenses for Health, Labor and Welfare Programs and the Foundation for the Promotion of Cancer Research, and by 2nd-Term Comprehensive 10-year Strategy for Cancer Control.
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References |
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1 Goldhirsch A, Glick JH, Gelber RD, Coates AS, Senn HJ. Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Clin Oncol 2001;19:3817–27.
2 Krag DN, Weaver DL, Alex JC, Fairbank JT. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 1993;2:335–40.[CrossRef][Web of Science][Medline]
3 Cody III HS. Clinical aspects of sentinel node biopsy. Breast Cancer Res 2001;3:104–8.[CrossRef][Web of Science][Medline]
4 Imoto S, Hasebe T. Initial experience with sentinel node biopsy in breast cancer at the National Cancer Center Hospital East. Jpn J Clin Oncol 1999;29:11–5.
5 Imoto S, Fukukita H, Murakami K, Ikeda H, Moriyama N. Pilot study on sentinel node biopsy in breast cancer. J Surg Oncol 2000;73:130–3.[CrossRef][Web of Science][Medline]
6 Imoto S, Wada N, Hasebe T, Ochiai A, Ebihara S, Moriyama N. Sentinel node biopsy for breast cancer patients in Japan. Biomed Pharmacother 2002;56:192s–5s.
7 Imoto S, Murakami K, Ikeda H, Fukukita H, Moriyama N. Mammary lymphoscintigraphy with various radiopharmaceuticals in breast cancer. Ann Nucl Med 1999;13:325–9.[Medline]
8 Tsuda H, Hirohashi S, Shimosato Y, Hirota T, Tsugane S, Watanabe S, et al. Correlation between histologic grade of malignancy and copy number of c-erbB-2 gene in breast carcinoma. Cancer 1989;65:1794–800.
9 Fisher B, Redmond C, Fisher ER, Bauer M, Wolmark N, Wickerham L, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. New Engl J Med 1985;312:674–81.[Abstract]
10 Noguchi M, Motomura K, Imoto S, Miyauchi M, Sato K, Iwata H, et al. A multicenter validation study of sentinel lymph node biopsy by the Japanese Breast Cancer Society. Breast Cancer Res Treat 2000;63:31–40.[CrossRef][Medline]
11 Cserni S, Amendoeira I, Apostolikas N, Bellocq JP, Bianchi S, Bussolati G, et al. Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines. Eur J Cancer 2003;39:1654–67.[CrossRef][Web of Science][Medline]
12 Schrenk P, Haltzl-Griesenhofer M, Shamiyeh A, Waynad W. Follow-up of sentinel node negative breast cancer patients without axillary lymph node dissection. J Surg Oncol 2001;77:165–70.[CrossRef][Web of Science][Medline]
13 Giuliano AE, Haigh PI, Brennan MB, Hansen NM, Kelly MC, Edwin WY, et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2000;18:2553–9.
14 Veronesi U, Paganelli G, Vilae G, Luini A, Zurrida S, Galimberti V, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. New Engl J Med 2003;349:546–53.
15 Braun S, Cevatli BS, Assemi C, Janni W, Kentenich CRM, Schindlbeck C, et al. Comparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy. J Clin Oncol 2001;19:1468–75.
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