Japanese Journal of Clinical Oncology 32:517-524 (2002)
© 2002 Foundation for Promotion of Cancer Research
Indications for Sentinel Lymph Node Biopsy in Patients with Breast Cancer: Retrospective and Simulation Analyses
Departments of 1 Nuclear Medicine, 2 Breast Surgery, 3 Breast Pathology and 4 Internal Medicine, Cancer Institute Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The disease status of axillary lymph nodes at diagnosis is the most powerful predictor of prognosis for patients with breast cancer. Axillary lymph node dissection (ALND) has been the standard treatment. Recently, lymphatic mapping and sentinel lymph node biopsy (SNB) have been suggested as alternatives to ALND. However, a clear indication for SNB has not yet been established. The goal of this study was to determine which patients might best benefit from the SNB method.
Methods: A retrospective study compared the relationship of age, menopausal status, tumor size group, histology and clinical evaluation of nodes to histological axillary lymph node status in 5892 consecutive Japanese breast cancer patients who underwent ALND. A simulation analysis with reported SNB sensitivity and specificity was carried out.
Results: Clinical lymph node evaluation was the most relevant factor to predict axillary nodal status. However, even patients with no clinical nodal involvement (N0) showed only 71% axillary nodal negativity. Tumor group based on tumor size and histology also related to axillary nodal status. The simulation analysis revealed that of patients with negative lymph node probability, more than 66% were good candidates for SNB.
Conclusion: The clinically negative node (N0) is the most important indication for SNB. Therefore, the candidates for SNB should be picked from the patients with N0. When no histological information is available, patients whose tumor is 20 mm or smaller are candidates for SNB. When histological information is available, the SNB indication extends to patients whose type of tumor has histologically good prognosis or a low probability of having nodal involvement, regardless of tumor size.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Axillary lymph node status at surgery is the most powerful predictor of prognosis for patients with breast cancer (1–3). Axillary lymph node dissection (ALND) has been the standard treatment. Recently, lymphatic mapping and sentinel lymph node biopsy (SNB) have been reported to be alternatives to ALND (4–12). Potential advantages of SNB over ALND include smaller axillary incision size, improved postoperative function of the arm and shoulder and elimination of chronic lymphoedema. The SNB technique is robust, since different groups have used many variations in the technique at every step of the SNB procedure yet have reported encouraging results (8–10,13). Keshtgar and Ell indicated that SNB is a technique suitable for patients with high-risk non-invasive cancer, non-palpable breast cancer, T1 or T2 carcinoma and especially good prognosis tumors (mucinous, papillary and adenoid cystic) (12). They also stated that the only remaining reason for excluding breast cancer patients from SNB was evidence of clinical involvement of axillary nodes. Although these findings are encouraging, the indications for SNB can only be made after well-designed clinical studies.
To begin establishing these guidelines, information on patients’ characteristics and disease outcome must be collected. Previous studies have clearly established that tumor size and histology are associated with lymph node status (14,15). Many studies have shown that two-thirds of patients with breast cancer have no metastasis to axillary nodes (14,15). However, few large-scale studies have focused on the efficacy of SNB (16,17). As indicated previously, patients who have no metastatic cells or tumors in axillary nodes will benefit most from SNB. Therefore, to make study protocols to determine which patients would benefit from SNB, the rate of metastasis to axillary lymph nodes must be determined and analyzed according to the patients’ characteristics and disease status.
The purpose of this study was to estimate the likelihood of metastasis to axillary lymph nodes based on the physical characteristics of patients and the status of the disease that could be obtained preoperatively. A simulation analysis to establish the indications for SNB was then carried out using the reported SNB sensitivity and specificity and these probabilities.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Retrospective Analysis
All patients with either invasive or non-invasive breast cancer treated at the Cancer Institute Hospital, Tokyo from 1988 through 1998 who underwent ALND as part of their treatment were included. The total number of patients enrolled in this study was 5892. Age, menopausal status, tumor size, histology and clinical nodal evaluation (N) were used as independent variables.
Five age groups were categorized: <40, 40–49, 50–59, 60–69 and >70 years old. Tumor groups were categorized by T category using the TNM system (18,19) with some modifications: Tis, any ductal carcinoma in situ; T0 or T1mic, 1 mm or less; T1a, 1.1–5.0 mm; T1b, 5.1–10.0 mm; T1c, 10.1–20.0 mm; T2small, 20.1–30.0 mm, T2large, 30.1–50.0 mm; T3, 50.1 mm or more; T4, attachment to chest wall or skin, presence of skin edema or ulceration or presence of inflammatory carcinoma. The histology of the tumor was categorized according to guidelines outlined in the ‘General Rules for Clinical and Pathological Recording of Breast Cancer’ of the Japanese Breast Cancer Society (19). Results of clinical evaluation of the nodes were categorized according to the criteria established by the Japanese Breast Cancer Society: N0, no regional lymph node metastasis; N1, metastasis to movable ipsilateral axillary node(s); N2, metastasis to ipsilateral axillary node(s) fixed to one another or the other structures; N3, metastasis to ipsilateral internal mammary lymph nodes; M1, metastasis to further lymph node(s).
Axillary nodes were evaluated by ALND and conventional hematoxylin and eosin (H&E) staining. The results were divided to positive and negative groups and the positive results were sub-divided into one node positive, two nodes positive, three nodes positive and four or more nodes positive groups.
Because it is thought that the patients who have no metastasis to axillary nodes will gain the greatest benefit from SNB, the percentage of patients with no metastasis to axillary nodes was obtained for each group of previously mentioned characteristics. The SNB indications for each of these groups were evaluated by determining which characteristics have a strong correlation with the metastatic status of axillary nodes. The 95% confidence interval (CI) was calculated by the binomial method. Logistic regression analysis was used to analyze the data.
Simulation Analysis
The following simulation analysis was performed to try to establish such a criterion. Breast cancer patients can be divided into four categories based on histologically determined metastatic status of axillary nodes and SNB result: (1) SNB true negative (TN), (2) SNB true positive (TP), (3) SNB false positive (FP) and (4) SNB false negative (FN). SNB false positive patients are unlikely. The results of SNB will have a large influence on the treatment that patients will undergo. For example, since the standard or most probable procedure taken after positive sentinel node is complete ALND, patients with SNB-TP will receive minimal benefit from SNB. In contrast, patients with SNB-TN will gain the greatest benefit from the SNB procedure and patients with SNB-FN will not benefit and might be hampered by this method. To determine criteria for the use of SNB, Bayesian probability theory can be used. In this analysis, the rate of no metastasis to axillary nodes is the prior probability. Using the sensitivity (se) and specificity (sp) of SNB and negative axillary node rate (X), the posterior probabilities of SNB and axillary nodal status can be expressed as follows: TP rate = (se) x (1 – X), FN rate = (1 – se) x (1 – X), FP rate = (1 – sp) x (X) and TN rate = (sp) x (X). Sensitivity and specificity values of 0.9 and 1.0, respectively, have been reported for SNB (6,8,9) and were used in this analysis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Table 1 shows the histologically determined metastatic status of axillary nodes in all patients, grouped by patients’ characteristics and disease status. Of 5892 patients examined, 3563 exhibited no metastasis to the axillary nodes [3563/5892 (60.5%; 95% CI: 59.2–61.7%)]. Logistic regression analysis showed that clinical node evaluation, tumor size group, histology and age correlate significantly with metastatic status. Age group correlated slightly with metastatic status. In contrast, menopausal status did not show any correlation. The results of clinical node evaluation show the clearest difference: 71% (95% CI: 69.7–72.3%) of patients with clinical node negative (N0) had no metastasis in the axillary nodes, but only 15.5% of N1 patients, 4.5% of N2 patients and 7.0% of N3 or more patients had no evidence of metastasis in the axillary nodes. The next stage of analysis was performed on the data from N0 patients only.
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Table 2 shows the histologically determined metastasis of axillary nodes in N0 patients grouped by patients’ characteristics and disease status. Even though all these patients were N0, 29% had metastasis to the axillary nodes. Tumor group and histology correlated strongly with metastasis to axillary nodes. As the tumor size group advances, the number of patients with no metastasis to axillary nodes decreases. The rate of nodes negative for metastasis was 99.8% for patients with Tis, 93% for patients with T0 or Tmin, 83.3% for patients with T1a, 80.4% for patients with T1b, 76.3% for patients with T1c, 62.9% for patients with T2small, 61.1% for patients with T2large, 54.7% for patients with T3 and 36.4% for patients with T4. For some histological classes, the percentage of axillary nodes with metastasis is low (Table 2). Patients with non-invasive cancer (non-invasive ductal and lobular carcinoma in situ) showed almost no evidence of metastasis to the axillary nodes. Additionally, more than 80% of patients with special types of carcinomas, such as mucinous carcinoma, adenoid cystic cancer, spindle cell carcinoma, apocrine cell carcinoma, tubular carcinoma, secretory carcinoma or Paget’s disease of the breast, had no evidence of metastasis to the axillary nodes. In the invasive ductal carcinoma subclass, patients with papillotubular carcinoma and solid tubular carcinoma had similar values for metastasis to axillary nodes, 76.4 and 74.4%, respectively. In contrast, patients with scirrhous carcinoma had a value of 55.9%.
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Table 3 shows the percentage of no histological evidence of metastasis to axillary nodes in N0 patients grouped by tumor histology and tumor size group. In this table, non-invasive carcinomas were grouped together and other kinds of cancer were grouped separately. New groups were invasive lobular carcinoma, cancers with favorable prognosis (mucinous carcinoma, adenoid cystic carcinoma, spindle cell carcinoma, apocrine cell carcinoma, tubular carcinoma, secretary carcinoma and Paget’s disease of the breast) and others (medullary carcinoma, squamous cell carcinoma and carcinoma with cartilaginous and/or osseous metaplasia and others). The percentage of patients with non-invasive carcinoma who had no histological evidence of metastasis to the axillary nodes was 99.8%. Similarly, for patients with cancers that have histologies of favorable prognosis, the percentage of patients who had no histological evidence of metastasis to the axillary nodes was more than 80%, except for patients with T4 tumors. For patients with other cancers, there was also a low percentage of metastasis to axillary nodes. The percentage of patients with papillotubular cancer who had no histological evidence of metastasis to the axillary nodes was more than 80% for T0 and T1 tumors, about 70% for T2 tumors, 59% for T3 tumors and 50% for T4 tumors. Patients with solid tubular cancer showed similar results: more than 80% for T0 or T1min and T1 tumors, about 70% for T2 tumors, 70% for T3 tumors and 52% for T4 tumors. However, patients with scirrhous cancer showed different results: more than 80% for T0 or T1min and T1a tumors, 74% for T1b tumors, 68% for T2c tumors, 50% for T2small tumors, 43% for T2large tumors, 21% for T3 tumors and 25% for T4 tumors. The percentage of patients with invasive lobular carcinoma who had no histological evidence of metastasis to the axillary nodes was more than 80% for T0 or T1min tumors, T1a and T1b tumors, 75.5% for T1c tumors, 63.0% for T2small tumors, 46.2% for T2large tumors, 35.3% for T3 tumors and 55.6% for T4 tumors.
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Table 4 shows the values calculated for TN, FP, TP (FP is 0 because the specificity is 1.0) and the rate of false negatives in sentinel node negative patients [FN/(FN + TN) x 100]. The rate of false negatives in sentinel node negative patients is considered to be most important. The FN/(FN + TN) rate decreases as X increases: a value of X = 0.6 gives 6.3% of FN/(FN + TN) rate, X = 0.66 gives 5% and X = 0.7 gives 4.1%. A 5% failure rate may be a good candidate for a cut-off point. Therefore, a disease condition that gives an X value of >0.66 yields an FN/(FN + TN) rate of <5.0% and patients with such a condition are good candidates for the SNB procedure.
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Together with retrospective and simulation analyses, candidates for SNB can be summarized as in Table 5. In N0 patients, when no histological information on the tumor is available, patients with T1c tumor or smaller are good candidates for SNB. If there is some histological information available on the tumor, patients with non-invasive cancer or invasive cancers with histologies of favorable prognosis are candidates for SNB regardless of tumor size. For other special types of cancers, patients with T2small tumors or smaller are candidates for SNB. Similarly, for papillotubular or solid tubular cancers, patients with T2 tumors or smaller are candidates for SNB and for scirrhous cancer or invasive lobular cancer, patients with T1c tumors or smaller are candidates for SNB.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The sentinel node biopsy procedure has been studied as an alternative to ALND (5–12). The results of these previous studies showed that the technique fails when the sentinel nodes are filled by metastatic tumors. Therefore, the possibility that the technique will fail increases if the patient has a higher probability of having metastasis to axillary nodes. Consequently, this retrospective study was conducted to determine the percentage of breast cancer patients with no evidence of metastasis to axillary nodes.
As yet, there is no distinct criterion for the false positive rate of SNB. Therefore, the retrospective and simulation analyses were carried out to try to establish such a criterion. A simulation was then performed for SNB assuming a sensitivity of 0.9 and a specificity of 1.0. The rate of false negatives in sentinel node negative patients [FN/(FN + TN) rate] is considered to be most important among the values shown in Table 4. A 5% FN/(FN + TN) rate may be a good candidate for a cut-off point. Therefore, a disease condition that gives an X value of >0.66 yields an FN/(FN + TN) rate of <5.0% and patients with such a condition are good candidates for the SNB procedure. Although the above-described patients [FN/(FN + TN) rate <5.0%] are the best candidates to benefit from SNB, other patients might also benefit. For example, patients with an X value between 0.5 and 0.66 have a probability FN/(FN + TN) rate between 5.0 and 9.1%. While these patients might also be suitable candidates for SNB, caution should be exercised and if possible other criteria used to assess patient suitability. However, to keep this discussion simple, the following additional indications assume that patients have an X value of 
0.66 [a 5.0% of FN/(FN + TN) rate]. Additionally, patients with clinical evaluation values that indicate metastasis to axillary nodes (N1 or more) are excluded, because more than 80% of these patients have metastatic tumors or cells in the axillary nodes (Table 1).
The histological procedure used to detect axillary lymph node metastasis in this study was standard H&E tissue staining. However, an immunohistochemical method using a cytokeratin antibody has been reported to improve the detection of metastasis. A study by Cox et al. compared the percentage of axillary nodes with metastatic tumors or cells detected by H&E staining alone and by the combination of the H&E and immunohistochemical methods (20). The results for the combined method indicated that 4.6% of patients with T0 tumors (DCIS), 16.0% of patients with T1a–T1b, 32.8% of patients with T1c tumors, 40.8% of patients with T2 and 75.0% of patients with T3 had metastatic tumors to axillary nodes. The values are similar to the N0 results described in the present study (1.1% for non-invasive and T0, 19.2% for T1a–T1b, 23.7% for T1c, 38.4% for T2 and 45.3% for T3). The only statistically significant difference between these two data sets was shown for the T0 group (P = 0.039, Fisher’s exact test), no statistical difference was obtained for other tumor groups (P = 0.58 for T1a–1b, 0.09 for T1c, 0.74 for T2 and 0.33 for T3). Therefore, the results for histological examination of axillary nodes performed during the present study are almost the same as the reported results for Cox et al.’s study in which both H&E and immunohistochemical methods were used. This close agreement despite the use of different techniques might result, in part, from the analysis in the present study being performed by experienced pathologists in dedicated breast pathology in this study center.
Although ALDN is accurate, it is highly invasive. Therefore, other techniques with similar accuracy are being sought. One such technique uses radiotracers to locate sentinel lymph nodes. Relatively constant results have been reported for radionuclide-guided SNB, despite the use of different radiopharmaceuticals, radioactivity, volume and route of administration and time from injection to SNB (5,7–10,13). Results of an interesting study by Wong et al. indicate that the number of sentinel lymph nodes examined during the biopsy significantly influences the rate of false negative results (21). They reported a significantly higher false negative result rate (14.3%) in patients who had a single sentinel lymph node examined than in those patients who had several sentinel lymph nodes examined (4.3%). As mentioned previously, the false negative rate is a very important indicator in determining which patients benefit from SNB. Technical improvements to SNB, including the development of new radiopharmaceuticals to provide a better signal-to-noise ratio, have been extensively studied (11, 22) and might soon improve the accuracy of this technique. If this occurs, the indications for SNB might be extended to breast cancer patients other than those previously described.
Another approach that might extend the indications for SNB is to improve the accuracy of current techniques for the clinical evaluation of axillary nodes. Currently used imaging techniques, such as ultrasonography (23,24), Tc-99m Sestamibi scintigraphy (25), magnetic resonance imaging (26) and positron emission tomography (27), are not very accurate when used on their own. However, the use of these techniques in combination or with other diagnostic methods might improve the accuracy in detecting metastasis to axillary nodes, thus allowing better use of SNB and also less invasive treatment overall.
In conclusion, the present study analyzed the correlation of the histologically determined rate of metastasis to axillary nodes with patients’ characteristics and indicators of disease status to establish guidelines for SNB. This information is crucial to physicians who want to use SNB with their breast cancer patients. The results show that clinical evaluation of axillary lymph nodes is the most important factor in predicting the success of SNB, followed by tumor groups based on tumor size and histology, if available. Consequently, the indications for SNB can be summarized as follows. A simulation analysis revealed that patients with disease and physical characteristics that give a probability of success >0.66 are good candidates for SNB, assuming a sensitivity of 0.9 and specificity of 1.0 for the technique. These patients must be chosen from among those with no evidence of metastasis to nodes clinically (N0). When no histological information is available, patients with tumor group T1c or smaller groups are good candidates for SNB (Table 5). When the histological information is available, the SNB indications extend to patients with cancer who have histology of good prognosis or who have a low probability of metastasis to nodes regardless of tumor size (Table 5). This scenario will change as the accuracy of the SNB technique improves. In such cases, the present data set can still be applied by changing the sensitivity when SNB technical improvements warrant it.
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FOOTNOTES |
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+ For reprints and all correspondence: Mitsuru Koizumi, Department of Nuclear Medicine, Cancer Institute Hospital, Kami-ikebukuro 1–37–1, Toshima-ku, Tokyo 170-8455, Japan. E-mail: mitsuru@jfcr.or.jp
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Received June 28, 2002; accepted September 13, 2002
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