Work

Risk factors for non-sentinel lymph node metastases in breast cancer patients with positive sentinel lymph nodes

Year: 2008

Type: article

Abstract: The presence or absence of metastases in the axillary lymph nodes has remained the most powerful prognostic factor in breast carcinoma. Axillary lymph node dissection (ALND) is the standard procedure for obtaining this information. However, postoperative complications are common. Sentinel lymph node (SLN) biopsy has been proposed as a potential alternative to ALND for staging breast carcinoma. This technique has been shown to be sensitive and specific for predicting the status of the axillary lymph nodes.1 Furthermore, it has the potential advantage of decreasing the morbidity associated with ALND. For patients with SLN metastases, about 35%-67% of metastases are only located in SLN, but non-sentinel lymph nodes (nSLN) have no metastases.2 Removal of further axillary lymph nodes may not benefit the patients. So patients without nSLN involvement can also be spared from further axillary surgery. In this study, we analyzed various clinicopathological features in cases of SLN-positive breast cancers to determine factors that might help predict the involvement of nSLN. CLINICAL DATA Patients We reviewed the database at the Affiliated Hospital of Hebei University that includes all patients who have undergone SLN biopsy for invasive breast cancer. Between May 1999 and December 2006, 180 SLN biopsies were performed on patients with invasive breast cancer who had a clinically negative axilla by physical examination. ALND was followed after SLN biopsy in all these patients. Within this group, we identified 108 SLN-positive patients by hematoxylin and eosin (HE) or immunohistochemical (IHC) stain. Surgical procedures Each patient had 1 ml of Technetium-99m dextran (37 megabecquerels (1 millicurie), Syncor Pharmic Limited Company, Beijing, China) injected around the primary tumor or the wall of the biopsy cavity 2 hours prior to surgery. Intraoperatively, the SLN was identified by a hand-held gamma probe (Navigator, USA Tyco). Usually, the SLN is located at axillary level one. In all cases, ALND was performed after removal of the SLNs. Then each SLN was sent to the department of pathology as a separate specimen. Histological examination of SLNs and nSLNs All SLNs were sectioned at 2-3 mm intervals. Those sections were embedded in paraffin blocks, and one level from each block was stained with HE. All negative SLNs were subsequently examined for micrometastases by additional HE and IHC. Each paraffin block was serially sectioned at 100 μm intervals to produce 3 levels. In each level, 4 sections were examined by HE and IHC stain using pan cytokeratin, mucin 1, cytokine 19 (Maixin Company, Beijing, China). The maximum dimension of the metastasis in each SLN was measured. If more than one deposit of tumor was found in a SLN or if multiple SLNs were positive, the size of the largest tumor deposit was recorded. nSLNs from the ALND specimen were analyzed by HE staining only. Each primary tumor was evaluated for primary tumor size, histological type, Black's nuclear grade, estrogen and progesterone receptor status, human epidermal growth factor receptor 2 (HER-2/neu) status, presence of lymphovascular invasion, etc. Statistical analysis Descriptive statistics were used to assess the frequency distribution among the study population. Associations between the presence of positive nSLNs and various characteristics including primary tumor size, histological type, estrogen and progesterone receptor status, HER-2/neu overexpression, Black's nuclear grade, lymphovascular invasion in the primary tumor, number of SLNs removed, size of the largest SLN metastasis, etc., were analyzed with the χ2 test. P <0.05 was considered statistically significant. Characteristics that were found to be significant by univariate analysis was then entered into a forward stepwise method in a Logistic regression analysis to develop a multivariate model of independent factors for predicting the presence of positive nSLN. The SPSS 11.5 software package was used for all statistical analyses. Patient and primary tumor data We evaluated the records of 180 consecutive patients who underwent SLN biopsy for breast cancer. Among these patients, 108 had positive SLN. In this study group, the average patient age was 46.9 years (range, 29-71 years). All patients were T1-2N0M0, among whom 27 patients were T1 and 81 patients were T2. The predominant primary tumor histological type was invasive ductal carcinoma (89 patients, 82.4%). The average tumor size was 3.2 cm (range, 1-4.5 cm), and most tumors were Black's nuclear grade two. A total of 50.9% of tumors were estrogen receptor positive, 49.1% were progesterone receptor positive, and 19.4% were HER-2/neu positive. Lymphovascular invasion was identified in 25.9% of patients. Characteristics of SLNs and nSLNs The median number of SLNs identified was 2.0 (range 1-4). The average size of the largest SLN metastasis was 4 mm (range 0.3-14 mm). Micrometastasis (≤2 mm) was identified in 40 cases (37%). Among these patients, 11 micrometastases were identified in the SLN only by IHC; however none of these were found to have a positive nSLN. The average number of nSLNs harvested with ALND was 16.5 (range 11-25), and the average number of positive nSLNs was 3.2 (range 1-8). A total of 60.2% of the 108 patients were found to have positive nSLNs by HE or IHC. Correlation between clinicopathological features and positive nSLNs The following table summarizes the results of the statistical analysis to determine the relationship between clinicopathological variables and positive nSLNs. Univariate analysis revealed that primary tumor size >2 cm, the largest SLN metastasis >2 mm, and presence of lymphovascular invasion were significantly associated with positive nSLN.Table: Correlation between clinicopathological features and positive nSLNsThe risk of positive nSLNs with primary tumors >2 cm was 3.2 times as great as which with primary tumors ≤2 cm (P=0.023, odds ratio (OR) 3.2). When the largest SLN metastasis was > 2 mm in maximum diameter, the risk of positive nSLNs was 6.7 times as high as the risk when the largest SLN metastasis was a micrometastasis (P=0.001, OR 6.7). The presence of lymphovascular invasion in the primary tumor increased the risk of positive nSLNs to 4.6 times compared with those without lymphovascular invasion (P=0.016, OR 4.6). Our patients with primary tumor size >2 cm, or the largest SLN metastasis >2 mm, or with presence of lymphovascular invasion were associated with positive nSLNs in 66.7%, 69.1%, and 82.4% of cases respectively. When primary tumor size >2 cm and the largest SLN metastasis >2 mm, or primary tumor size >2 cm in the presence of lymphovascular invasion, or the largest SLN metastasis >2 mm and with presence of lymphovascular invasion, 93.6%, 64.1%, and 96.8% of the patients were found to have positive nSLNs respectively. If patients had primary tumor size >2 cm, with the largest SLN metastasis >2 mm, and the presence of lymphovascular invasion, metastases were identified in all patients. DISCUSSION Regional control of metastatic breast carcinoma is important, because clinical recurrence in the axilla may be the source of distant metastases and poor survival. In recent years however, ALND has been regarded primarily as a staging rather than a therapeutic procedure.3 The acceptance of SLN biopsy as an accurate staging technique has accentuated the controversy regarding ALND. It is complicated to determine which patients with metastatic SLN may benefit from ALND. Controlled trials with extended clinical follow up are needed to determine the value of these therapies. If SLNs are positive and nSLNs are negative, ALND can be avoided after SLNs are excised. However, in the interim, treatment decisions may be aided by knowing which patients are likely to have additional metastatic carcinoma in nSLNs. In this study, 65 (60.2%) of 108 patients with a positive SLN were found to have residual disease in the axilla. In the other 39.8% of the patients, the SLN was the only node involved with a tumor. This rate is similar to that found at other high-volume breast centers.4 The results of these studies demonstrated that primary tumor size >2 cm, the largest SLN metastases >2 mm, and the presence of lymphovascular invasion are independent factors which predict additional disease in nSLNs. Furthermore, with an increasing number of negative SLNs removed, the likelihood of having additional positive nSLNs decreases significantly. Several other groups have also identified the same factors associated with the presence of positive nSLN.5-11 In these studies, primary tumor size >2 cm was significantly associated with additional nSLN metastases. We also found that the risk of positive nSLNs with primary tumors >2 cm was 3.2 times as great as which with primary tumors ≤2 cm. None of our patients with T1a tumors had positive nSLN, whereas T2 tumors were associated with positive nSLN in 66.7% of cases. Other groups found, as we did, that the largest SLN metastasis >2 mm was a significant predictor of positive nSLNs.12 In the study of Turner et al,8 47% of patients with the largest SLN metastasis >2 mm were found to have positive nSLNs. In fact, the amount of disease in the SLN was the strongest positive predictor of all the factors which we analysed, with an OR of 6.7, which confirms the results by Chu et al.10 Lymphovascular invasion was another significant predictor of nSLNs involvement which represents tumor cells in transit to other sites.13 More than 80% of tumors with lymphovascular invasion had positive nSLNs, compared with half of tumors without lymphovascular invasion. Abdessalam et al9 and Turner et al8 also demonstrated that lymphovascular invasion was significantly associated with positive nSLNs. When this variable was present, 62% of the patients in the Abdessalam series had positive nSLNs. In our study, lymphovascular invasion was correlated strongly with nSLNs metastases (P=0.001), which identified 82.4% of patients with nSLNs metastases. In a review of 206 patients with positive SLN who underwent ALND, Weiser et al11 found that three variables were inversely related to the likelihood of positive nSLNs. When primary tumor size was ≤1.0 cm, lymphovascular invasion was absent, and SLN metastasis size was ≤2 mm, no nSLNs metastases were identified in 24 patients. In this study, we also found that the more correlating variables the patients have, the higher the likelihood of positive nSLNs is. When primary tumor size >2 cm, lymphovascular invasion was present, and SLN metastasis size was >2 mm, we found positive nSLNs in all patients. To sum up, axillary treatment decisions are complex and require individualized scrutiny of all available data. The presence and extent of nSLNs metastases in patients with SLN metastases are associated most closely with the size of the primary tumor, SLN metastases, and the presence of lymphovascular invasion. A scoring system based on these factors may be useful in determining the status of the nSLNs.14,15 Now we are studying a scoring system to decide which patients would benefit from ALND.

Source: Chinese Medical Journal

DOI: 10.1097/00029330-200810020-00031