Abstract
Background: The prognostic value and clinical implication of micrometastases and isolated tumor cells (ITCs) in sentinel lymph nodes are still not clearly defined. This study was designed to collect clinical pathological data in our Institution. Patients and Methods: Twenty-five cases of micrometastases and nine cases of ITCs were identified among 1,000 sentinel lymph node biopsies performed at our institution in the last 10 years. Results: In the 25 patients with sentinel node micrometastases, 12 had completion axillary node dissection, and only one of these twelve had non-sentinel node micrometastasis. In this group, two patients developed local recurrence, and two patients developed distant metastases (one with and one without prior local recurrence) and later died. Both patients had negative non-sentinel lymph nodes. In the 9 patients with sentinel node ITCs, no patient had completion axillary node dissection and no patient developed local or distant metastases. Conclusion: Completion axillary node dissection may not be necessary in patients with sentinel node micrometastases and ITCs as it does not impact local recurrence. ITCs do not seem to have prognostic significance. Micrometastases, however, may be associated with local and/or distant metastasis.
Sentinel lymph node dissection (SLND) has replaced axillary lymph node dissection (ALND) as the primary axillary node staging procedure for invasive breast carcinomas. According to the 7th edition of the American Joint Committee (AJCC) Cancer Staging Handbook (1), micrometastases in lymph nodes are defined as nodal metastases measuring greater than 0.2 mm, and/or more than 200 cells, but none greater than 2.0 mm. Isolated tumor cell clusters (ITCs) are defined as small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section. The prognostic value and clinical implication of micrometastases and ITCs in sentinel lymph nodes are still not clearly defined. Reed et al. (2) published a prospective study in which they found that sentinel node micrometastases, but not ITCs, were associated with the presence of additional positive nodes and with distant recurrence, and suggested that ALND and more aggressive adjuvant therapy should be considered in patients with SLN micrometastases. Another study published in the same year, however, concluded that ITCs and micrometastases in regional lymph nodes were both associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy (3).
Up until recently, most consensus statements recommend completion ALND as the follow-up management for patients with SLN metastases. Completion ALND for women with micrometastases or ITCs in SLNs remains controversial because of uncertain clinical implications and the low-yield of additional positive lymph nodes. Although the American Society of Clinical Oncology recommended ALND for patients with SLN micrometastases or ITCs (4, 5), this concept has been re-examined in selected patients due to the recently published study of the American College of Surgeons Oncology Group Z0011 Randomized Trial (6) that compared local and regional recurrence in patients with positive SLND with or without follow-up ALND. In this study, 37.5% of patients in the ALND group and 44.8% of patients in the SLND only group had SLN micrometastases. In the ALND group, 10% of patients with micrometastases had additional positive lymph nodes. However, the study was initiated when the fifth edition of AJCC was in use and there was no definition and distinction between micrometastases and ITCs at the time. Therefore, it is likely that the micrometastasis group in this study also included some ITCs. Nevertheless, the study demonstrated that there were no statistically significant differences in locoregional recurrence after SLND with or without ALND in selected patients with SLN metastases (including macrometastases and micrometastases). It is to be noted that the Z0011 study was performed in patients with early-stage breast cancer treated with breast-conserving therapy. All patients received whole breast irradiation and over 95% of patients received adjuvant systemic therapy. The results of this study definitely raise further doubt of the necessity of completion ALND in patients with micrometastases or ITCs.
We carried out the current study to compare locoregional recurrence, distant metastases and survival in breast cancer patients with micrometastases or ITCs in their SLNs. Histologic features of the primary tumors including tumor type, size, grade, status of lymphovascular invasion, and biomarker expression were also collected and compared.
Patients and Methods
Approximately 1,000 axillary sentinel lymph node biopsies were performed at our hospital between 2002 and 2010. A retrospective chart review of the pathology reports was conducted on these cases, and among them, 25 cases of micrometastases (2.5%) and 9 cases of ITCs (0.9%) were identified and retrieved from the files. A strict size criterion for the metastasis was used in the selection of the cases per AJCC's staging criteria.
All SLNs were processed using the same protocol. SLNs were serially sectioned at 2-mm intervals and submitted for intraoperative frozen section assessment with four levels. If negative, three more levels of H&E-stained permanent sections and immunohistochemical stain for pan-cytokeratin were obtained and evaluated (Figure 1). Patients treated with neoadjuvant chemotherapy were excluded from this study. Primary tumor type, grade, size, lymphovascular invasion (LVI), additional axillary lymph node information, tumor biomarkers, local and distant metastasis, as well as survival, were recorded.
Results
The results are shown in Table I. Patient ages ranged from 34 to 81 (median 50) years for the micrometastasis group and 30 to 78 (median 54) years for the ITC group. The majority of the primary tumors in the micrometastasis group were invasive ductal carcinoma (96%). In the ITC group, 44% of the primary tumors were invasive ductal carcinoma, 33% were invasive lobular carcinoma and 22% were ductal carcinoma in situ. The size of the primary tumor at the time of resection was smaller in the ITC cases compare to the micrometastasis cases (median 1.5 cm vs. 2.2 cm). LVI was identified in 32% of the cases of micrometastasis and none of the cases of ITCs. The majority of the tumors had an ER-positive/Her-2-negative expression profile in both the micrometastasis group (68%) and ITC group (71%).
The time to follow up ranged from 8-96 months for the micrometastasis group (median 52 months) and 11-84 months for the ITC group (28 months). Axillary dissection was performed in 12 out of the 25 cases of micrometastasis and only one of those cases had additional micrometastasis identified (8%). In the 25 patients with micrometastases, one patient developed local recurrence (after previous lumpectomy) in the breast and another patient developed local recurrence in the chest wall and axilla (after previous mastectomy). Both cases had completion ALND prior to local recurrence and had no additional positive nodes at the time. Two patients in the micrometastasis group also developed distant metastases (lung, spine, liver, neck) 12 and 6 months, respectively, after the primary breast cancer surgery and later died. One of these patients had local recurrence prior to distant metastasis and the other patient did not have prior local recurrence. Both cases had grade III invasive ductal carcinoma with LVI and negative estrogen receptor/Her-2/neu expressions. In contrary, none of the 9 cases of ITC had follow-up axillary dissections, and none had local recurrence, distant metastases, or death in the follow-up studies.
Discussion
ALND following positive sentinel lymph node micrometastases or ITCs. Controversy still remains about appropriate surgical management and prognostic implications of micrometastases and isolated tumor cells in SLN of breast cancer patients. The reported rate varies for additional positive lymph nodes in patients with micrometastases or ITCs (7-10). In our study, none of the patients with ITCs underwent ALND. No evidence of locoregional recurrence was seen in these cases. Twelve out of 25 cases with SLN micrometastases had follow-up ALND; among them, only one case had one additional positive node with micrometastasis (8%). This rate is similar to that reported in the ACOSOG Z11 trial (10%) for the micrometastatic group. Two out of 25 patients with micrometastatic disease developed local recurrence in the breast/chest wall and axilla; both cases had completion ALND prior to the local recurrence and there were no additional positive lymph nodes at the time. Therefore, the completion ALND did not seem to affect local recurrence in patients with SLN micrometastases. This conclusion is in concordance with the recently published literature (11-13).
All of the factors that influence locoregional recurrence of breast cancer are not clearly understood. In the ACOSOG Z11 trial, about 25% of patients in the ALND group had additional positive non-SLNs. It is most likely that the SLN-only arm had a similar rate of non-SLN metastases. However, fewer than 1% of the patients in either arm of the trial developed locoregional recurrence. The systemic adjuvant therapy and/or local radiation therapy these patients received, and the possible indolent nature of some of these nodal metastases, may have contributed to the low level of locoregional recurrence of the tumor.
Prognostic significance of positive SLN micrometastases and ITCs. The biologic nature of ITCs in SLN is not entirely clear. However, it is generally favored that ITCs represent mechanical displacement of benign breast epithelial cells or neoplastic tumor cells instead of true metastatic spread (14, 15). It has been reported by various studies that patients with SLN micrometastases, but not ITCs, have poorer overall survival and disease-free survival when compared with that for node-negative patients (2, 16). A more recent report by de Boer et al. systematically reviewed studies published from January 1, 1997 to August 11, 2008 on this subject and in pooled analyses of long-term survival found that the presence of metastases of 2 mm or less in diameter as detected by one H&E section of each ALN (without differentiation between ITCs and micrometastases) was negatively associated with prognosis (17). The authors also pointed out that due to nonstandardized pathological assessment of SLN, the translation of the results from those older studies to the current practice of intensified examination of the SLNs is limited. A multicenter cohort study conducted in the Netherlands revealed that patients with micrometastases did not have significant different overall and disease-free survival compared with patients without lymph node metastases (18). However, this study also suffered from the weakness of non-standardized pathology procedures among different hospitals. Weaver et al. in a randomized prospective study found that small occult metastases (including ITCs and micrometastases) in sentinel nodes are an independent predictor of overall survival, disease-free survival, and distant-disease-free interval (19). However, the magnitude of the difference in outcome at 5 years was small (1 to 3 percentage points) and warrants continued follow-up and analysis.
Our study is limited by a small sample size and its retrospective nature, however, the pathologic evaluation procedure of the SLNs was consistent. In our study, 2 out of 25 patients with micrometastases developed distant metastases followed by death, while none of the 9 patients with ITCs developed any local recurrence or distant metastases. These results support the notion that ITCs do not possess true metastatic potential, while micrometastases represent early-stage nodal metastases.
It is noteworthy that the two cases with distant metastases and death in the micrometastasis group had primary tumors that were high grade with LVI and negative expression of estrogen receptor and Her-2. One of these two patients experienced locoregional recurrence prior to distant metastasis. Further subgroup analysis of micrometastatic cases with confounding tumor factors, such as LVI, tumor grade and estrogen receptor/Her-2 expression, may provide more accurate prognostic information.
In summary, this is a retrospective study of a single institution and is limited by numbers. However a few conclusions can still be drawn from the study. Completion ALND may not be necessary in patients with micrometastases and ITCs in SLNs as it does not appear to impact local disease recurrence. The presence of ITCs in SLNs may not carry prognostic significance. Micrometastases, however, may be associated with distant metastasis in certain patients, especially when the primary tumor was of high grade and triple negative. This topic will remain controversial until there is a large prospective study with long-term follow-up data.
- Received June 24, 2011.
- Revision received August 10, 2011.
- Accepted August 11, 2011.
- Copyright © 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved