To assess strategies to decrease LR rates after BCT, several RCTs were performed and revealed numerous and varying risk factors that might be associated with LR (Table ). A large meta-analysis of 72 trials, containing information on >42,000 patients, assessed that local surgical control at 5 years showed a significant improvement in disease-free survival and overall mortality at 15 years follow-up.24
Independent risk factors for local recurrence
The influence of “close” margins, usually defined as tumor cells being present within >0 and ≤2 mm from the cut edge, is still controversial.4
Several studies reported close margins to be a significant risk for increased rates of LR, as well as the apparent quantity of cancerous cells approaching the cut edge.31
In a recent trial conducted by Zavagno et al., 431 patients who underwent re-excision due to margin involvement were evaluated from a total of 1,520 patients who underwent BCT.35
The authors found LR rates after positive margins and close margins to be 51.8% and 34.1%, respectively (p
= 0.001). However, no correlation was found between the distance of the tumor from the cut edge (range: 0.08–3 mm) and LR rate.35
These findings are consistent with the results of most of the studies performed on the correlation between margin width and LR rate, as reviewed by Singletary.4
Margin closeness is therefore currently not seen as an indication for re-excision.
Zavagno et al. suggest that residual disease in close margin involvement may be largely due to the existence of multiple cancerous foci and not to margin closeness by itself.35
Breast tumors are shown to grow multifocally in 59%, of which 71% grow at a distance >2 cm from the reference tumor.36
Therefore, margin status as such may be considered an important judgment factor in planning re-excision, but cannot be seen as an indicator for the presence of residual tumor in the surrounding tissue.35
Adequate perioperative imaging of cancerous foci may be of great value to the surgeon.
Singletary reviewed 34 studies on margin status and LR, in which a total of >15,000 patients were assessed.4
In 30 of 34 reviewed studies, persistent microscopic inadequate (R1) or macroscopic inadequate (R2) surgical margins were highly significant for LR compared with negative margins (p
= 0.0001), depicting the relevance of margin status on the outcome of BCT. In a study by Jobsen et al. of approximately 2,300 patients, the LR rate was found to be related to positive margin status and young age.37
The authors found the 10-year LR-free survival rate for young women (≤40 years) with positive margins to be significantly lower compared with negative margins (34.6% vs. 84.4%, respectively; p
= 0.008). The effect of positive margin status for invasive carcinoma seems to be limited to young women and is not only restricted to local control, but also to distant metastasis and survival.37
Because positive margin status is found to be an important risk factor for LR, substantial efforts have been made to understand the causes of the relatively high percentage of positive margins after BCT. A number of risk factors for positive margin status have been identified over the years (Table ). Again, young age is reported to be a strong risk factor for positive margin status.20
Vrieling et al. reported that the tumor was significantly larger in young patients (≤40 years) compared with older patients (p
Furthermore, re-excisions occurred more often in younger patients (34–35% vs. 20–28%; p
= 0.001), which was probably related to a more frequent incomplete excision at the first attempt (24–26% vs. 14–21%; p
= 0.001). Vicini et al. suggested that a lesser extent of the excision, for cosmetic reasons, might be the cause of less optimal margin resection in younger patients.34
When adequate negative margins were obtained, no difference in LR was seen in different age groups.34
Independent risk factors associated with positive margins
Other reported risk factors for positive margin status are large tumor size, multifocality, and lobular histological type.17
Furthermore, the number of positive lymph nodes (N-status) is reported to be a risk factor.44
However, it should be noted that there is a strong variability in the reported findings of these studies.
An explanation for the high rate of positive margins reported in literature might be the restricted visibility of the tumor and coexisting ductal carcinoma in situ (DCIS) during surgery. To give an adequate perspective on the problems surrounding the pre- and intraoperative visibility of the tumor, the techniques currently used are summarized in the following sections and judged on their merits.