Positive margin rates in wire localization-guided breast-conserving surgery for non-palpable invasive breast cancer: a retrospective cohort study

Introduction

Background

Breast cancer is the most prevalent cancer among females worldwide, accounting for approximately 25.2% of all cancer cases and 14.7% of cancer-related deaths in women (1). The implementation of widespread screening programs, such as mammography, has significantly improved the early detection of breast cancer, enabling more patients to opt for breast-conserving surgery (BCS) instead of mastectomy (2). Due to improvement of diagnostic modalities, earlier detection of non-palpable masses has been increasing. One of the most widely used techniques for non-palpable lesions localization is wire localization using imaging modalities, such as mammograms and ultrasounds (3-5). BCS involves the wide local excision of the breast lesion while preserving as much healthy breast tissue as possible. This approach is the preferred treatment modality for early-stage breast cancer, as it offers comparable morbidity and mortality rates to mastectomy while providing superior cosmetic outcomes and being more cost-effective (6,7).

The incidence of positive surgical margins following BCS varies widely, ranging from 21% to 41%, depending on factors such as tumor characteristics, surgical techniques, and imaging modalities (8,9). Tumor characteristics represent fundamental determinants of positive margin risk, with histologic subtype emerging as one of the most significant predictors. The systematic review by Switalla et al. found that invasive lobular carcinoma (ILC) patients undergoing oncoplastic BCS had a pooled positive margin rate of 31% [95% confidence interval (CI): 21–40%], significantly higher than invasive ductal carcinoma (IDC) patients [risk ratio (RR) 3.4, 95% CI: 1.5–7.4] (8). The evolution of surgical techniques represents the most modifiable factor influencing positive margin rates, with substantial evidence demonstrating significant improvements in margin outcomes through technical innovations. The cohort study by Falade et al. demonstrated dramatic differences in positive margin rates based on surgical technique: standard BCS showed positive margin rates of 42.6%, while BCS with oncoplastic techniques achieved rates of 29.7% (9). Preoperative imaging plays a crucial role in surgical planning and ultimately influences margin outcomes through improved tumor localization, extent assessment, and surgical approach selection. The evolution of breast imaging techniques has contributed significantly to improvements in margin outcomes over the past two decades.

Magnetic resonance imaging (MRI) has emerged as a valuable tool for preoperative assessment, particularly in cases where conventional imaging underestimates disease extent (10).

Positive margins are a significant concern as they are strongly associated with higher local recurrence (LR) rates. Other factors contributing to increased LR include multifocality, larger tumor size, and poor tumor differentiation (11-16). Among these, positive margins have been identified as the most critical risk factor for LR, with studies showing that patients with margins of ≤1 mm have a 21% incidence of LR and reduced disease-free survival rates (17).

Rational and knowledge gap

BCS can be categorized into two levels based on the extent of tissue removal: Level I, which involves the removal of less than 20% of the breast tissue, and Level II, which involves the removal of 20–50% of the breast tissue. The choice between these levels depends on the tumor size, location, and the surgeon’s assessment of achieving clear margins (18). Despite the widespread use of wire localization-guided BCS for non-palpable breast cancer, several important knowledge gaps remain in the literature. Positive margin rates have been extensively studied in general breast cancer populations; however, there is limited specific data focusing exclusively on non-palpable invasive breast cancer patients undergoing wire localization techniques. Most existing studies include mixed populations of palpable and non-palpable tumors, making it difficult to determine the true positive margin rates and associated factors specific to non-palpable lesions. While the association between positive margins and LR is well-established in general breast cancer populations, the long-term correlation between positive margins and LR outcomes specifically in non-palpable tumors managed with wire localization remains inadequately characterized.

Objective

Given these identified knowledge gaps, our study aims to provide comprehensive data specifically focused on non-palpable invasive breast cancer patients undergoing wire localization-guided BCS. By identifying the factors associated with positive margins, we seek to enhance surgical precision and improve the quality of care for breast cancer patients undergoing BCS. We present this article in accordance with the STROBE reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-25-16/rc).

Methods

Study design and setting

This study is a retrospective cohort analysis conducted to evaluate the incidence of positive surgical margins following BCS in patients with non-palpable invasive breast cancer. The study was carried out in the Department of Breast and Endocrine Surgery at Prince Sultan Military Medical City, a tertiary care and referral hospital located in Riyadh, Saudi Arabia. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board (IRB) of Prince Sultan Military Medical City (No. E-2421- Protocol ID: 824) and individual consent for this retrospective analysis was waived. Patient confidentiality was maintained by anonymizing all data during collection and analysis.

Study population

The study included all female patients aged 18 years and older who were diagnosed with histologically confirmed breast cancer and underwent BCS between October 2014 and October 2023. Patients were excluded if they met any of the following criteria: (I) surgery performed outside Prince Sultan Military Medical City; (II) presentation with recurrent breast cancer or metastatic disease at the time of diagnosis; (III) presence of a palpable breast mass at diagnosis; (IV) diagnosis of inflammatory breast cancer, multicentric breast cancer, or metastatic disease at presentation; or (V) diagnosis of breast cancer in pregnant patients. The study flowchart is presented in Figure 1.

Figure 1 Study flowchart. BCS, breast-conserving surgery; PSMMC, Prince Sultan Military Medical City.

Data collection

Data were retrospectively collected from electronic medical records and entered into a structured Excel database. The collected data included: (I) demographic information [age at diagnosis, gender, body mass index (BMI), marital status, menopausal status (pre/postmenopausal), history of oral contraceptive pill use, and breastfeeding history]; (II) clinical and pathological characteristics of the tumor (histologic type of cancer, breast cancer subtype, tumor location, tumor size, pretreatment lymph node staging, and nodal surgery type [sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND), or none]; (III) treatment details [use of neoadjuvant therapy (chemotherapy, hormonal therapy, or radiotherapy), estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor status, as well as adjuvant chemotherapy and radiotherapy usage]; and (IV) follow-up data: (10-year follow-up outcomes, including LR, and mortality). Study outcomes were post-resection positive margins and recurrence.

Outcome definitions

Positive surgical margins

Positive margins were defined as invasive carcinoma in the ink margins or ductal carcinoma in situ (DCIS) with less than 2 cm from the resection margin, described pathologically as ‘tumor on ink’ or ‘ink on tumor’. For the invasive carcinoma, this definition includes any microscopic tumor cells that directly contact the inked surgical margin surface, regardless of the extent of involvement. Margins were considered negative for “invasive carcinoma” when no tumor touched the inked margin surface, with any distance greater than 0 mm between tumor cells and the inked margin classified as negative. Margins were considered negative for “DCIS” when there is 2 mm or greater from the margin surface, and DCIS close margins (tumor within 1–2 mm of the margin but not touching the ink).

LR

LR was defined as the histologically confirmed reappearance of invasive breast carcinoma or DCIS in the ipsilateral breast (including the surgical bed and remaining breast tissue) or ipsilateral chest wall after the initial BCS. LR required tissue confirmation through core needle biopsy or surgical excision with pathological examination. Clinical or radiological suspicion alone, without histological confirmation, was not considered sufficient for the diagnosis of LR.

Surgical technique

Preoperative localization techniques using wire localization were used for non-palpable tumors. During the procedure, the tumor is excised with a margin of surrounding healthy tissue, typically 2 mm to 1 cm, to ensure clear margins. Sentinel lymph node biopsy was performed to assess lymph node involvement. Postoperative pathological examination confirms margin status, and adjuvant therapies like radiation are often recommended.

Follow-up

This study employed a passive follow-up methodology whereby patient outcomes were assessed through retrospective review of electronic medical records rather than active patient contact or prospective data collection. The standard institutional follow-up protocol for breast cancer patients undergoing BCS includes:

• Initial post-operative visit at 2–4 weeks;
• Subsequent visits every 3–4 months for the first 2 years;
• Every 6 months for years 3–5;
• Annual visits thereafter.

However, as this was a retrospective study with passive follow-up, the actual follow-up intervals varied based on individual patient compliance with scheduled appointments and clinical circumstances.

Statistical analysis

Continuous variables were assessed for normality using the Shapiro-Wilk test and histograms. Normally distributed data were analyzed using the Student’s t-test, while non-normally distributed data were analyzed using the Wilcoxon rank-sum test. Categorical variables were expressed as frequencies and percentages and compared using the chi-squared test or Fisher’s exact test when expected frequencies were less than 5. Time-to-event data, such as recurrence and mortality, were analyzed using Kaplan-Meier curves, and comparisons were made using the log-rank test. Missing data were addressed using multiple imputation techniques. The multiple imputation procedure was implemented using the multivariate normal (MVN) method, and a total of 20 imputed datasets were created. The imputation model included all variables with missing data <20%. Variables with missing data >20% were excluded from the analysis. To assess the robustness of our findings and validate the multiple imputation approach, a comprehensive sensitivity analysis was conducted by comparing the results obtained from the multiple imputation analysis with those derived from complete case analysis, which included only participants with complete data for all variables of interest. Univariable logistic regression was performed to identify factors associated with positive margins. Variables with a P value <0.2 in univariable analysis were included in the multivariable logistic regression model. ER status was included in the multivariable model because of its clinical significance. All statistical analyses were performed using Stata 18 (Stata Corp, College Station, TX, USA), and a two-sided P value <0.05 was considered statistically significant.

This retrospective cohort study included all consecutive patients who met the inclusion criteria during the study period, resulting in a sample size of 308 patients. The sample size was determined by practical considerations (i.e., all available eligible patients during the study timeframe) rather than formal a priori power calculations.

Results

Preoperative characteristics

The study included 308 female patients with breast cancer. Patients were grouped according to the positive margins post resection as patients with negative margins (n=265) and with positive margins (n=43).

Comparison of the baseline data revealed no difference in age, BMI, smoking status, marital status, age of menarche, number of pregnancies, menopause, history of OCPs use, history of breast-feeding, history of pregnancy, and family history of pregnancy (Table 1).

Tumor characteristics and operative data

All patients were diagnosed with IDC. The histological types did not significantly differ between groups. Preoperative therapy did not differ between groups. DCIS was diagnosed in 40 patients (15%) with negative margins and 10 patients with positive margins (23%) (P=0.18). There were no differences between groups regarding the ER, PR and HER2 receptors and percentage of Ki67 proteins. The median tumor size was 2 cm in both groups. There was no significant difference in tumor grading between groups (P=0.47). T-stage was significantly higher in patients with positive margins (P=0.04), with no difference between groups regarding N-stage and M-stage. Postoperative size and multifocality did not significantly differ between groups. Postoperative DCIS was significantly higher in patients with positive margins (P<0.001) (Table 2).

Follow-up outcomes

The median follow-up time was 6 years (Q1–Q3: 2–8 years), and the minimum follow-up duration was 10 months. Recurrence occurred in 30 (11.32%) patients with negative margins and 8 patients (18.60%) with positive margins (log-rank P=0.01) (Figure 2). Mortality occurred in 14 patients (5.28%) with negative margins and 2 (4.65%) patients with positive margins (log-rank P=0.90).

Figure 2 Freedom from recurrence in patients with negative and positive margins.

Factors associated with positive margins

Multivariable analysis identified higher T-stage [odds ratio (OR) 1.78, 95% CI: 1.11–2.85, P=0.02] and the presence of postoperative DCIS (OR 31, 95% CI: 4.13–236, P=0.001) as significant predictors of positive margins (Table 3).

Sensitivity analysis showed consistent results of multivariable analysis performed after multiple imputation and using complete case analysis.

Discussion

Key findings

The principle of BCS has been adopted in early breast cancer, with similar morbidity and mortality compared to radical surgery (6-8). The most dominant risk factor for LR is surgical margin status (18). This retrospective cohort study evaluated the incidence of positive surgical margins following BCS in 308 patients with non-palpable invasive breast cancer. The study found that 14% of patients (n=43) had positive margins, which were significantly associated with higher LR rates (18.6%) compared to negative margins (11.32%). Multivariable analysis identified higher T-stage tumors and the presence of postoperative DCIS as key predictors of positive margins.

Comparison with the literature

A study by Park et al. found that patients with positive surgical margins had a LR rate of 27%, which was three times higher than those with negative or close margins. Additionally, the administration of systemic therapy significantly reduced the LR rate to 7% compared to patients who did not receive such therapy (16). In one of the largest studies conducted by Freedman et al. in the United States, involving 1,262 patients, the cumulative incidence of LR at 5-year did not differ significantly among patients with negative, positive, or close margins. However, patients with positive invasive cancer margins who underwent re-excision experienced a reduction in LR rates to levels comparable to those with negative margins. Conversely, the 10-year cumulative LR incidence was significantly higher in patients with negative margins (P=0.04), with no significant difference observed in cases involving DCIS margins (15). In contrast to Freedman et al., our study found significantly higher LR rates in patients with DCIS-involved margins, which may be attributed to the higher incidence of DCIS in our sample.

For non-palpable breast lesions, wire localization is commonly used to guide tumor resection and assess radiological margins. Studies have shown that a radiological margin of <5 mm or the presence of multifocality increases the risk of microscopic positive margins (18,19). A variety of techniques were also developed to identify non-palpable breast lesions, such as magnetic seed. In a study conducted by Jordan et al., which compared electromagnet seed localization (ESL) to wire localization and concluded that higher precision was found in ESL and a lower incidence of positive margin compared to wire localizations (19).

A study by Kurtz et al. involving 586 patients with early breast cancer treated with BCS and radiation reported a positive margin rate of 10.4%. The LR rate was 15% over a median follow-up period of 71 months, with higher recurrence observed in cases of multifocal disease. This finding contrasts with our results, likely due to the lower incidence of multifocality in our sample (20).

Intraoperative ultrasound is another modality used for localizing non-palpable lesions, offering the potential for lower compromised margin rates. However, this technique was not utilized in our center, representing a limitation of our study, as wire localization was the sole method employed (21-25). To further reduce postoperative positive margins, the use of frozen section analysis has been advocated, with a sensitivity of up to 90% (26). Additionally, touch prep cytology is another modality that provides faster results than frozen sections, though its variable sensitivity has limited its widespread use (27).

Implications

The study highlights the importance of achieving negative surgical margins during BCS to reduce the risk of LR, particularly in patients with higher T-stage tumors and DCIS. The findings underscore the need for improved surgical techniques and intraoperative margin assessment methods to minimize positive margins and enhance patient outcomes. The higher LR rates associated with positive margins emphasize the critical role of adjuvant therapies, such as radiation and systemic treatments, in managing patients with close or positive margins.

Limitations

The study has several limitations that should be acknowledged. The study’s retrospective nature limits the ability to establish causal relationships and may introduce biases related to data collection and patient selection. Conducted at a single tertiary care center, the findings may not be generalizable to other settings, particularly those with different patient demographics or resource availability. The study relied exclusively on wire localization for non-palpable tumors, which may have contributed to the observed positive margin rates. The lack of utilization of intraoperative ultrasound or other advanced techniques represents a significant limitation. The extremely wide confidence interval for the postoperative DCIS odds ratio reflects the limited sample size and the resulting statistical instability of this estimate. The high prevalence of postoperative DCIS among patients with positive margins (97.7%) creates a sparse data structure that limits the precision of our estimates. While the association between postoperative DCIS and positive margins appears statistically significant, the wide confidence interval indicates substantial uncertainty regarding the precise magnitude of this relationship. While the sample size was adequate, a larger multicenter study with longer follow-up periods would provide more robust evidence on long-term outcomes, including LR and survival rates.

Conclusions

This study demonstrates that positive surgical margins after wire localization-guided BCS are associated with significantly higher LR rates, with higher T-stage tumors and postoperative DCIS serving as key predictors of positive margins. Based on these findings, we recommend implementing a risk-stratified approach to margin assessment in non-palpable breast cancer patients. High-risk patients with T2 or higher stage tumors should receive enhanced intraoperative assessment, including consideration of intraoperative ultrasound, wider initial excision margins, and potential frozen section analysis when DCIS is suspected. Additionally, enhanced preoperative planning with multidisciplinary team input and consideration of oncoplastic techniques may help reduce positive margin rates in this population. While BCS remains an effective treatment for early breast cancer, these targeted interventions based on identified risk factors may significantly improve surgical outcomes and reduce the need for re-excision procedures. Future prospective studies should evaluate the effectiveness of these risk-stratified approaches in reducing positive margin rates and improving patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-25-16/rc

Data Sharing Statement: Available at https://abs.amegroups.com/article/view/10.21037/abs-25-16/dss

Peer Review File: Available at https://abs.amegroups.com/article/view/10.21037/abs-25-16/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-25-16/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board (IRB) of Prince Sultan Military Medical City (No. E-2421- Protocol ID: 824) and individual consent for this retrospective analysis was waived. Patient confidentiality was maintained by anonymizing all data during collection and analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ravichandran K, Hamdan NA, Dyab AR. Population based survival of female breast cancer cases in Riyadh Region, Saudi Arabia. Asian Pac J Cancer Prev 2005;6:72-6.
2. Tabár L, Fagerberg CJ, Gad A, et al. Reduction in mortality from breast cancer after mass screening with mammography. Randomised trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1985;1:829-32. [Crossref] [PubMed]
3. DeSantis CE, Fedewa SA, Goding Sauer A, et al. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin 2016;66:31-42. [Crossref] [PubMed]
4. Luini A, Zurrida S, Paganelli G, et al. Comparison of radioguided excision with wire localization of occult breast lesions. Br J Surg 1999;86:522-5. [Crossref] [PubMed]
5. Landercasper J, Gundersen SB Jr, Gundersen AL, et al. Needle localization and biopsy of nonpalpable lesions of the breast. Surg Gynecol Obstet 1987;164:399-403.
6. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227-32. [Crossref] [PubMed]
7. Van Dongen JA, Voogd AC, Fentiman IS, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000;92:1143-50. [Crossref] [PubMed]
8. Switalla KM, Falade IO, Quirarte A, et al. Positive Margin Rates After Breast-Conserving Surgery by Histologic Subtype: A Systematic Review and Meta-analysis Evaluating the Impact of Oncoplastic Surgery. Ann Surg Oncol 2025;32:4899-909. [Crossref] [PubMed]
9. Falade I, Switalla K, Quirarte A, et al. Oncologic Safety of Immediate Oncoplastic Surgery Compared with Standard Breast-Conserving Surgery for Patients with Invasive Lobular Carcinoma. Ann Surg Oncol 2024;31:7409-17. [Crossref] [PubMed]
10. Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol 2008;26:3248-58. [Crossref] [PubMed]
11. Rubio IT, Ahmed M, Kovacs T, et al. Margins in breast conserving surgery: A practice-changing process. Eur J Surg Oncol 2016;42:631-40. [Crossref] [PubMed]
12. Meric F, Mirza NQ, Vlastos G, et al. Positive surgical margins and ipsilateral breast tumor recurrence predict disease-specific survival after breast-conserving therapy. Cancer 2003;97:926-33. [Crossref] [PubMed]
13. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41. [Crossref] [PubMed]
14. Abdulla HA, Rajab B, Hammad M, et al. Risk Factors for Positive Margins in Breast-Conserving Surgery. Cureus 2023;15:e38399. [Crossref] [PubMed]
15. Freedman G, Fowble B, Hanlon A, et al. Patients with early stage invasive cancer with close or positive margins treated with conservative surgery and radiation have an increased risk of breast recurrence that is delayed by adjuvant systemic therapy. Int J Radiat Oncol Biol Phys 1999;44:1005-15. [Crossref] [PubMed]
16. Park CC, Mitsumori M, Nixon A, et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol 2000;18:1668-75. [Crossref] [PubMed]
17. Singletary SE. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 2002;184:383-93. [Crossref] [PubMed]
18. Maishman T, Cutress RI, Hernandez A, et al. Local Recurrence and Breast Oncological Surgery in Young Women With Breast Cancer: The POSH Observational Cohort Study. Ann Surg 2017;266:165-72. [Crossref] [PubMed]
19. Jordan RM, Rivera-Sanchez L, Kelley K, et al. The Impact of an Electromagnetic Seed Localization Device Versus Wire Localization on Breast-Conserving Surgery: A Matched-Pair Analysis. Ann Surg Oncol 2023;30:4111-9. [Crossref] [PubMed]
20. Kurtz JM, Jacquemier J, Amalric R, et al. Breast-conserving therapy for macroscopically multiple cancers. Ann Surg 1990;212:38-44. [Crossref] [PubMed]
21. Mazouni C, Rouzier R, Balleyguier C, et al. Specimen radiography as predictor of resection margin status in non-palpable breast lesions. Clin Radiol 2006;61:789-96. [Crossref] [PubMed]
22. Frank HA, Hall FM, Steer ML. Preoperative localization of nonpalpable breast lesions demonstrated by mammography. N Engl J Med 1976;295:259-60. [Crossref] [PubMed]
23. Olsha O, Shemesh D, Carmon M, et al. Resection margins in ultrasound-guided breast-conserving surgery. Ann Surg Oncol 2011;18:447-52. [Crossref] [PubMed]
24. Thompson M, Henry-Tillman R, Margulies A, et al. Hematoma-directed ultrasound-guided (HUG) breast lumpectomy. Ann Surg Oncol 2007;14:148-56. [Crossref] [PubMed]
25. Krekel NM, Zonderhuis BM, Stockmann HB, et al. A comparison of three methods for nonpalpable breast cancer excision. Eur J Surg Oncol 2011;37:109-15. [Crossref] [PubMed]
26. Atkins J, Al Mushawah F, Appleton CM, et al. Positive margin rates following breast-conserving surgery for stage I-III breast cancer: palpable versus nonpalpable tumors. J Surg Res 2012;177:109-15. [Crossref] [PubMed]
27. Klimberg VS, Westbrook KC, Korourian S. Use of touch preps for diagnosis and evaluation of surgical margins in breast cancer. Ann Surg Oncol 1998;5:220-6. [Crossref] [PubMed]