Abstract
Purpose
Positive margins after breast-conserving surgery (BCS) are an important risk factor for local tumor recurrence and the need for re-excision in women with breast cancer. It remains unclear which factors collectively influence positive margins after BCS and whether the outcomes vary among hospitals. This study investigated the occurrence and risk factors of positive margins after BCS in women with breast cancer in two Dutch hospitals.
Methods
Data were collected retrospectively from medical records of women who were diagnosed with newly invasive breast carcinoma or carcinoma in situ and underwent primary BCS between January 1, 2018 and December 31, 2020 in two Dutch hospitals.
Results
A total of 423 cases (410 patients) were included, with a median age of 58 years (interquartile range 51–66). On average, the positive margin rate after BCS was 8.0%, which was significantly higher in the low-volume hospital (14.9%) than in the high-volume hospital (5.9%). Invasive lobular carcinoma (odds ratio [OR] = 4.97, confidence interval [CI] = 1.91–12.94), postoperative tumor size (OR = 1.07, CI = 1.03–1.11), low hospital volume (OR = 3.90, CI = 1.58–9.66), and lumpectomy size (OR = 0.97, CI = 0.94–1.00) were significantly associated with positive margins after BCS.
Conclusion
Positive margin rate after BCS was low, with 8.0% among all cases and varied significantly between the hospitals. Patient-, tumor-, radiological-, and surgery-related factors may contribute to these variations. An optimized collaborative multidisciplinary approach to breast cancer care, particularly between radiologists and surgeons, should be strived to achieve improved oncological outcomes in women after BCS.
Keywords: Breast cancer, Breast-conserving surgery, Oncoplastic surgery, Radical resection, Surgical margin status
Introduction
Breast cancer is the most frequently diagnosed cancer and leading cause of cancer-related mortality amongst women worldwide [1]. Breast-conserving surgery (BCS), also known as lumpectomy or partial mastectomy, is a standard treatment option for early-stage breast cancer and locally advanced tumors after neoadjuvant chemotherapy [2, 3]. While BCS is associated with good cosmetic outcomes and preserved breast function, it is not without challenges [4, 5].
The presence of positive margins after surgery is an important risk factor for tumor recurrence, leading to the need for additional surgery or radiotherapy [6, 7]. Approximately one-fourth of patients who undergo initial BCS for breast cancer additionally undergo a subsequent surgical intervention [8]. Therefore, minimizing the occurrence of positive margins is an important goal in BCS, as it reduces the risk of cancer recurrence and the need for additional treatment. Several risk factors for positive margins after BCS have been identified in previous studies, including size and location of the tumor, type of cancer, patient factors (i.e., age and comorbidities), and the experience of the surgeon [9–12].
Breast cancer treatment follows a multidisciplinary approach that aims to deliver personalized and effective care to patients, involving coordinated care among different specialties [13]. Decisions made by multidisciplinary teams have been shown to improve clinical decisions, evidence-based practice, and better treatment outcomes [13, 14]. In the Netherlands, breast cancer is treated in hospitals by multidisciplinary teams in accordance with the established breast cancer guidelines [15]. However, the composition and level of experience of the multidisciplinary teams may vary across hospitals and there may be (minor) differences in the work-up process and hospital volume. It is unclear whether those differences between hospitals are associated with the positive margin rate after BCS. To address this, we compared data from BCS in women with invasive or in situ breast cancer from two hospitals in search of factors related to positive margin status.
Materials and Methods
Study Design and Population
This study included all consecutive female adult patients clinically diagnosed with invasive breast carcinoma or carcinoma in situ who underwent BCS between January 1, 2018, and December 31, 2020, in two Dutch hospitals, an academic hospital (University Medical Center Utrecht) and a breast cancer clinic (Alexander Monro Hospital Bilthoven). The study population was a subset of a previously conducted cohort study [16]. Exclusion criteria were as follows: patients undergoing surgery for presumed malignant lesion in whom final pathology was benign, malignant and benign lesions combined in the same breast, previous oncological surgery to the same breast, previous breast augmentation, surgery for Paget’s disease, and surgery requiring two separate lumpectomies in one breast. The study was approved by the hospital’s Institutional Review Board (No. 21/327).
Data Collection
Standard clinical variables were retrospectively collected from the electronic medical health records by two data collectors, including age, weight, height, smoking status, physical exam findings, cup size, tumor location, pathological TNM staging, findings from any imaging studies performed, resection margin status, and histopathological details including tumor type.
Clinical Work-Up
Before surgery, a standard diagnostic evaluation was performed in all patients, including medical history, physical examination, and recent radiological imaging (mammography, ultrasonography, and/or magnetic resonance imaging [MRI] and/or core needle biopsy). All radiological images were reviewed and reported by specialized radiologists as part of routine clinical care. The maximum diameter of the tumor in the breast was reported for each radiological modality, and the largest measurement was used in the analysis. All cases were discussed during a multidisciplinary meeting. In the case of neoadjuvant therapy, sizes were determined before and after therapy. Surgery was performed by an oncologic surgeon regularly in collaboration with a plastic surgeon. Perioperative tumor localization was performed by palpation, wire localization, and/or radio-guided with iodine-125 seeds. Additional surgery due to incomplete resection was also reported. All removed tissues were processed according to standard procedures at grossing, applying ink to the resection margins, and evaluated by specialized breast pathologists. Reports were reviewed for the maximum diameter of the excised lump, maximum diameter of the tumor, tumor type (ductal versus lobular), and the margin status.
The radiological estimation was calculated as the difference between the maximal pre-operative radiological diameter of the tumor and the post-operative maximum pathological diameter of the tumor. Radiological underestimation was reported for analysis.
Definition Margin Status
The closest distance between the inked lumpectomy edge and any cancerous tissue was analyzed. Resection was considered incomplete (positive margins) if the margins were more than focally positive (tumor touching the inked margin over a length of more than 2 mm or multiple focally positive foci). In most of these cases, re-excision surgery was performed. However, for focally positive margins, defined as tumor touching the inked margin over a length of 2 mm or less in one focus, in most cases, adjuvant radiotherapy was administered, but in some cases, secondary surgery was performed. Suspicion of multifocality was defined as the presence of two or more tumor foci within the same quadrant of the ipsilateral breast.
Previous Studies
A search in EMBASE was conducted using search terms related to “breast conserving surgery,” “lumpectomy,” “positive margins,” and “incomplete resection” to identify studies about the proportions of positive margins after BCS and factors associated with non-radical resections. Reference lists from these articles were also examined to determine publications. This resulted in an overview of data from 14 studies about factors associated with positive margins in patients with invasive breast cancer or carcinoma in situ to compare to our results.
Statistical Analysis
Prevalence and means with standard deviation or medians with interquartile range were calculated to describe the study population. Chi-square (χ2) test was used to compare categorical variables between women with positive and clear resection margins after BCS. Multivariable logistic regression analysis estimating odds ratios (OR) and 95% confidence intervals was performed to identify factors associated with positive margins after BCS. In this multivariable logistic regression model, all variables were adjusted for all other variables except for the one of interest. Variables with an estimated p value of <0.05 in the univariable logistic regression, i.e., presence of invasive lobular carcinoma (ILC), postoperative pathological tumor size, and hospital type, were included in the multivariable logistic regression model. Also, variables that have been identified in the literature study as potential risk factors, i.e., age [9, 11], node positivity [12, 17], cup size [18], radiological underestimation [19, 20], and pathological lumpectomy size [21, 22], were included in the model. p values <0.05 were considered to be statistically significant. SPSS v29.0 was used to analyze the data for this study.
Results
Baseline Characteristics
From 2018 to 2020, a total of 529 cases (508 patients) clinically diagnosed with invasive breast carcinoma and/or carcinoma in situ underwent primary BCS. We excluded 106 cases (20%) for the following reasons: 40 cases (7.6%) due to surgery for benign lesions or malignant and benign lesions combined, 2 cases (0.4%) due to surgery for Paget’s disease, 24 cases (4.5%) due to previous oncological breast surgery to the same breast, and 9 cases (1.7%) had received breast augmentation. Fourteen patients (2.6%) had two separate lumpectomies in 1 breast, and in 7 cases (1.3%), the tumor was removed “en bloc” with the reduction tissue. Ten patients (1.9%) objected to participating in pseudonymized research. The remaining 423 cases (410 patients) were eligible for analysis. Thirteen patients were included with tumors in both breasts, which were considered as 2 separate cases eligible for analysis.
Tumor Characteristics and Radiological Findings
The median age of the total study population was 58 years at the time of surgery (interquartile range 51–66 years) and a mean body mass index of 25.0 kg/m2 (standard deviation 4). Of the 423 cases, 34 (8.0%) had positive margins and 389 cases (92.0%) had clear margins after BCS. Of the 34 cases with positive margins, 29 (85.3%) had invasive breast cancer and 5 (14.7%) ductal carcinoma in situ (DCIS).
Tumor and surgery characteristics (Table 1) showed that most tumors were in the upper outer quadrant (43.7%) and were diagnosed as infiltrating ductal cancer (53.7%). Patients with positive margins were significantly more frequently diagnosed with ILC (32.4%) than patients with clear margins (5.9%, p = 0.00). Moreover, a significant difference in tumor classification between the groups (p = 0.01) was observed, in which clinical primary tumor size (cT)-2 (41.2% vs. 26.7%) and cT3-4 (8.8% vs. 1.0%) tumors were more likely to present in the positive margin group. Additionally, cases with positive margins had significantly a higher median radiological underestimation of the tumor size than cases with clear margins (12 vs. 4 mm, p = 0.00). No significant differences were found in the nodal status and neo-adjuvant therapy rates between both groups.
Table 1.
Tumor and surgical characteristics of 423 cases with breast cancer with clear or positive resection margins after BCS in two hospitals
| Variable | Total cases (n = 423) | Cases with positive margins (n = 34, 8%) | Cases with clear margins (n = 389, 92%) | p value |
|---|---|---|---|---|
| Age at time of surgery, median (IQR), years | 58 (51–66) | 60 (50–69) | 58 (51–65) | 0.21 |
| BMI, mean±SD, kg/m2 | 25±4.0 | 25.2±4.8 | 25±3.9 | 0.74 |
| Smoker, yes, n (%) | 57 (13.5) | 5 (14.7) | 52 (13.4) | 0.83 |
| Cup size, n (%) | 0.56 | |||
| A–B | 123 (29.1) | 8 (23.5) | 115 (29.6) | |
| C–D | 207 (49) | 20 (58.8) | 187 (48.1) | |
| E–I | 83 (19.6) | 6 (17.6) | 77 (19.8) | |
| Missing | 10 (2.3) | 0 (0.0) | 10 (2.5) | |
| Tumor localization, n (%) | 0.60 | |||
| Upper inner quadrant | 67 (15.8) | 2 (5.9) | 65 (16.7) | |
| Lower inner quadrant | 44 (10.4) | 5 (14.7) | 39 (10.0) | |
| Upper outer quadrant | 185 (43.7) | 15 (44.1) | 170 (43.7) | |
| Lower outer quadrant | 72 (17.0) | 6 (17.6) | 66 (17.0) | |
| Central | 44 (10.4) | 5 (14.7) | 39 (10.0) | |
| Overlapping | 11 (2.6) | 1 (2.9) | 10 (2.6) | |
| Histological finding, n (%) | 0.00 | |||
| DCIS | 69 (16.3) | 5 (14.7) | 64 (16.5) | |
| IDC | 227 (53.7) | 13 (38.2) | 214 (55.0) | |
| IDLC | 68 (15.7) | 5 (14.7) | 63 (16.2) | |
| ILC | 34 (8.0) | 11 (32.4) | 23 (5.9) | |
| Othera | 25 (5.9) | 0 (0.0) | 25 (6.4) | |
| cT categoryb, n (%) | 0.01 | |||
| 1a–c | 224 (53) | 12 (35.3) | 212 (54.5) | |
| 2 | 118 (27.9) | 14 (41.2) | 104 (26.7) | |
| 3–4 | 7 (1.6) | 3 (8.8) | 4 (1.0) | |
| is | 74 (17.5) | 5 (14.7) | 69 (17.7) | |
| cN status, n (%) | 0.20 | |||
| Positive | 37 (8.7) | 5 (14.7) | 32 (8.2) | |
| Negative | 386 (91.3) | 29 (85.3) | 357 (91.8) | |
| Neo-adjuvant therapy, n (%) | 109 (25.8) | 11 (32.4) | 98 (25.2) | 0.36 |
| MRI before surgery, n (%) | 305 (72.1) | 28 (82.4) | 277 (71.2) | 0.32 |
| Maximal radiological diameter of disease, median (IQR), mm | 15.5 (9–23) | 19.5 (7–40) | 15 (9–23) | 0.01 |
| Radiological underestimation of tumor size, median (IQR), mm | 5 (2–12) | 12 (6–24) | 4 (2–11) | 0.00 |
| Maximal pathological lumpectomy diameter, median (IQR), mm | 55 (45–70) | 60 (49–73) | 55 (45–70) | 0.55 |
| Postoperative maximal pathological tumor size, median (IQR), mm | 16 (9–25) | 25 (18–45) | 15 (9–24) | 0.00 |
| Presence of DCIS component in resection, n (%) | 261 (61.7) | 22 (64.7) | 239 (61.4) | 0.73 |
| Hospital, n (%) | 0.00 | |||
| High-volume | 322 (76.1) | 19 (55.8) | 303 (77.9) | |
| Low-volume | 101 (23.9) | 15 (44.2) | 86 (22.1) |
Chi-square test was used to compare categorical covariates between cases with clear and positive resection margins after BCS.
BCS, breast-conserving surgery; IQR, interquartile range; BMI, body mass index; SD, standard deviation; IDC, invasive ductal carcinoma; IDLC, invasive ductolobular carcinoma; ILC, invasive lobular carcinoma; DCIS, ductal carcinoma in situ; cT, clinical primary tumor size; cN, clinical lymph node status; MRI, magnetic resonance imaging; is, in situ.
aLobular carcinoma in situ, mucinous carcinoma, metaplastic carcinoma, papillary carcinoma and tubular carcinoma.
bTNM classification following the American Joint Committee on Cancer Eighth Edition Cancer Staging.
Surgical and Pathological Outcomes
The median postoperative pathological tumor size showed a significant difference between both groups: 25 mm in positive margins vs. 15 mm in clear margins (p = 0.00). However, no significant difference was observed in the maximal pathological lumpectomy diameter (60 mm in positive margins vs. 55 mm in clear margins, p = 0.55). Among the 34 patients with positive margins, 79.4% (27/34) underwent additional surgery, 5.9% (2/34) had clear margins after reduction surgery, 11.8% (4/34) received adjuvant radiotherapy, and 2.9% (1/34) received no additional therapy due to her underlying medical condition.
After surgery, histological analysis showed 40 (9.5%) patients with focally positive margins after BCS. These margins were considered as clear margins after adjuvant radiotherapy or surgery when indicated. No difference was observed in DCIS involvement in the resection between positive and clear margins.
Factors Associated with Non-Radical Resection
The multivariable logistic regression analysis showed that ILC (OR = 4.97, p = 0.001) and larger postoperative tumor size (OR = 1.07, p = 0.001) were the strongest factors associated with positive margins, followed by low hospital volume (OR = 3.90, p = 0.003) and smaller lumpectomy size (OR = 0.97, p = 0.022) (Table 2). Age at time of surgery, cup size, node status, and radiological underestimation of the tumor size were not independently associated with positive margins.
Table 2.
Multivariable logistic regression analysis results of factors associated with positive margins after BCS in 423 cases with breast cancer or carcinoma in situ
| Variable | Adjusted OR | 95% CI | p value |
|---|---|---|---|
| Age at time of surgery (years) | 1.01 | 0.97–1.05 | 0.685 |
| Cup size | |||
| A–B | 0.85 | 0.22–3.19 | 0.804 |
| C–D | 0.97 | 0.31–3.02 | 0.958 |
| >E | 1 (reference) | ||
| Node status | |||
| Positive | 1.13 | 0.27–4.77 | 0.865 |
| Negative | 1 (reference) | ||
| Invasive lobular carcinoma | |||
| Yes | 4.97 | 1.91–12.94 | 0.001 |
| No | 1 (reference) | ||
| Radiological underestimation (mm) | 0.99 | 0.95–1.04 | 0.663 |
| Lumpectomy size (mm) | 0.97 | 0.94–1.00 | 0.022 |
| Postoperative pathological tumor size (mm) | 1.07 | 1.03–1.11 | 0.001 |
| Hospital type | |||
| Low-volume | 3.90 | 1.58–9.66 | 0.003 |
| High-volume | 1 (reference) | ||
In this multivariable logistic regression model, all variables were adjusted for all other variables except for the one of interest.
BCS, breast-conserving surgery; OR, odds ratio; CI, confidence interval.
Differences between Hospitals
In the high-volume hospital (322 cases), surgical procedures were performed by 4 breast surgeons and 6 plastic surgeons. In the low-volume hospital (101 cases), surgical procedures were conducted by a team comprising 2 breast surgeons, 2 fellow surgeons, surgeons in training, and 2 plastic surgeons.
Table 3 shows the differences of tumor and surgical characteristics between both hospitals. Patients in the low-volume hospital were significantly older (59 years, p = 0.01) and had more often positive margins after BCS (14.9% vs. 5.9%, p = 0.00), and a larger maximal pathological lumpectomy diameter (70 mm vs. 53 mm, p = 0.00) was observed. The postoperative maximal pathological tumor size was slightly higher in the high-volume hospital (16 mm vs. 18 mm, p = 0.13), as was the median maximal radiological tumor diameter (16 vs. 12 mm, p = 0.00). The high-volume hospital had a lower median of the radiological underestimation of the tumor size (4 vs. 7 mm, p = 0.04) and had more often an MRI before surgery (75.2% vs. 62.4%, p = 0.04). In the high-volume hospital, localization was performed by palpation or a wire, and in the low-volume hospital, localization was performed by palpation and iodine-125. Oncoplastic surgery was more common in the high-volume hospital than in the low-volume hospital (81.1% versus 13.9% of operations per hospital).
Table 3.
Tumor and surgical characteristics for 423 cases with breast cancer or carcinoma in situ undergoing BCS in two hospitals
| Variable | Cases treated in high-volume hospital (n = 322) | Cases treated in low-volume hospital (n = 101) | p value |
|---|---|---|---|
| Age at time of surgery, median (IQR), years | 57 (51–65) | 59 (53–69) | 0.01 |
| BMI, mean±SD, kg/m2 | 24.8±3.6 | 25.7±5.0 | 0.06 |
| Smoker, yes, n (%) | 44 (13.7) | 13 (12.9) | 0.84 |
| Cup size, n (%) | 0.73 | ||
| A–B | 94 (29.2) | 29 (28.7) | |
| C–D | 159 (49.4) | 48 (47.5) | |
| E–I | 67 (20.8) | 16 (15.8) | |
| Missing | 2 (0.6) | 8 (7.9) | |
| Tumor localization, n (%) | 0.56 | ||
| Upper inner quadrant | 51 (15.8) | 16 (15.8) | |
| Lower inner quadrant | 32 (9.9) | 12 (11.9) | |
| Upper outer quadrant | 141 (43.8) | 44 (43.6) | |
| Lower outer quadrant | 58 (18.0) | 14 (13.9) | |
| Central | 34 (10.6) | 10 (9.9) | |
| Overlapping | 6 (1.9) | 5 (5.0) | |
| Histological finding, n (%) | 0.06 | ||
| DCIS | 48 (14.9) | 21 (20.8) | |
| IDC | 185 (57.5) | 42 (41.6) | |
| IDLC | 51 (15.8) | 17 (16.8) | |
| ILC | 22 (6.8) | 12 (11.9) | |
| Othera | 16 (4.3) | 9 (6.2) | |
| cT categoryb, n (%) | 0.01 | ||
| 1a–c | 174 (54) | 50 (49.5) | |
| 2 | 94 (29.2) | 24 (23.7) | |
| 3–4 | 4 (1.2) | 3 (3.0) | |
| is | 50 (15.5) | 24 (23.8) | |
| cN status, n (%) | 0.62 | ||
| Positive | 31 (9.6) | 6 (5.9) | |
| Negative | 291 (90.4) | 95 (94.1) | |
| Neo-adjuvant therapy, n (%) | 89 (27.6) | 20 (19.8) | 0.12 |
| MRI before surgery, n (%) | 242 (75.2) | 63 (62.4) | 0.04 |
| Maximal radiological diameter of disease, median (IQR), mm | 16 (10–24) | 12 (0–57) | 0.00 |
| Radiological underestimation of tumor size, median (IQR), mm | 4 (2–11) | 7 (3–15) | 0.04 |
| Maximal pathological lumpectomy diameter, median IQR), mm | 53 (45–65) | 70 (53–85) | 0.00 |
| Postoperative maximal pathological tumor size, median (IQR), mm | 16 (9–24) | 18 (10–31) | 0.13 |
| Focally positive margins, n (%) | 33 (10.2) | 7 (6.9) | 0.32 |
| Non-radical resection (positive margins)c, n (%) | 19 (5.9) | 15 (14.9) | 0.00 |
| Positive margins: DCIS, n (%) | 4 (21.1) | 1 (6.7) | |
| Positive margins: invasive tumor, n (%) | 15 (78.9) | 14 (93.3) | |
| Presence of DCIS component in resection, n (%) | 208 (64.3) | 53 (52.5) | 0.02 |
BCS, breast-conserving surgery; IQR, interquartile range; BMI, body mass index; SD, standard deviation; IDC, invasive ductal carcinoma; IDLC, invasive ductolobular carcinoma; ILC, invasive lobular carcinoma; DCIS, ductal carcinoma in situ; cT, clinical primary tumor size; cN, clinical lymph node status; MRI, magnetic resonance imaging.
aLobular carcinoma in situ, mucinous carcinoma, metaplastic carcinoma, papillary carcinoma, and tubular carcinoma.
bTNM classification following the American Joint Committee on Cancer Eighth Edition Cancer Staging.
cResection was considered incomplete if the margins were more than focally positive. Focally positive margins were considered as negative margins.
Discussion
The present study shows that 8.0% of all breast cancer or carcinoma in situ cases treated with BCS had positive margins post-BCS. The multivariable adjusted logistic regression showed that the presence of ILC, a larger postoperative tumor, a smaller lumpectomy size, and a low hospital volume were associated with a higher risk of a positive margin after BCS. There were significant differences in several (radiological and surgical) variables between both hospitals related to age at time of surgery, presence of ILC histological type, radiological underestimation of the tumor size, MRI rates, lumpectomy size, and positive margin rate.
The positive margin rates after BCS in this study, i.e., 5.9% and 14.9%, were lower than or similar to those in prior studies, which reported ranges between 7.3% and 52% [9–12, 17, 21, 23–29] (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000544904). In our study, factors associated with a positive margin were both tumor- and hospital-related factors. Tumor-related factors, such as ILC histological type [10, 23, 24, 27] and larger postoperative tumor size [10, 12, 29], were consistent with those in prior studies. In this study, we found that a larger lumpectomy size significantly reduced the risk of a positive margin after BSC. This association was verified by another cohort study and could be related to novel approaches in BCS to improve reconstructive outcomes [22]. BCS is associated with an average 2- to 4-fold removal of excessive tissue [30]. However, according to previous studies, with oncoplastic surgery (BCS in combination with reconstruction), more extensive resection can be performed without aesthetic limitations, the incidence of tumor-free margins increased, and the need for re-excision can be decreased [31, 32]. Therefore, it is crucial to thoroughly evaluate each case prior to surgery to make a resection plan aimed at achieving clear margins. According to this study, this plan should consider relevant factors such as tumor size and ILC type. Our study team has developed a tool to predict lumpectomy size with the body mass index, breast size, and radiological tumor size; however, further validation is needed [16].
Although many studies have looked at factors affecting positive margins after initial surgery, less is known about the influence of hospital characteristics on margin involvement in BCS. Previous studies have only shown that breast cancer surgery in specialized, teaching, and high-volume hospitals is associated with improved long-term survival [33, 34]. The results of this study indicate that patients treated in a high-volume specialized breast clinic less often had positive margins than patients treated in the low-volume center, likely due to several patient-, tumor-, radiological, surgeon-, and hospital-related factors.
The age of patients at the time of surgery was significantly different between both hospitals. In the low-volume hospital, more older patients with multimorbidity were treated. There is evidence that age [9, 11] and multimorbidity [12] may be related to higher non-radical resection rates. However, our multivariable logistic regression analysis did not show a significant association between age and positive margins. Tumor-related factors, such as cT, presence of ILC, and presence of DCIS component in resection were also significantly different between the two hospitals. In the low-volume hospital, cTs were larger and there were more ILC and less DCIS component in the resection compared to the high-volume hospital. According to our multivariate analysis, the presence of ILC and larger tumor size led to positive margins, which can at least partially explain the higher positive margin rate in the low-volume hospital.
Radiological factors were also found to play a role between both hospitals. The high-volume hospital performed significantly more often an MRI scan before surgery than the low-volume hospital. However, according to this study, the absence of MRI did not result in more positive margins. This is in line with a multicenter trial in which preoperative MRI was also not associated with positive margins [35]. In contrast with our findings, there are prior studies that have shown that omitting MRI can lead to more positive margins after BCS [17], and that MRI is generally superior to ultrasound and mammography in tumor size measurement [36, 37]. However, MRI has the highest overestimation rate and might cause overtreatment by increasing the mastectomy rate [38]. Therefore, caution should be taken for the indication and interpretation of MRI influence. Moreover, the radiological diameter of the disease and underestimation rate were different between both hospitals.
The present study did not show an association between radiological underestimation and positive margins. However, in two other studies, the radiological underestimation of the tumor size showed an association with positive margins and re-excision rate after BCS [19, 20]. Radiological underestimation can lead to less accurate lumpectomy sizes performed by surgeons, resulting in more resections with positive margins. Furthermore, the difference in estimation of the radiological diameter of the disease can be related to the significant difference in performing an MRI for tumor size measurement between both hospitals. Nevertheless, the MRI utilization rate observed in this study (75.2% and 62.4% for the high- and low-volume hospitals, respectively) was far above the rate reported in a separate population-based cohort study involving 36,050 patients in the Netherlands (29.8%) [39]. Additionally, both hospitals performed different localization techniques: wire-marking in the high-volume hospital and iodine-125 in the low-volume hospital. The literature shows that localization of non-palpable breast cancer using iodine-125 seeds is, at least, as good as the standard wire localization procedure, while iodine-125 is an easier and more comfortable method [40]. Also, positive margin, re-excision, and mastectomy rates seem to be similar in both groups [41]. Therefore, we did not consider the localization technique to be a factor associated with positive margins in this study.
Furthermore, surgeon- and hospital-related factors such as hospital volume and lumpectomy diameter were different between both hospitals. In the low-volume hospital, fewer BCS were performed than those the high-volume hospital. An increasing body of literature demonstrates a positive correlation between volume (either surgeon or hospital) and oncological outcomes, resulting in centralization for procedures [42]. However, a previous multicenter study derived from 20 institutions in the Netherlands, including community-based and university-affiliated hospitals, showed no difference between positive surgical margin rates from university-affiliated and community hospitals [17]. This was supported by two other studies investigating hospital volume [21, 43]. As a result, we should not consider hospital volume to be the major predictor of positive margins since many other closely associated characteristics also contribute to BCS margin status like patient characteristics and radiological work-up. Moreover, oncoplastic surgery was performed more frequently in the high-volume hospital, which may affect the lumpectomy size and, consequently, the margin status.
Apart from hospital volume, surgeon volume has also been previously identified as a predictive factor for positive margins. Since the low-volume hospital is an academic teaching hospital, there were also fellow surgeons and surgeons in training with less experience performing BCS. The available literature is inconsistent regarding the impact of surgeon volume on the occurrence of positive margins. A former cohort study indicated that surgeons with a higher case volume tended to inflict less often positive margins after the initial resection. [21]. Also, another study analyzing the re-operation rates across breast surgeons in a single center stated that performing BCS demonstrated variability in re-operation rates and margin practices among the breast surgeons [44]. In contrast, another study found no correlation between surgeon volume and margin status [21]. Consequently, there is a need for studies to analyze surgeon-specific factors that may affect re-operation rates.
Limitations
In this study, we provide an important overview of factors that are associated with a positive margin and the influence of hospital characteristics on margin involvement in BCS. However, the retrospective data collection of this study did not allow for the collection of certain baseline factors, long-term follow-up data, and detailed information about the work-up in both centers. Furthermore, the relatively small sample size in the low-volume hospital may result in wider confidence intervals, potentially increasing the uncertainty of the results. Moreover, the impact of differences in surgical teams, surgical volume, and tumor localization techniques were not analyzed in this study. As a result, a future prospective study is needed to further investigate the multidisciplinary approach to breast cancer and its effect on margin status and re-operation rates in greater detail.
Conclusion
In summary, 8.0% of all cases with breast cancer or carcinoma in situ had positive margins after BCS. Several factors were associated with positive margins after BCS, including ILC histological type, higher postoperative tumor size, smaller lumpectomy size, and low hospital volume. Significant variations in hospital characteristics influenced radiological and surgical outcomes between both hospitals, emphasizing the importance of a multidisciplinary approach to breast cancer care that optimizes collaboration between radiologists and surgeons to minimize location-related differences and improve oncological outcomes for women undergoing BCS.
Statement of Ethics
The study was approved by the hospital’s Institutional Review Board (nr 21/327). In accordance with local/national guidelines, written informed consent was not required from the participants as this was an observational study.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors declare that they did not receive any funds, grants, or other support during the preparation of this manuscript.
Author Contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by S.M., S.A.M.G., A.J.W., and P.J.D. The first draft of the manuscript was written by S.M. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding Statement
The authors declare that they did not receive any funds, grants, or other support during the preparation of this manuscript.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are not publicly available due to privacy statements but are available from the corresponding author on reasonable request.
Supplementary Material.
References
- 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. [DOI] [PubMed] [Google Scholar]
- 2. Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twenty-year followup of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347(16):1227–32. [DOI] [PubMed] [Google Scholar]
- 3. Spronk PER, Volders JH, van den Tol P, Smorenburg CH, Vrancken Peeters MJTFD. Breast conserving therapy after neoadjuvant chemotherapy; data from the Dutch Breast Cancer Audit. Eur J Surg Oncol. 2019;45(2):110–7. [DOI] [PubMed] [Google Scholar]
- 4. Cardoso MJ, Oliveira H, Cardoso J, Cardoso J. Assessing cosmetic results after breast conserving surgery. J Surg Oncol. 2014;110(1):37–44. [DOI] [PubMed] [Google Scholar]
- 5. Fitzal F, Mittlboeck M, Trischler H, Krois W, Nehrer G, Deutinger M, et al. Breast-conserving therapy for centrally located breast cancer. Ann Surg. 2008;247(3):470–6. [DOI] [PubMed] [Google Scholar]
- 6. Mechera R, Viehl CT, Oertli D. Factors predicting in-breast tumor recurrence after breast-conserving surgery. Breast Cancer Res Treat. 2009;116(1):171–7. [DOI] [PubMed] [Google Scholar]
- 7. Kreike B, Hart AAM, van de Velde T, Borger J, Peterse H, Rutgers E, et al. Continuing risk of ipsilateral breast relapse after breast-conserving therapy atlong-term follow-up. Int J Radiat Oncol Biol Phys. 2008;71(4):1014–21. [DOI] [PubMed] [Google Scholar]
- 8. Wilke LG, Czechura T, Wang C, Lapin B, Liederbach E, Winchester DP, et al. Repeat surgery after breast conservation for the treatment of stage 0 to II breast carcinoma A report from the national cancer data base, 2004-2010. JAMA Surg. 2014;149(12):1296–305. [DOI] [PubMed] [Google Scholar]
- 9. Aziz D, Rawlinson E, Narod SA, Sun P, Lickley HLA, McCready DR, et al. The role of reexcision for positive margins in optimizing local disease control after breast-conserving surgery for cancer. Breast J. 2006;12(4):331–7. [DOI] [PubMed] [Google Scholar]
- 10. Kurniawan ED, Wong MH, Windle I, Rose A, Mou A, Buchanan M, et al. Predictors of surgical margin status in breast-conserving surgery within a breast screening program. Ann Surg Oncol. 2008;15(9):2542–9. [DOI] [PubMed] [Google Scholar]
- 11. Saadai P, Moezzi M, Menes T. Preoperative and intraoperative predictors of positive margins after breast-conserving surgery: a retrospective review. Breast Cancer. 2011;18(3):221–5. [DOI] [PubMed] [Google Scholar]
- 12. Hanna J, Lannin D, Killelea B, Horowitz N, Chagpar AB. Factors associated with persistently positive margin status after breast-conserving surgery in women with breast cancer: an analysis of the national cancer database. Am Surg. 2016;82(8):748–52. [PubMed] [Google Scholar]
- 13. Saini KS, Taylor C, Ramirez AJ, Palmieri C, Gunnarsson U, Schmoll HJ, et al. Role of the multidisciplinary team in breast cancer management: results from a large international survey involving 39 countries. Ann Oncol. 2012;23(4):853–9. [DOI] [PubMed] [Google Scholar]
- 14. Vinod SK, Sidhom MA, Delaney GP. Do multidisciplinary meetings follow guideline-based care. J Oncol Pract. 2010;6(6):276–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. FMS: Dutch guideline breast construction.
- 16. Makineli S, Strijbis R, Tsehaie J, Schellekens PPA, Moman MR, Veenendaal LM, et al. Predictors of lumpectomy size after breast-conserving surgery in patients with breast cancer: a retrospective cohort study. Plast Reconstr Surg. 2024;154(3):503–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Pleijhuis RG, Kwast ABG, Jansen L, de Vries J, Lanting R, Bart J, et al. A validated web-based nomogram for predicting positive surgical margins following breast-conserving surgery as a preoperative tool for clinical decision-making. Breast. 2013;22(5):773–9. [DOI] [PubMed] [Google Scholar]
- 18. van Loevezijn AA, Geluk CS, van den Berg MJ, van Werkhoven ED, Vrancken Peeters MJTFD, van Duijnhoven FH, et al. Immediate or delayed oncoplastic surgery after breast conserving surgery at The Netherlands Cancer Institute: a cohort study of 251 cases. Breast Cancer Res Treat. 2023;198(2):295–307. [DOI] [PubMed] [Google Scholar]
- 19. Schultek G, Gerber B, Reimer T, Stubert J, Hartmann S, Martin A, et al. Radiological underestimation of tumor size as a relevant risk factor for positive margin rate in breast-conserving therapy of pure ductal carcinoma in situ (DCIS). Cancers. 2022;14(10):2367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Simpson D, Allan J, McFall B. Radiological underestimation of tumor size influences the success rate of Re-excision after breast-conserving surgery. Eur J Breast Health. 2021;17(4):363–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Lovrics PJ, Cornacchi SD, Farrokhyar F, Garnett A, Chen V, Franic S, et al. Technical factors, surgeon case volume and positive margin rates after breast conservation surgery for early-stage breast cancer. Can J Surg. 2010;53(5):305–12. [PMC free article] [PubMed] [Google Scholar]
- 22. Alves-Ribeiro L, Osório F, Amendoeira I, Fougo JL. Positive margins prediction in breast cancer conservative surgery: assessment of a preoperative web-based nomogram. Breast. 2016;28:167–73. [DOI] [PubMed] [Google Scholar]
- 23. Moore MM, Borossa G, Imbrie JZ, Fechner RE, Harvey JA, Slingluff CL Jr, et al. Association of infiltrating lobular carcinoma with positive surgical margins after breast-conservation therapy. Ann Surg. 2000;231(6):877–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Chagpar AB, Martin RCG 2nd, Hagendoorn LJ, Chao C, McMasters KM. Lumpectomy margins are affected by tumor size and histologic subtype but not by biopsy technique. Am J Surg. 2004;188(4):399–402. [DOI] [PubMed] [Google Scholar]
- 25. Dzierzanowski M, Melville KA, Barnes PJ, MacIntosh RF, Caines JS, Porter GA. Ductal carcinoma in situ in core biopsies containing invasive breast cancer: correlation with extensive intraductal component and lumpectomy margins. J Surg Oncol. 2005;90(2):71–6. [DOI] [PubMed] [Google Scholar]
- 26. Dillon MF, Hill ADK, Quinn CM, Mcdermott EW, O'Higgins N. A pathologic assessment of adequate margin status in breast-conserving therapy. Ann Surg Oncol. 2006;13(3):333–9. [DOI] [PubMed] [Google Scholar]
- 27. Smitt MC, Horst K. Association of clinical and pathologic variables with lumpectomy surgical margin status after preoperative diagnosis or excisional biopsy of invasive breast cancer. Ann Surg Oncol. 2007;14(3):1040–4. [DOI] [PubMed] [Google Scholar]
- 28. Shin HC, Han W, Moon HG, Cho N, Moon WK, Park IA, et al. Nomogram for predicting positive resection margins after breast-conserving surgery. Breast Cancer Res Treat. 2012;134(3):1115–23. [DOI] [PubMed] [Google Scholar]
- 29. Barentsz MW, Postma EL, Van Dalen T, van den Bosch MAAJ, Miao H, Gobardhan PD, et al. Prediction of positive resection margins in patients with non-palpable breast cancer. Eur J Surg Oncol. 2015;41(1):106–12. [DOI] [PubMed] [Google Scholar]
- 30. Krekel NMA, Haloua MH, Lopes Cardozo AMF, de Wit RH, Bosch AM, de Widt-Levert LM, et al. Intraoperative ultrasound guidance for palpable breast cancer excision (COBALT trial): a multicentre, randomised controlled trial. Lancet Oncol. 2013;14(1):48–54. [DOI] [PubMed] [Google Scholar]
- 31. Losken A, Dugal CS, Styblo TM, Carlson GW. A meta-analysis comparing breast conservation therapy alone to the oncoplastic technique. Ann Plast Surg. 2014;72(2):145–9. [DOI] [PubMed] [Google Scholar]
- 32. Heeg E, Jensen MB, Hölmich LR, Bodilsen A, Tollenaar RAEM, Laenkholm AV, et al. Rates of re-excision and conversion to mastectomy after breast-conserving surgery with or without oncoplastic surgery: a nationwide population-based study. Br J Surg. 2020;107(13):1762–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Chaudhry R, Goel V, Sawka C. Breast cancer survival by teaching status of the initial treating hospital. CMAJ (Can Med Assoc J). 2001;164(2):183–8. [PMC free article] [PubMed] [Google Scholar]
- 34. Hebert-Croteau N, Brisson J, Lemaire J, Latreille J, Pineault R. Investigating the correlation between hospital of primary treatment and the survival of women with breast cancer. Cancer. 2005;104(7):1343–8. [DOI] [PubMed] [Google Scholar]
- 35. Cairns A, Chagpar AB, Dupont E, Levine EA, Gass JS, Chiba A, et al. Does preoperative MRI reduce positive margins after breast-conserving surgery? Ann Surg Oncol. 2023;30(10):6053–8. [DOI] [PubMed] [Google Scholar]
- 36. Marinovich ML, Macaskill P, Irwig L, Sardanelli F, Mamounas E, von Minckwitz G, et al. Agreement between MRI and pathologic breast tumor size after neoadjuvant chemotherapy, and comparison with alternative tests: individual patient data meta-analysis. BMC Cancer. 2015;15:662–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Azhdeh S, Kaviani A, Sadighi N, Rahmani M. Accurate estimation of breast tumor size: a comparison between ultrasonography, mammography, magnetic resonance imaging, and associated contributing factors. Eur J Breast Health. 2021;17(1):53–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Sardanelli F, Trimboli RM, Houssami N, Gilbert FJ, Helbich TH, Álvarez Benito M, et al. Magnetic resonance imaging before breast cancer surgery: results of an observational multicenter international prospective analysis (MIPA). Eur Radiol. 2022;32(3):1611–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Lobbes MBI, Vriens IJH, van Bommel ACM, Nieuwenhuijzen GAP, Smidt ML, Boersma LJ, et al. Breast MRI increases the number of mastectomies for ductal cancers, but decreases them for lobular cancers. Breast Cancer Res Treat. 2017;162(2):353–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. In ‘t Hout BA, Schenk KE, Van Der Linden AN, Roumen RMH. Efficacy of localization of non-palpable, invasive breast cancer: wire localization vs. Iodine-125 seed: a historical comparison. Breast. 2016;29:8–13. [DOI] [PubMed] [Google Scholar]
- 41. Dryden MJ, Dogan BE, Fox P, Wang C, Black DM, Hunt K, et al. Imaging factors that influence surgical margins after preoperative 125I radioactive seed localization of breast lesions: comparison with wire localization. AJR Am J Roentgenol. 2016;206(5):1112–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Levaillant M, Marcilly R, Levaillant L, Michel P, Hamel-Broza JF, Vallet B, et al. Assessing the hospital volume-outcome relationship in surgery: a scoping review. BMC Med Res Methodol. 2021;21(1):204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Van Der Schors W, Kemp R, van Hoeve J, Tjan-Heijnen V, Maduro J, Vrancken Peeters MJ, et al. Associations of hospital volume and hospital competition with short-term, middle-term and long-term patient outcomes after breast cancer surgery: a retrospective population-based study. BMJ Open. 2022;12(4):e057301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Valero MG, Mallory MA, Losk K, Tukenmez M, Hwang J, Camuso K, et al. Surgeon variability and factors predicting for reoperation following breast-conserving surgery. Ann Surg Oncol. 2018;25(9):2573–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are not publicly available due to privacy statements but are available from the corresponding author on reasonable request.