Effect of pre-operative breast biopsy type on frozen margin status and surgical treatment of breast cancer patients undergoing breast-conserving surgery
Woo-Gyeong Kim1, JungSun Lee2
1Department of Pathology, Haeundae Paik Hospital, University of Inje, College of Medicine, Busan, Korea
Address: #1435, Jwa-dong, Haeundae-gu, Busan, Korea, Zip-code: 612-030
2Department of Surgery, Haeundae Paik Hospital, University of Inje, College of Medicine, Busan, Korea
#1435, Jwa-dong, Haeundae-gu, Busan, Korea, Zip-code: 612-030
Corresponding author: JungSun Lee
Department of Surgery, Haeundae Paik Hospital, University of Inje, College of Medicine, Busan, Korea
#1435, Jwa-dong, Haeundae-gu, Busan, Korea, Zip-code: 612-030
We evaluated the impact of pre-operative biopsy types on interpreting frozen resection margins. We included 301 patients who underwent breast conserving therapy (BCT). During operation, we evaluated the frozen biopsy for resection margin status, and if a positive resection margin was found, re-excision was performed. The following factors were evaluated for correlation with initial frozen margins, re-excision rate, and final operation method: mean age, histologic grade, histology, lymphovascular invasion (LVI), estrogen receptor (ER) status and biopsy type: excisional, vacuum-assisted breast biopsy (VABB) or needle biopsy. A total of 265 patients (88.0%) had negative frozen resection margins, and 36 patients (12%) had positive frozen margins. For patients who underwent needle biopsy, 10.5% (23/219) had positive frozen margins compared with 14.0% (8/57) for excisional biopsy and 20.0% (5/25) for VABB. HG (
Key words: mastectomy, breast neoplasm, vacuum-assisted, breast, biopsy
Abbreviation: BCT: Breast conserving therapy, LVI: lymphovascular invasion, ER: Estrogen receptor, VABB: Vacuum-assisted breast biopsy, HG: Histologic grade, DCIS: Ductal carcinoma
A positive margin is defined as the presence of invasive ductal carcinoma or ductal carcinoma
The management of breast cancer ideally involves the coordination of a multidisciplinary team appropriately using a combination of treatment modalities. The first step in this process is a histological diagnosis obtained after a biopsy. Several studies [7, 8] have demonstrated that surgeons performing breast cancer operations are more likely to obtain clear resection margins when a pre-operative diagnosis has been made with a needle biopsy. In fact, recent research demonstrates that establishing a pre-operative diagnosis of cancer is one of the most significant predictors of initial margin status when performing breast surgery. The literature indicates that after open biopsy, the positive margin rate is between 65% and 78% and the re-excision rate range is between 30% and 74%. In comparison, after obtaining a pre-operative diagnosis using percutaneous biopsy, positive margin rates are between 0% and 37% and re-excision rates are between 15% and 34% [9-11]. Needle biopsy is known to be more efficient in providing negative surgical margin compared with excisional biopsy.
Vacuum-assisted breast biopsy (VABB) is frequently used for diagnostic or therapeutic purpose in breast diseases in Korea. However, histopathological interpretation of resection margin after VABB has not been thoroughly investigated after or during BCT. We designed this study to examine the correlation between pre-operative biopsy methods including VABB and resection margin status of both frozen biopsy and permanent formalin-fixed paraffin-embedded tissue biopsy.
Patients and Methods
Patients and biopsy method
The clinical and pathological records of 588 patients who underwent curative surgery for newly diagnosed breast cancer in Haeundae Paik Hospital between March 2010 and December 2012 were retrospectively reviewed. We excluded 282 patients who received neoadjuvant chemotherapy, had unavailable pre-operative imaging or pathologic results, or received mastectomy as their initial operation. Of the remaining 306 patients, pre-operative biopsy in 219 patients (71.6%) was performed by 14-gauge core needle biopsy (Pro-Mag 2.2, Manan Medical Products, Northbrook, Ill, USA), 25 patients (8.2%) received biopsy using an 8-gauge vacuum-assisted device (Mammotome, Ethicon-Endosurgery, Cincinnati, OH, USA), 57 patients (18.6%) underwent excisional biopsy, and five patients (1.6%) received tissue diagnosis via incisional biopsy. A total of 301 patients were analyzed in this study, excluding those diagnosed by incisional biopsy. The breast biopsy device that was used depended primarily on the preference of the surgeon performing the biopsy, although the patient’s preferences also affected this decision. About 70% of the biopsies were performed by two radiologists who had 5 and 8 years’ experience with breast sonography and intervention, respectively. The other 30% of the biopsies and all VABB were performed by two surgeons who had 8 and 20 years’ experience with breast intervention.
We generally used curvilinear incisions, though radial incisions were sometimes used for tumors located at the three or nine o’clock positions. To achieve a clear surgical margin, we attempted to obtain a margin of 2–3 cm of grossly normal breast tissue around the tumor. A skin island overlaying the tumor was also excised for very superficial tumors. All the breast tissue under subcutaneous fat tissue was removed for tumor located close to the breast skin. Underlying breast tissue down to the pectoralis major muscle including the fascia of the muscle was excised for tumors located deep in the breast. Pre-operative localization of nonpalpable tumors was performed by wire localization or ultrasonography-guided skin marking for these tumors. All patients underwent sentinel lymph node biopsy with Tc-99 radiocolloid and patients with metastatic sentinel lymph node biopsy underwent level I and II axillary node dissection.
In all patients, breast-conserving therapy included, as an initial diagnostic procedure, resection of the clinically apparent tumor or tip of the needle localization wire when they were nonpalpable tumor. Those patients deemed candidates for BCT require an additional rim tissue of surrounding breast parenchyma when resection margin status was unknown. Patients underwent re-excision of the excisional biopsy bed following identification of inadequate margin distance after excisional biopsy.
When an invasive cancer or DCIS was found in the resection margin of the resected specimen, re-excision or mastectomy was performed to obtain tumor-free margins. Re-excision was performed by removal of the entire rim tissue of the affected margin rather than a representative section of that margin. If positive resection margins at several directions were identified, quadrantectomy with immediate reconstruction was carried out.
Method of pathologic margin assessment
Intraoperative frozen margin
Intraoperative margin excision and frozen section analysis were performed for intraoperative margin evaluation in all patients using a perpendicular method. Breast tissue contains a lot of fat which presents with particular difficulties when it comes to cryosection. The presence of atypical ductal/lobular hyperplasia (ADH/ALH), ductal carcinoma
The resection margin was classified as positive or clear based on a pathological evaluation. The presence of DCIS or invasive cancer at the edge of a specimen constituted a positive resection margin (Figure 1) and also these lesions identified in less than 1mm from the resection margin with ink mark or cauterization thermal artifact was considered to be evidence of a positive margin, in accordance with the 2011 NCCN clinical guidelines that defined margins <1 mm as inadequate .
Evaluation of resection margins
All slides from excisional breast specimens and re-excision specimens were reviewed by a single pathologist (W.G.K). The specimens were reviewed in order of consecutive surgical pathology numbers. The pathological features recorded included specimen dimensions, histologic type, grade and size of the tumor. All resected specimens were inked using six representative colors for each margin in the grossing laboratory after specimens were blotted dry. Pathology technicians examined radiologic findings of the specimen to evaluate for calcifications or location, number and size of the mass prior to sectioning. Each specimen was cut in approximately 5-mm sections and then submitted either completely or in representative sections depending on the specimen size, radiographic appearance, and macroscopic findings. Intraoperative and post-operative re-excision specimens were evaluated for presence of remnant tumor cells.
The pathologic slides were viewed in hematoxylin and eosin (H&E) stains, initially. The histologic grade of invasive ductal carcinomas of the main mass was determined using the modified Bloom and Richardson criteria  and staged according to the TNM system . This classification was recorded for pathological staging. The expressions of estrogen receptor (ER), progesterone receptor (PR), Her-2/neu (HER2), p53, and Ki-67 were assessed as immunohistochemical prognostic parameters [15, 16]. ER and PR expressions were scored using the Allred scoring system on a scale of 0 to 8 for nuclear staining only. The intensity score and percentage score were added to obtain the Allred score and scores of 0 to 2 were classified as negative and 3 to 8 were classified as positive. HER2 status was initially evaluated with an immunohistochemical assay (Dako HercepTest) where either 0 or 1+was considered negative, and 3+ was considered to be positive. A score of 2+ was considered as an equivocal result and silver in situ hybridization (SISH) was carried out to confirm the HER2 gene amplification. The presence or absence of an extensive intraductal component (EIC) was recorded, with a cut-off point of 25%.
The proportion of patients with clear resection margins and those with positive resection margins were compared using Pearson’s χ2 tests. Multivariate logistic regression analysis was used to analyze each variable with a
The mean age was 50.7 ? 9.3 years, (range: 28–81). Mean tumor diameter was 1.93 ± 1.31 cm. Among the 301 patients who underwent BCT, resection margins were positive in 36 (12%) patients after the initial lumpectomy. 257 patients (85.4%) had invasive breast cancers with or without DCIS and 42 patients (14.0%) had pure DCIS on permanent pathology.
Correlation of frozen resection margin and clinicopathologic features
Table 1 summarizes the variables that showed significant differences between patients whose excised tumors had clear margins and those with tumors showing positive margins. Variables found to be significantly associated with a positive resection margin were patient age (
In multivariate analysis, positive resection margin in frozen section analysis was correlated with histologic type (
Correlations between pre-operative biopsy method and frozen resection margin status, re-excision rate and change of operation method
Twenty-three patients (10.5%) assessed by core needle biopsy, 5 patients (20%) assessed by VABB, and 8 patients (14.0%) who received excisional biopsy had positive frozen resection margin (
Previously, it has been demonstrated that surgeons performing breast cancer operations are more likely to obtain clear margins when a pre-operative diagnosis has been made with a needle biopsy. In addition to improved margin clearance, establishing a pre-operative diagnosis of breast cancer has been associated with reduced time to adjuvant therapy and greater cost-effectiveness [7, 10, 17, 18].
Ultrasound-guided VABB is regarded as a feasible, effective, minimally invasive and safe method for removal of benign breast lesions without serious complication. Pan S
Our study revealed that metastatic axillary lymph node, LVI, EIC, histologic grade, and histologic type were associated with positive surgical margin after BCT. Young age [5, 26, 27], high grade , and high breast density  have been reported as factors affecting positive surgical margin after BCT. Contrary to these studies, others have reported that young age [30, 31] and tumor grade [32, 33] do not have any influence on the rate of surgical margin positivity. Several studies in which tumor size was analyzed reported an association with likelihood of positive surgical margin [34, 35]. In the present study, while age, LVI, EIC, histologic grade, histology, metastatic lymph node and pre-operative biopsy method were important in univariate analysis, in multivariate analysis only histologic type showed significance. Park
There are relatively few studies analyzing the frequency of surgical margin positivity during BCT in different molecular intrinsic subtypes of breast cancers in patients. Sioshansi
There are also technical limitations to lumpectomy margin evaluation that confound the interpretation of data relating margin width. Once a lumpectomy specimen is removed from the breast, flattening occurs because of lack of support from the surrounding tissue. This is further exaggerated by compression of the specimen submitted for radiography. These factors result in artifactually narrower margins that exist
Presence of EIC, high histologic grade, DCIS or invasive lobular carcinoma, patient age, and number of metastatic lymph node should be considered as predictors for positive surgical margin in deciding the extent of the lumpectomy required to achieve negative surgical margin before BCT. A change of operation method was more frequent in patients diagnosed by VABB than by core needle or excisional biopsy. The pre-operative diagnosis of carcinoma by VABB leads to the planning of a wider resection than core needle biopsy, but the need for re-excision was not significantly different from the pre-operative core needle biopsy method. However, the relative reduction in positive resection margin status in individual studies depends on several additional factors, including institutional guidelines regarding margin status and re-excision as well as the rate of BCT as the operation method and the proportion of patients with DCIS as compared with invasive cancer. The limitation of this study was the relatively small number of patients included in the groups of pre-operative diagnostic VABB and excision method and in the future, more detailed studies with a larger population are necessary for more confirmations.
The authors declare that they have no conflicts of interest.
Authors indicate that they have no financial relationship with the organization that sponsored the research.
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