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Effect of pre-operative breast biopsy type on frozen margin status and surgical treatment of breast cancer patients undergoing breast-conserving surgery

Research

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

Tel: +82-51-797-0695

Fax: +82-51-895-1864

e-mail: gsjslee@gmail.com

Abstract

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 (p=0.002), mean age (p=0.04), histologic type (p<0.001), and number of metastatic lymph node (p<0.001) were significantly correlated with frozen resection margins. In a multivariate analysis, however, only histologic type (p=0.001) was significantly correlated with frozen resection margins. The rate of re-excision was 20% for patients diagnosed with VABB, versus 8.2% with needle biopsy and 8.8% with excisional biopsy (p=0.08). Immediate reconstruction was found more frequently in patients diagnosed by VABB (12.0%) than core needle biopsy (1.8%) and excisional biopsy (3.5%; p=0.02). The use of VABB for pre-operative diagnostic biopsy resulted in a marginal increase of re-excision rate or wider excision in patients undergoing BCT.

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 in situ, IBTR: Ipsilateral breast tumor recurrence, EIC: Extent of intraductal component, SISH: Silver in situ hybridization, OR: Odds ratio, CI: confidence interval, PR: Progesterone receptor, HER2: Her-2/neu, IDC: invasive ductal carcinomas

Introduction

A positive margin is defined as the presence of invasive ductal carcinoma or ductal carcinoma in situ (DCIS) at the inked surface of the surgical specimen and implies a potentially incomplete resection that is associated with a significantly higher risk of ipsilateral breast tumor recurrence (IBTR). Positive resection margin during breast conserving therapy (BCT) is associated with an increased risk of local recurrence of breast cancer (17–59%) [1-3]. In EORTC(European Organization for Research and Treatment of Cancer) 2012, incomplete resection margins were associated with a 15% cumulative risk of local recurrence compared with an 8% cumulative risk in patients with microscopically tumor-free resection margins [4]. Established risk factors of positive resection margin are lobular carcinoma, tumor size, tumor grade, multifocality, extent of intraductal component (EIC) and lymphovascular invasion (LVI) [5]. Despite the well-recognized benefit of systemic therapy in reducing IBTR, the effects of a positive margin do not appear to be negated by the use of either adjuvant endocrine therapy or chemotherapy [6].

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.

Surgery

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 in situ(DCIS), or invasive ductal carcinomas (IDC)at the margins of excised breast tissues for invasive breast cancers was considered to be evidence of positive surgical margin.

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 [12].

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 [13] and staged according to the TNM system [14]. 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%.

Statistical analysis

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 p-value <0.05 on the Pearson’s χ2 tests. A p-value of less than 0.05 was considered statistically significant. All analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, NC, USA).

Results

Patients’ characteristics

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 (p=0.04), number of metastatic lymph nodes (p=0.03), histologic grade (p=0.002), and histological type (p<0.001). EIC (p=0.06), pre-operative biopsy type (p=0.09), and LVI (p=0.07) showed an association with frozen resection margins that was of borderline significance. However, ER (p=0.37), PR (p=0.15), lymph node status (p=0.58), lymphovascular invasion (p=0.07), and mean tumor size (p=0.86) were not significantly associated with a positive resection margin.

In multivariate analysis, positive resection margin in frozen section analysis was correlated with histologic type (p=0.001), such as invasive lobular carcinoma (odds ratio (OR) =1.04, 95% confidence interval (CI): 1.9–5.7), or ductal carcinoma in situ (OR = 4.97, 95% CI: 2.54–9.7). Other clinicopathological features were not associated with likelihood of positive initial resection margin (Table 2).

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 (p=0.09), and re-excision rate was, respectively, 8.2%, 20%, and 8.8% (p=0.08). Immediate reconstructions were performed more commonly in patients diagnosed primarily by VABB (12.0%) than by core needle biopsy (1.8%) or excisional biopsy (3.5%; p=0.02; Table 3).

Discussion

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 et al. [19] reported that the sensitivity and specificity of the detection of malignancy were excellent for ultrasound-guided VABB using the Mammotome biopsy system (both 100%), and recommended this system as the method of choice for the detection of nonpalpable early breast cancer. Advances in percutaneous core needle biopsy techniques, such as increasing the needle diameter from 14-gauge to 11-gauge and adding vacuum assistance, have allowed larger samples of tissues to be obtained [20-22]. VABB was also found to have potential benefits for specific types of lesions [23-25]; these included calcified lesions, intraductal lesions and solid nodules of less than 1.0 cm in size. The automated gun biopsy was preferred for the multifocal lesions and for the lesions in the subareolar or axillary areas.

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 [28], and high breast density [29] 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 et al. [36] reported that patients who had four or more metastatic lymph nodes had a higher likelihood of positive surgical margins. In our study, we found that metastatic axillary lymph nodes affected the rate of positive surgical margin significantly.

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 et al. [37] reported that triple negative breast cancer is associated with an increased risk of residual invasive carcinoma after lumpectomy. Ataly and Irkkan [38] have demonstrated that the presence of tumor in re-excision following BCT is significantly higher in patients with Her-2/neu overexpression. A limited study performed by Smitt and Horst [8] analyzed the factors affecting positive surgical margin among 67 invasive breast cancer patients who had pre-operative core or fine-needle biopsy. In the latter analysis, only lobular histology and LVI were significantly associated with positive surgical margin.

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 in vivo [39]. Many breast cancer specimens obtained from a diagnostic open biopsy are not oriented to the tumor bed, increasing the difficulty of determining which margins need to be re-excised, which may result in the entire cavity being subject to re-excision with a greater risk of compromising breast appearance [40]. Specific microscopic findings from surgical specimens obtained after pre-operative VABB often include extensive fibrosis, hemorrhage, and foreign body reactions, which would all give rise to solid breast parenchyma and may influence the surgeon’s decision making regarding the extent of surgical margins. In our view, evaluating the remnant tumor component adjacent to the prior VABB site can be difficult as the basement membrane of breast ducts are distorted and can give rise to a suspicion for microinvasion. This is especially true in DCIS. In addition, measuring microscopic tumor size is unfeasible after massive VABB. Furthermore, ink applied to the surface of the resection margins of the specimens often tracks into deeper portions of the specimen, which, in turn, can pose significant challenges for the pathologist in microscopically determining the location of the true margin. There is also no standard method for margin evaluation. We attained 85.9% negative margins after excisional biopsy, which is a higher rate than previously reported (22 to 45%). Our rate of re-excision after VABB was almost 20%, which is considerably lower than reported values in prior studies (30.5% to 74%) [8-11]. However, the number of patients with positive surgical margin was low in our study, particularly in the VABB cohort, which is likely to impact on statistical power in demonstrating differences between pre-operative biopsy methods.

Conclusion

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.

Acknowledgments

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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