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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 2  |  Page : 235-238
 

Role of frozen section in the intra-operative margin assessment during breast conserving surgery


1 Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
2 Department of Surgical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
3 Regional Cancer Centre, Thiruvananthapuram, Kerala, India

Date of Web Publication6-Jan-2017

Correspondence Address:
K R Anila
Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.197732

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 » Abstract 

Background: Breast conserving surgery (BCS) is increasingly done for early breast cancers in many countries since it has been demonstrated by randomized trials that survival rates after BCS followed by adjuvant therapy are equivalent to those obtained after mastectomy. Frozen section analyses (FSA) is a technique used for intra-operative assessment of margin status in BCS. The aim of this study was to assess the concordance of margin status assessment by FSA and permanent sections and to assess correlation with local recurrence. Materials and Methods: A total of 162 patients underwent BCS for in situ or invasive carcinoma with FSA of margins during the year 2008 at our center. The inclusion criteria in this study were patients with intact tumor at the time of surgery. After application of the inclusion criteria, 60 patients could be included in this study. Results: After frozen section, 20 patients had an initial negative margin. 40 subjects underwent additional excisions at the time of initial surgery because of close or positive margins. Of these 40 patients, in 32 patients a negative margin could be achieved with re-excisions. Pathological analyses of frozen section showed concordance to permanent sections in all cases. At a median follow-up of 40 months, there were no local recurrences. Conclusion: Intra-operative FSA allows resection of suspicious margins at the time of primary conservative surgery and results in low rates of local recurrence and second surgeries. There is good concordance between results of FSA and the final paraffin section in assessing margin status.


Keywords: Breast conserving surgery, frozen section, intra-operative


How to cite this article:
Anila K R, Chandramohan K, Mathews A, Somanathan T, Jayasree K. Role of frozen section in the intra-operative margin assessment during breast conserving surgery. Indian J Cancer 2016;53:235-8

How to cite this URL:
Anila K R, Chandramohan K, Mathews A, Somanathan T, Jayasree K. Role of frozen section in the intra-operative margin assessment during breast conserving surgery. Indian J Cancer [serial online] 2016 [cited 2020 May 30];53:235-8. Available from: http://www.indianjcancer.com/text.asp?2016/53/2/235/197732



 » Introduction Top


Randomized control trials have demonstrated that in early breast cancer breast conserving surgery (BCS) followed by adjuvant radiotherapy results in comparable local control and survival rates as achieved with mastectomy.[1] This has lead to increased use of BCS in many countries. A microscopically clear margin free of tumor is critical in BCS for minimizing the risk of local recurrence. The most important drawback of BCS is the possible presence of microscopic tumor at or close to the margin of excision.[2] Positive margins later identified in permanent sections necessitate repeated surgeries, which causes delay in starting adjuvant therapy, poor cosmetics due to removal of greater volume of breast tissue when compared with primary surgery, anesthesia risks, increased patient anxiety, increased cost and greater morbidity.[3] Accurate intra-operative assessment of margin status can overcome such problems to a large extent. Intra-operative frozen section is a suitable technique for intra-operative assessment of margins. The aim of this study was to determine the concordance between results of frozen section analysis (FSA) and the final paraffin section in assessing margin status in BCS and to study re-excision rates and local control of disease in patients subjected to FSA.


 » Materials and Methods Top


This study was conducted in a tertiary cancer care center catering to a large population, after approval from the institutional review board. Being a referral center, apart from cases worked-up in our center, many cases are referred to us with diagnosis of breast carcinoma following un planned surgery. In our center, all cases of BCS are done under frozen control for margin status. A total of 162 women with in situ/invasive breast cancer underwent BCS with intra-operative FSA of margins during the year 2008. Patients (102 numbers) who had either a prior lumpectomy from peripheral centers before the planned conservative surgery or post-neoadjuvant systemic therapy cases taken up for BCS were excluded from the study. Patients (60 numbers) with a pre-operative fine-needle aspiration cytology or tru-cut biopsy diagnosis of in situ or invasive carcinoma who underwent BCS with FSA analyses of margins were included in this study. Pertinent data regarding patient demography, operative findings, tumor type, tumor localization, pathologic tumor size, grade, hormone receptor status, human epidermal growth factor receptor 2 neu status, lymphovascular invasion, extensive intraductal carcinoma (EIC), axillary nodal status, stage, frozen section and permanent section results, follow-up, recurrence and mortality were collected for each patient according to availability of details.

Frozen section procedure

As a standard institutional protocol during surgery, the breast tumor is initially excised with a macroscopic margin of at least 1 cm and the surgical specimen is immediately marked with orienting sutures and submitted for intra-operative pathologic examination by frozen section. A negative surgical margin was defined as tumor cells more than 5 mm from the inked surface of the lumpectomy specimen. Presence of tumor cells at the inked edge of the specimen was considered as a positive margin and a margin of less than 5 mm was considered to be close. Specimen is sliced into 4-5 mm thickness perpendicular to longest axes of tumor mass. The tissue selected for frozen is placed on tissue freezing medium (Leica Microsystems) and mounted in cryostat (Leica CM 1510S). Sections 5 micron thickness are taken and placed on slides and fixed in alcohol-acetic acid-formalin fixative for 40 s and stained with hematoxylin and eosin (H and E). After preparation, the slides are examined by the pathologist and status of margins reported as positive, close or negative. For close margins distance in millimeters between the surgical margins and tumor is mentioned in the report. Median duration of frozen section procedure is 20 min. Patients with positive or close margins underwent one or two re-excisions. If negative margins could not be achieved with even two re-excisions mastectomy was done. The specimen is then submitted for routine processing, fixed in phosphate-buffered 10% formalin, embedded in paraffin and sections are stained with H and E, so that final margin status is obtained by examination of permanent paraffin sections. In this study, the final report of the margin status was compared with that of the frozen section result.

All patients with invasive carcinoma underwent axillary dissection along with BCS. Post-operative radiotherapy was given to ipsilateral breast in all cases. Chemotherapy was given according to stage of the disease.


 » Results Top


A total of 60 patients were evaluable for this study. The patient and tumor characteristics are described in [Table 1]. The median age at diagnosis was 46 years (range 23-71 years). The mean pathological tumor size was 3.02 cm (range 1-4.5 cm). The majority of patients 55 cases (92%) presented with palpable breast tumors and these cases had a core biopsy or fine needle aspiration based pathologic diagnosis prior to BCS. Five patients had radiologically detected non-palpable tumors. Twenty-nine patients (48.33%)had pathologically node positive disease of which 18 patients had 1-3 positive nodes and 11 patients had four or more positive nodes.
Table 1: Patient and tumor characteristics

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After intra-operative frozen section examination, 20 cases had sufficient initial margins (>5 mm) and required no re-excision, but 40 patients (66% initial re-excision rate) underwent re-excision during initial operation because of close or positive margins identified by FSA. Negative surgical margins were obtained in 32 patients following re-excision. For eight patients, negative margins could not be achieved in spite of even two re-excisions and required mastectomy. Three of these patients had multifocal disease. Comparison of FSA and permanent paraffin section analyses revealed concordance in assessment of margin status for all patients.

After a median follow-up of 40 months (range 15-54 months), there was no local recurrence; two patients developed distant metastases in the liver and pleura 2 years after the initial surgery. Patient who developed hepatic metastases had multifocal disease and hence had undergone mastectomy. Patient with pleural metastases however had a negative margin at the time of initial surgery.


 » Discussion Top


Several prospective randomized controlled trials have demonstrated that BCS followed by radiotherapy is an alternative to mastectomy in management of early breast cancer. The most important drawback of BCS is that when compared to mastectomy it is associated with a higher risk of local recurrence due to the possible presence of residual microscopic tumor at the surgical margins and also due to the possibility of carcinoma arising in residual breast tissue. Previous studies have observed that a negative surgical margin is critical in minimizing local recurrence. Hence, the most important factor in BCS is to achieve a microscopically negative margin.

There is no consensus among various study groups regarding the clearance width to be achieved for a negative margin.[4] In this study, we had taken a clearance of 5 mm as adequate margin. The lack of uniformity in the definition of close margin is a limitation in comparing local recurrence and survival results of BCS of different studies. In previous studies, the authors have accepted that tumor recurrence rate is extremely higher in patients who have tumor cells on the surgical margin of the specimen. Radiotherapy alone cannot compensate for inadequate surgery.[5] The outcome will be definitely guarded for a patient with positive margin receiving adjuvant therapy when compared to that of a patient with negative margin.

In BCS if margins are not assessed intra-operatively and margin status is known only at the time of permanent paraffin sections, and if margin status happens to be positive or close, then a repeat surgery for re-excision of margins becomes necessary. This result in poor cosmetic outcome delay in initiating adjuvant therapy, increased morbidity, patient anxiety, increased cost etc.[6] Furthermore, it becomes difficult for surgeons to identify the margin to be re-excised at the time of the second surgery because of the tissue changes produced by the initial surgery.[7]

The major advantage of intra-operative evaluation of margin status is that immediate re-excision can be performed during the same operation.[8] FSA and touch imprint cytology are two methods available for intra-operative assessment of margin status. Both these methods have their own advantages and disadvantages. Imprint cytology as a technique for rapid microscopical diagnosis was introduced as early as 1927. Imprint cytology should be the procedure of choice in intra-operative evaluation for cost-effective management, especially in centers where frozen section facilities are not available.[9] An advantage of frozen section is that it not only gives status of margins it also aids in measuring the distance of clearance whereas imprint cytology can only tell whether the tumor is present at the margin or not, the distance of clearance cannot be measured by imprint cytology.[10],[11] Both methods have drawbacks such as drying artifact. However, these technical drawbacks can be kept to the minimum in the hands of an experienced technician and pathologist.

Re-excision rates are considerably reduced if margins are assessed intra-operatively by frozen sections.[8],[12] In a study by Camp et al. in 2005 it was found that the re-excision rates for patients who had margins analyzed intra-operatively by frozen section and margins analyzed by permanent section were 6.3% and 36.5%, respectively, which was a significant difference.[11] There are few studies from Asia on re-excision rates after intra-operative margin analysis of BCS specimen with frozen section [13],[14],[15] [Table 2]. Esbona et al. has done a systematic review comparing re-excision rates, sensitivity and specificity of the intra-operative use of the margin assessment techniques of imprint cytology and FSA in BCS against permanent histopathology sections. In their study, they reviewed 15 cohorts that used FSA, 19 cohorts that used permanent section and 7 cohorts that used imprint cytology.[9] They observed significantly low final re-excision rates with FSA. The low rate of local recurrence observed in our study is similar to reported rates in other studies assessing the role of FSA in BCS. Though we had a re-excision rate of 66% during the initial surgery due to close margins picked up with frozen, our final re-excision rate was 0%. Some studies observed that patients who had intra-operative margin analysis had lower recurrence and mortality rates than those who had conventional histological margin analysis.[16] In the present study, we did not come across cases of lobular carcinoma. However, we have experienced difficulty in achieving negative margin in case of invasive lobular carcinoma similar to other studies in the literature because of the diffuse and infiltrative nature of this tumor.[17] EIC and multi-centricity are other situations where difficulty can arise in achieving a negative margin.
Table 2: Comparison of studies from Asia reporting on intra-operative margin analysis using frozen section in breast carcinoma

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Our series had no local recurrence during a median follow-up of 40 months. Some studies showed that the risk of local recurrence is lower during the first 5 years of BCS, but higher after 5 years.[18] Freedman et al. reported that local recurrence could be delayed by adjuvant systemic chemotherapy.[19] Our patients had received adjuvant chemotherapy and radiotherapy. All patients were given radiotherapy to ipsilateral breast. Adjuvant systemic chemotherapy was given to patients depending on stage of the disease. Patients with estrogen or progesterone receptor positive tumors received tamoxifen. We however feel that the benefits of adjuvant therapy will be limited if given in margin positive cases. We have obtained 1 cm macroscopic margin width during BCS and also performed intra-operative margin assessment with >5 mm negative margin. Our follow-up time was an average of 40 months that is more than 3 years. Some of the similar studies in the literature have taken a follow-up period of 5 years.[20]

There are several studies in the literature on the role of frozen section in BCS. Results of the current study are comparable to similar previous studies in the literature and suggest that intra-operative margin assessment by frozen section is an effective procedure in reducing the need of a second operation for a negative margin. Furthermore, sufficient margin width is obtained during the same operation. Nearly 66% of our patients underwent re-excision during initial operation because of close or positive margins, so they were protected from risks of the second surgery. The high rate of intra-operative re-excisions observed in our study may be due to the wider microscopic margin width we maintained in our study (5 mm) compared to other studies with a 2 mm margin.[4],[21] This larger margin clearance may also be the cause of low recurrence rate that we observed in this study.

Many of the latest studies are of the opinion that a margin status needs to be taken as positive only if tumor is at the inked surface.[22] Taking a wider margin according to these authors will result in only a bad cosmetic outcome with no added advantage in minimizing local recurrence. However, these authors have proposed a 2 mm clearance for duct carcinoma in situ [DCIS] taking into consideration the multifocal nature of DCIS. However, these observations need to further studied before being universally applied.

The relationship between the size of the tumor and the breast size is another factor, which determines the outcome of breast-conserving surgery. A large sized tumor in a small sized breast is a limitation in achieving satisfactory cosmetic results. Breast conservation therapy (BCT) is an appropriate method of primary therapy for the majority of women with early breast cancer. BCT provides long-term survival rates equivalent to those of total mastectomy while preserving the breast. The risk of local recurrence after BCS has decreased over time with the use of FSA for margin assessment and because of the use of adjuvant systemic therapy along with radiotherapy.

A successful BCS requires margins clear of invasive and in situ tumor with good cosmetic results. Frozen section is a technique, which aids in achieving a negative microscopic margin during the primary surgery. There is no universal definition of what constitutes a negative microscopic margin. However, now we have data telling us that there is no added advantage in unnecessarily increasing the width of clearance. There should be universal consensus as to what constitutes a negative margin so that the results of various studies can be compared and better patient management offered. The observations of this study are similar to those made by previous studies in the literature and confirm the utility of FSA in the intra-operative margin assessment in conserving surgeries of breast.


 » Acknowledgment Top


The authors wish to thank Dr. Beela Sarah Mathew, Additional Professor, Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram and Dr. Aleyamma Mathew, Additional Professor, Department of Statistics and Epidemiology, Regional Cancer Centre, Thiruvananthapuram for their support.

 
 » References Top

1.
Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, 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.  Back to cited text no. 1
    
2.
Singletary SE. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 2002;184:383-93.  Back to cited text no. 2
    
3.
Wazer DE, DiPetrillo T, Schmidt-Ullrich R, Weld L, Smith TJ, Marchant DJ, et al. Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1992;10:356-63.  Back to cited text no. 3
    
4.
Dener C, Inan A, Sen M, Demirci S. Interoperative frozen section for margin assessment in breast conserving energy. Scand J Surg 2009;98:34-40.  Back to cited text no. 4
    
5.
Keskek M, Kothari M, Ardehali B, Betambeau N, Nasiri N, Gui GP. Factors predisposing to cavity margin positivity following conservation surgery for breast cancer. Eur J Surg Oncol 2004;30:1058-64.  Back to cited text no. 5
    
6.
Sauter ER, Hoffman JP, Ottery FD, Kowalyshyn MJ, Litwin S, Eisenberg BL. Is frozen section analysis of reexcision lumpectomy margins worthwhile? Margin analysis in breast reexcisions. Cancer 1994;73:2607-12.  Back to cited text no. 6
    
7.
Barros A, Pinotti M, Ricci MD, Nisida AC, Pinotti JA. Immediate effects of intraoperative evaluation of surgical margins over the treatment of early infiltrating breast carcinoma. Tumori 2003;89:42-5.  Back to cited text no. 7
    
8.
Weinberg E, Cox C, Dupont E, White L, Ebert M, Greenberg H, et al. Local recurrence in lumpectomy patients after imprint cytology margin evaluation. Am J Surg 2004;188:349-54.  Back to cited text no. 8
    
9.
Esbona K, Li Z, Wilke LG. Intraoperative imprint cytology and frozen section pathology for margin assessment in breast conservation surgery: A systematic review. Ann Surg Oncol 2012;19:3236-45.  Back to cited text no. 9
    
10.
Gibson GR, Lesnikoski BA, Yoo J, Mott LA, Cady B, Barth RJ Jr. A comparison of ink-directed and traditional whole-cavity re-excision for breast lumpectomy specimens with positive margins. Ann Surg Oncol 2001;8:693-704.  Back to cited text no. 10
    
11.
Camp ER, McAuliffe PF, Gilroy JS, Morris CG, Lind DS, Mendenhall NP, et al. Minimizing local recurrence after breast conserving therapy using intraoperative shaved margins to determine pathologic tumor clearance. J Am Coll Surg 2005;201:855-61.   Back to cited text no. 11
    
12.
Cox CE, Ku NN, Reintgen DS, Greenberg HM, Nicosia SV, Wangensteen S. Touch preparation cytology of breast lumpectomy margins with histologic correlation. Arch Surg 1991;126:490-3.  Back to cited text no. 12
    
13.
Ikeda T, Enomoto K, Wada K, Takeshima K, Yoneyama K, Furukawa J, et al. Frozen-section-guided breast-conserving surgery: Implications of diagnosis by frozen section as a guide to determining the extent of resection. Surg Today 1997;27:207-12.  Back to cited text no. 13
    
14.
ark S, Park HS, Kim SI, Koo JS, Park BW, Lee KS. The impact of a focally positive resection margin on the local control in patients treated with breast-conserving therapy. Jpn J Clin Oncol 2011;41:600-8.  Back to cited text no. 14
    
15.
Fukamachi K, Ishida T, Usami S, Takeda M, Watanabe M, Sasano H, et al. Total-circumference intraoperative frozen section analysis reduces margin-positive rate in breast-conservation surgery. Jpn J Clin Oncol 2010;40:513-20.  Back to cited text no. 15
    
16.
Olson TP, Harter J, Muñoz A, Mahvi DM, Breslin T. Frozen section analysis for intraoperative margin assessment during breast-conserving surgery results in low rates of re-excision and local recurrence. Ann Surg Oncol 2007;14:2953-60.  Back to cited text no. 16
    
17.
Mai KT, Yazdi HM, Isotalo PA. Resection margin status in lumpectomy specimens of infiltrating lobular carcinoma. Breast Cancer Res Treat 2000;60:29-33.  Back to cited text no. 17
    
18.
Arriagada R, Lê MG, Guinebretière JM, Dunant A, Rochard F, Tursz T. Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients. Ann Oncol 2003;14:1617-22.  Back to cited text no. 18
    
19.
Freedman G, Fowble B, Hanlon A, Nicolaou N, Fein D, Hoffman J, 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.  Back to cited text no. 19
    
20.
Tartter PI, Kaplan J, Bleiweiss I, Gajdos C, Kong A, Ahmed S, et al. Lumpectomy margins, reexcision, and local recurrence of breast cancer. Am J Surg 2000;179:81-5.  Back to cited text no. 20
    
21.
Kunos C, Latson L, Overmoyer B, Silverman P, Shenk R, Kinsella T, et al. Breast conservation surgery achieving ≥2 mm tumor-free margins results in decreased local-regional recurrence rates. Breast J 2006;12:28-36.  Back to cited text no. 21
    
22.
Scopa CD, Aroukatos P, Tsamandas AC, Aletra C. Evaluation of margin status in lumpectomy specimens and residual breast carcinoma. Breast J 2006;12:150-3.  Back to cited text no. 22
    



 
 
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