Intraoperative Evaluation of Surgical Margins in Breast Conserving Therapy

Abstract

Negative surgical margins at the time of lumpectomy are essential to achieving optimal patient outcomes. Numerous techniques have been investigated to enhance the accuracy of intraoperative margin analysis. Achieving clear margins at the time of lumpectomy is important because it can facilitate time to treatment of the breast cancer patient and reduce the need for subsequent reoperative procedures to achieve negative margins.

Keywords

lumptectomy, partial mastectomy, margins, intraoperative, cavity margins, specimen radiography, touch prep, frozen section

Breast conserving therapy (BCT) is the preferred treatment approach for most patients with early-stage breast cancer. The combination of complete resection of the primary lesion with tumor-free margins and radiotherapy provides excellent local tumor control. There exists a balance between the extent of lumpectomy performed to achieve tumor-free margins and the resultant cosmesis of the breast. Because pathologic margin status is an important prognostic factor for local failure after segmental resection of in situ or invasive breast carcinoma, pathologic examination of margin status plays a key role in BCT. The inability to obtain clear margins at the time of partial mastectomy for malignancy remains a significant clinical problem. Intraoperative evaluation of margin status may permit immediate reexcision of involved margins, minimizing the need for secondary operative procedures. Unfortunately, at present, all methods used to evaluate margin status intraoperatively have some technical or practical limitations. The technique of margin evaluation varies significantly between institutions because it is unclear which approach is most accurate and cost effective. This chapter reviews data regarding the prognostic significance of margin status, describes the techniques currently used for intraoperative evaluation of margins, and compares the relative benefits and limitations of each approach.

The 1990 National Institutes of Health Consensus Conference on Breast Cancer stated that breast conservation surgery followed by radiation therapy is the preferred method of treatment for stage I and II breast cancer. This recommendation was made after several large, randomized clinical trials found that women with early-stage breast cancer treated with BCT had long-term survival rates equivalent to those treated with mastectomy. These studies report local failure rates of 5% to 15% at 5 to 12 years after wide excision and radiation therapy.

Women with isolated local recurrence are usually treated with salvage mastectomy, and 64% to 92% of them remain disease free at 5 years. Although local failure is relatively uncommon, it represents a failure of breast conservation and should be prevented when possible. This concern has led to the investigation of the risk factors for local recurrence after BCT.

Local recurrence after BCT may be the result of inappropriate patient selection, inadequate operative technique or radiation therapy, or inherent biological characteristics of the tumor. Margin status, tumor size, axillary lymph node status, tumor grade, hormone receptor status, patient age, lymphovascular invasion, presence of extensive intraductal carcinoma, and not receiving chemotherapy or hormonal treatment have been identified as prognostic factors for local recurrence. Historically, numerous studies have found that surgical margin status is an important predictor of local recurrence after wide excision of invasive breast cancer ( Table 44.1 ). Singletary performed a meta-analysis of these studies and found that 30 of the 34 studies show a significantly higher local recurrence rate after “margin-positive” resection compared with those with negative margins. Furthermore, when these studies were grouped according to how the negative margin was defined (i.e., not defined, >1 mm, >2 mm), the differences in local recurrence rates between positive and negative margins were highly significant for each group. On the basis of these collective data, it is now generally agreed that a margin-negative resection is required for optimal local tumor control.

TABLE 44.1

Margin Status and Local Recurrence After Breast Conserving Therapy

Study	Definition	Follow-Up (yr)	LOCAL RECURRENCE (%)
Study	Definition	Follow-Up (yr)	Negative Margin	Positive Margin
Anscher et al.	ND ^a	3.5	1.5	9
Burke et al.		5	2	15
Clarke et al.		10	4	10
Cooke et al.		4.2	3	13
Fourquet et al.		8.6	8	29
Heimann et al.		5	2	11
Leborgne et al.		6.3	9	6
Mansfield et al.		10	8	16
Pezner et al.		4	0	14
Pierce et al.		5	3	10
Ryoo et al.		8	5	13
Slotman et al.		5.7	3	10
van Dongen et al.		8	9	20
Veronesi et al.		6.6	9	17
Assersohn et al.	>1 mm	4.8	0	3
Gage et al.		9.1	3	9/28 ^b
Park et al.		10.6	7	14/27 ^c
Recht et al.		4.8	3	22
Schnitt et al.		5	0	21
Dewar et al.	>2 mm	10	6	14
Freedman et al.		6.3	7	12
Hallahan et al.		3	5	9
Kini et al.		10	6	17
Markiewicz et al.		6	10	4
Obedian et al.		10	2	18
Peterson et al.		6.1	8	10
Solin et al.	5	3	0
Smitt et al.	10	2	22
Touboul et al.		7	6	8
Wazer et al.		7.2	4	16
Pittinger et al.	>3 mm	4.5	3	25
Horiguchi et al.	>5 mm	3.9	1	11
Schmidt-Ullrich et al.	5	0	0
Bartelinke et al.	Micro ^d	6	2	9
Borger et al.	Micro ^d	5.5	2	16
Spivack et al.	Micro ^e	4	4	18

Modified from Singletary SE. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg. 2002;184:383-393.

a Negative margin not defined.

b Nine percent with focally positive margin; 28% with greater than focally positive margin.

c Fourteen percent with focally positive margin; 27% with greater than focally positive margin.

d Negative margin defined as more than one microscopic field.

e Negative margin defined as no microscopic foci of tumor at inked margins.

Many early studies of BCT considered gross tumor excision to be adequate, regardless of the extent of microscopic margin involvement. More recently, attention has focused on the adequacy of microscopic margin status for patients undergoing BCT. A recent consensus panel of the Society of Surgical Oncology and The Society for American Radiation Oncology has recommended that the use of “no ink on tumor” should be the standard for a safe margin in patients with stages I and II invasive breast cancer undergoing BCT in the context of modern multidisciplinary therapy.

Surgical margin status is also an important determinant of local tumor control in ductal carcinoma in situ (DCIS). However, there is no consensus about what constitutes an adequate margin in patients with DCIS undergoing BCT. Silverstein and associates found margin width to be the most important prognostic factor for local recurrence after excision of DCIS. They stratified patients into three risk groups based on margin width: a high-risk group with margins 1 mm or smaller, an intermediate-risk group with margins 2 to 9 mm, and a low-risk group with margins 10 mm or larger. Their studies indicated that if appropriate adjuvant therapy is used, women with margins 1 mm or larger have low (12%) local recurrence rates at 8 years. Several other investigators have confirmed these findings, and they are also supported by a meta-analysis by Boyages and coworkers. A recent large retrospective analysis of 2996 patients with DCIS demonstrated that a wider margin width was associated with improved local control in patients not receiving adjuvant radiation therapy but not in those receiving adjuvant radiation therapy.

When inadequate surgical margins are obtained at the time of first operation, the required second operative procedure produces additional physical discomfort and emotional distress for patients and increases the cost of treating their disease. Furthermore, reexcision is associated with a less desirable cosmetic result and may delay initiation of adjuvant therapy. This has prompted extensive interest and research in the field of intraoperative analysis of the margins to reduce the need for reexcision of involved margins.

All methods used for intraoperative evaluation of margin status have some technical or practical limitations. For example, segmental resection specimens have a large surface area and are often irregular, making it difficult for the pathologist and surgeon to determine the “true” margin, even if orientation and inking methods are used. Any technique used to evaluate margin status in the operating room must be relatively simple, rapid, reproducible, and inexpensive for it to be practical and cost-effective.

Frequency of Margin-Positive Partial Mastectomy

Margin-positive mastectomy remains a significant clinical problem. Rates of margin-positive mastectomy range greatly in reported series and vary between 12% and 68%. A recent large analysis of 2206 women undergoing partial mastectomy demonstrated significant variation in rates of margin positive lumpectomy related to the surgeon and institution where procedures were performed. Some have suggested that certain histologic subtypes, such as invasive lobular carcinoma, are associated with higher rates of margin positivity after partial mastectomy. Other factors that have been associated with having margin-positive partial mastectomy include larger tumor size, extensive intraductal component, younger patient age, lymphovascular invasion, and axillary nodal metastases. Patients with these features may benefit from more aggressive intraoperative strategies to obtain clear margins.

Pathologic Assessment of Margin Status and Specimen Handling

Optimal margin assessment is predicated on proper specimen handling because improper handling can introduce artifacts that greatly limit sensitivity of margin analysis. The importance of specimen handling has been recently highlighted by the Consensus Conference on Nonpalpable Image-Detected Breast Cancers. Surgical specimens should be oriented by the surgeon for proper pathologic processing. When specimen radiography is performed, substantial compression should be avoided because it can fracture the specimen and create false (artifactual) margins after inking. Inking of the six sides of the specimen is performed by either the surgeon at the time of surgery or the pathologist before gross inspection.

Gross Intraoperative Inspection of Tumor Margins

Serial sectioning techniques have been the cheapest, most popular, and most widely used methods to evaluate margins. Most studies correlating local recurrence rates to surgical margin status used serial sectioning procedures of some type, although there is significant variability in the technique and extent of margin evaluation between studies.

Gross intraoperative specimen margin inspection involves careful handling and orientation of the specimen for the pathologist. Serial sectioning is performed intraoperatively after margin-directed inking of the specimen. The relationship of the tumor to gross margins is analyzed, and additional margins are excised at the time of surgery based on the findings. The results of recent studies using gross intraoperative analysis of tumor margins after partial mastectomy have been variable. Balch and associates studied 254 patients in whom gross intraoperative analysis of margins was performed. These authors found that this technique does not reflect true margin status in 25% of women, and the authors concluded that gross inspection alone is not ideal for intraoperative margin assessment. Cabioglu and coworkers recently studied 264 patients undergoing partial mastectomy. These authors combined gross specimen inspection with selective frozen section analysis and specimen radiography. They found that this aggressive approach reduced the incidence of margin-positive partial mastectomy by approximately 50% and demonstrated excellent rates of local control.

Cavity Shave Margin Technique

The cavity shave margin technique is also currently used by many surgeons for margin analysis. This technique samples the tumor bed by shaving samples from the walls of the excision cavity. The use of cavity margins has been well studied and is advocated by some groups. When the cavity margin technique is used, after the lumpectomy specimen is removed, separate specimen shave biopsies of the sides of cavity margin are performed and these specimens are oriented, inked and sent for permanent sectioning. The permanent hematoxylin and eosin (H&E) stains of the cavity margins are analyzed to determine the “final” or “true” margin status. Distance from tumor (if present) to ink on the cavity margin is used by some to determine adequacy of final margin. For some groups, cavity margins are interpreted as either positive or negative depending on the presence or absence of tumor in the cavity margin specimen. This particular technique has been associated with reduced rates of margin-positive resection and very low rates of ipsilateral recurrence after adjuvant therapy. Huston and colleagues and Cao and associates have both reported a reduction in margin-positive resection rates with the use of the “cavity margin” technique without intraoperative frozen section. A randomized controlled trial of cavity shave margins in patients having lumpectomy for stage 0 to III breast cancer demonstrated a 50% reduction in the rates of margin positive lumpectomy and the subsequent need for reexcision without an associated increase in complication rates or a worse cosmesis ( Table 44.2 ). It is noteworthy that the margin positive excision rate in the control group (lumpectomy with no cavity margins) of this randomized trial was high—34%—which limits somewhat the significance of the conclusions.

TABLE 44.2

Effect of Lumpectomy Cavity Shave Margin: Results of a Randomized Trial

Treatment	Total No. of Patients	No. of Positive Margins	Margin + Rate
Shave margin	119	23	19%
No shave margin	116	39	34%

Frozen Section Analysis

Frozen section analysis (FSA) is a commonly used technique for the intraoperative assessment of margin status. In the past, FSA was primarily used for the diagnosis of palpable breast lesions undergoing excisional biopsy, where it has demonstrated accuracy rates of 96% to 98% for both invasive and in situ lesions. With the emergence of fine-needle aspiration cytology and image-guided core biopsy as alternatives to excisional biopsy, the role of FSA has shifted primarily to intraoperative margin assessment. Frozen section is commonly used with the “shaved margin” technique. Using this technique, Weber and coworkers performed FSA in 166 patients and reported the sensitivity and specificity of FSA to be 91% and 100%, respectively. Reported work from the University of Florida also suggests that the use of frozen sections of cavity margins is an effective strategy for improving outcomes after partial mastectomy for breast cancer ( Table 44.3 ). Boughey and colleagues compared rates of reoperation in their institution, which routinely uses frozen section of margins to rates of reoperation reported through the National Surgical Quality Improvement Program (NSQIP). Patients having a lumpectomy for cancer in their institution with intraoperative frozen section analysis of margins had a significantly lower rate of reexcision compared with NSQIP patients (3.6% vs. 13.2%).

TABLE 44.3

Value of Lumpectomy Cavity Shave Margin-Frozen Section: University of Florida Experience