Annals of Surgical Oncology Sign the Guestbook
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
10.1245/s10434-006-9236-0
Annals of Surgical Oncology 14:1458-1471 (2007)
© 2007 Society of Surgical Oncology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cabioglu, N.
Right arrow Articles by Meric-Bernstam, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cabioglu, N.
Right arrow Articles by Meric-Bernstam, F.

Original Article

Role for Intraoperative Margin Assessment in Patients Undergoing Breast-Conserving Surgery

Neslihan Cabioglu, MD, PhD1,5, Kelly K. Hunt, MD1, Aysegul A. Sahin, MD2, Henry M. Kuerer, MD, PhD1, Gildy V. Babiera, MD1, S. Eva Singletary, MD1, Gary J. Whitman, MD3, Merrick I. Ross, MD1, Frederick C. Ames, MD1, Barry W. Feig, MD1, Thomas A. Buchholz, MD4 and Funda Meric-Bernstam, MD1,6

1 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
2 Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
3 Department of Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
4 Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
5 Istanbul Haseki Research Hospital, Istanbul, Turkey
6 1515 Holcombe Blvd., Unit 444, Houston, TX 77030, USA

Correspondence: Address correspondence and reprint requests to: Funda Meric-Bernstam, MD; E-mail: fmeric{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Positive/close margins are associated with higher in-breast failure rates after breast-conserving surgery (BCS). We investigated whether intraoperative margin assessment aids in obtaining negative margins, and to evaluate the local control thus achieved.

Methods: Between 1994 and 1996, 264 patients underwent BCS for stages 0–III breast cancer [invasive, n = 200; ductal carcinoma in situ (DCIS), n = 64]. Intraoperative margin assessment included gross tissue inspection, specimen radiography, with or without frozen section.

Results: Ninety-two patients (46%) with invasive cancer and 24 (38%) with DCIS had positive/close margins on the permanent section analysis of their initial surgical specimens. Fifty-eight patients (29%) with invasive cancer and six (9%) with DCIS had initial positive/ close margins, and were rendered margin-negative by intraoperative analysis and immediate re-excision. Final margins on permanent pathology were positive/close in 52 patients (20%): 34 patients (17%) with invasive cancer and 18 patients (28%) with DCIS. By multivariate analysis, excisional biopsy for diagnosis, larger tumor size, and multifocality were associated with final positive/close margins. Of these 52 patients, 23 underwent a second operation to achieve widely negative margins (13 completion mastectomies, 10 re-excisions). The 5-year ipsilateral breast recurrence-free survival rates after BCS and radiation were 99% for invasive cancer (n = 167) and 100% for DCIS (n = 27).

Conclusions: Intraoperative assessment of margins assisted in identifying positive/close margins and allowed over a quarter of the patients to be rendered margin-negative with intraoperative re-excision at their original operation. This approach resulted in excellent local control in patients treated with BCS and radiation.

Key Words: Breast conservation • Local recurrence • DCIS • Invasive breast cancer • Intraoperative margin assessment • Frozen section


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Breast-conserving therapy (BCT), including breast-conserving surgery (BCS) and radiotherapy, has become the preferred method of treatment for early-stage breast cancer. Large prospective trials have demonstrated that survival rates after BCT are similar to those obtained after mastectomy, although the local recurrence rates are generally higher for BCT than for mastectomy.1–6 Whether an ipsilateral breast tumor recurrence (IBTR) is simply a marker of more aggressive disease or is causally associated with a poor outcome has been debated. Several studies have shown that IBTR is associated with an increased risk of systemic recurrence and poorer survival, and increasingly it is being proposed that the occurrence of IBTR after BCT may be causally associated with an increase in mortality on long-term follow-up.7–12 In a recent overview of randomized trials of radiation therapy and extent of surgery for early breast cancer, the Early Breast Cancer Trialists’ Collaborative Group concluded that avoidance of four local recurrences would avoid one breast cancer-related death, in the absence of other causes of death.13 In an effort to avoid IBTR, the goal of the surgical treatment of breast cancer is to optimize local control while providing a satisfactory cosmetic outcome.

Numerous studies have shown that positive surgical margins are associated with IBTR in patients undergoing breast conservation.14–17 In patients with positive surgical margins, the likelihood of finding residual tumor in the surgical cavity has been found to be as high as 50%.18–22 While the likelihood of positive surgical margins could be reduced by removing more tissue, cosmesis is significantly impacted as the extent of surgery is increased. Furthermore, the volume of the resected breast tissue is, in general, greater with a second surgery for re-excision than with a single adequate primary excision of tumor mass.23 Therefore, accurate evaluation of surgical margins has become an essential part of successful local treatment of breast cancer.

Different approaches have been considered for the intraoperative evaluation of surgical margins, depending on the size and histologic type of the tumor (in situ vs invasive), the imaging findings, the surgical techniques used for excision, and whether or not the targeted lesion is palpable. For instance, specimen radiography is thought to be important in cases of ductal carcinoma in situ (DCIS), which usually present as microcalcifications without an associated mass,24,25 whereas gross pathologic evaluation with or without frozen section analysis or touch imprint cytology is more feasible for palpable invasive cancers.26–33

At The University of Texas M. D. Anderson Cancer Center, we initiated our intraoperative margin analysis in the early 1990s and this approach was routinely implemented by 1994. Therefore, we reviewed our experience with intraoperative margin assessment in the patients with DCIS or invasive cancer who underwent primary tumor excision from 1994 through 1996. In this retrospective study, our main objective was to evaluate the success rate for obtaining negative margins and the local control achieved with this approach at our institution.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
An Institutional Review Board-approved retrospective medical chart review was performed in patients who underwent BCS at M. D. Anderson Cancer Center between January 1994 and December 1996. The patient list was generated by searching the databases maintained by the Department of Medical Informatics for patients who underwent primary tumor excision (excisional biopsy or segmental mastectomy) (n = 555) during this timeframe. Patients were excluded from the study if they were in the following categories: primary tumor excision performed at an outside hospital (n = 178), treatment with preoperative hormonal therapy (n = 2) or chemotherapy (n = 104), or the presence of systemic metastases at presentation (n = 7). A chart review was performed to record the following variables: patient demographics including initial diagnostic procedures [fine needle aspiration (FNA), core biopsy, excisional biopsy], physical examination and imaging findings, methods used to localize the lesion for excision (sonographically or mammographically guided approach for nonpalpable lesions), definitive surgical procedure; a detailed intraoperative margin evaluation analysis including the initial and final margin status, whether any further tissue was excised at the first surgery, intraoperative evaluation procedures based on gross inspection, frozen section, and radiological evaluation with the corresponding permanent pathology; and clinicopathologic features including tumor size, histology, adjuvant treatment, and outcome. The 6th edition of the AJCC Cancer Staging system was used for staging.34

Pathologic Evaluation
All surgical specimens were evaluated intraoperatively in a standard fashion as previously described (Fig. 1Go).25,35 The surgeon routinely oriented the breast tissue with sutures and delivered the specimen to the pathology suite. A multicolor inking system was used to mark the superior, inferior, lateral, medial, anterior, and posterior surfaces of the resected specimen (Fig. 2aGo). The specimen was then sliced into 3- to 5-mm sections perpendicular to the longest axis through the tumor mass (Fig. 2cGo). The sections were aligned based on the anatomic orientation, and the margins were grossly examined for proximity to the tumor mass. If the mass appeared to approach or touch a margin, either a immediate re-excision of that margin was performed, or a perpendicular section including the questionable margin was made and submitted for frozen section analysis to determine the need for an immediate re-excision. The colored ink was visualized on frozen section and on final pathology slides, allowing orientation of the specific margin to the surgical cavity in the patient. If a positive margin was identified, additional tissue was excised during the same surgery, with the goal of ultimately obtaining a negative margin.


Figure 1
View larger version (28K):
[in this window]
[in a new window]

  		FIG. 1. Processing of breast specimens.

 

Figure 2
View larger version (125K):
[in this window]
[in a new window]

  		FIG. 2. (A) All six surfaces (medial, lateral, superior, inferior, superficial, and deep) of the resection specimen are inked with different colors. (B) Specimen radiograph of a DCIS lesion. (C) Sliced gross pathologic examination. (D) Sliced specimen radiograph.

 
For nonpalpable lesions, the whole specimen was radiographed to identify the targeted mammographic lesion and then inked using different colors to identify each face of the specimen (Fig. 2bGo). The specimen was then sectioned into 3- to 5-mm slices. The pathologist examined the slices grossly to identify suspicious areas and noted their proximity to the margins. The slices were then radiographed (Fig. 2dGo), and a breast imager reviewed the films to determine the extent of any abnormalities on specimen radiography and their proximity to the margins. These radiologic and pathologic findings were conveyed to the surgeon during the surgical procedure, who then decided whether additional excision was required to obtain adequate margins. The radiographic target margin was considered 1 cm when possible.

The decision for frozen section was made with close collaboration among surgeon, pathologist and radiologist, and taking the tumor type and other patient variables into consideration. For cases with invasive cancer, frozen section was selectively considered in addition to gross examination, to determine the exact margin distance during the operation to decide whether more additional tissue should be re-excised. However, frozen section was not performed when the margin grossly seemed to be positive or close (<2 mm), but rather, the decision for intraoperative re-excision was made on gross sectioning alone. In contrast, for DCIS, as it is more difficult to evaluate margins by gross examination, specimen radiography was essential for those cases to examine tumor extent and margin status. However, for cases with suspicious close margins where the surgeon did not desire to excise additional margins, often depending on the location of the tumor and concerns for unsatisfactory cosmesis, frozen section analysis was performed to assess margin adequacy.

Final margin status was determined by examination of the permanent paraffin-embedded sections. The number of permanent sections evaluated by the pathologist was based on the gross evaluation and the radiologic extent of the abnormality as well as the size of the specimen. In cases of microcalcifications, the entire specimen was evaluated. A positive surgical margin was defined as the presence of tumor at the inked margin, whereas a close margin was defined as tumor within 2 mm of a margin. Additional margins were excised if the initial margins were found to be positive, close, or suspicious for malignancy during intraoperative margin assessment. Overall, only the width of those margins that were the closest to the targeted lesion were considered in the analyses. For example, if a patient had two margins sampled, one measuring 1 mm and one measuring 5 mm away from the tumor, the margin width was considered to be 1 mm.

The margin status of the first operative specimen as assessed by permanent section analysis is referred to as initial margin. The status of the margins upon permanent section analysis, when the intraoperative re-excision specimens as well as the initial specimen were taken into account, is referred to as final margin. For example, a patient who had a <2 mm inferior margin on the first operative specimen, but had an immediate intraoperative re-excision of the inferior margin with no tumor in the specimen or residual tumor ≥2 mm away from the true margin of the re-excision specimen would be considered to have a close initial margin but negative final margin.

Surgical Therapy
Patients underwent wide local excision including complete tumor removal with the aim of achieving grossly normal tissue margins of at least 1 cm. If surgical margins were positive or close on permanent pathology, a re-excision at a second operation or mastectomy was considered. However, whether the patient will require a second operation is a multifactorial decision depending on the location of the close margin (i.e., whether it is a parenchymal margin vs approaching skin or is a deep margin in a patient who had an en bloc excision of pectoralis fascia), tumor characteristics, patient’s risk factors, attitude of the radiation oncologist, comorbidities of the patient, cosmesis, or patient and surgeon. Patients underwent level I and II axillary lymph node dissection, with (n = 9) or without sentinel lymph node biopsy, at the discretion of the surgeon.

Systemic Therapy
Adjuvant chemotherapy was considered for patients with histologic evidence of lymph node involvement and for patients with lymph node–negative disease who had an invasive tumor greater than 1 cm in size. Most patients received a doxorubicin-containing regimen. Tamoxifen was prescribed to patients with estrogen or progesterone receptor–positive tumors after chemotherapy or following radiation therapy in those patients who did not receive chemotherapy after surgery.

Radiation Therapy
The majority of patients underwent adjuvant external-beam radiation therapy to the breast with medial and lateral tangential fields. Over a 5-week period, 45–50 Gy was delivered in 25 fractions by using 6-MeV or higher energy photons. A 10- to 16-Gy boost was typically delivered to the tumor bed at the discretion of the radiation oncologist after whole breast treatment.

Follow-up
Patients were followed with a history and physical examination at least every 6 months for the first 5 years and then annually thereafter. Mammograms were obtained at 6 months after radiation therapy and then every year thereafter to screen for IBTR and any new contralateral cancers. A biopsy was indicated if a suspicious lesion was detected by mammography and/or sonography or if a palpable abnormality was detected on physical examination. Any carcinoma detected in the ipsilateral breast was considered an IBTR.

Statistical Analyses
The SPSS 10.1 software package (SPSS Inc., Chicago, IL) was used for statistical analyses. To evaluate the value of intraoperative margin assessment, all patients with primary tumor excision, regardless of whether they underwent breast conservation or mastectomy as their final definitive surgery type, were included in the analyses. However, only patients with breast conservation were considered in the outcome analyses regarding IBTR.

Descriptive analyses were performed to assess the frequency of the demographic and the pathologic features of patients diagnosed with DCIS and invasive cancer. Margins that were found to be ≥2 mm were defined as surgically negative margins, whereas margins positive or close (<2 mm) or suspicious for malignancy were considered as surgically positive margins because the latter might require a re-excision by the surgeon. The surgically positive and negative margins were considered in calculations of sensitivity, specificity, and accuracy of frozen section analysis used for intraoperative margin assessment by using permanent pathology as the reference. These calculations were performed only for the assessment of the intraoperative margins as determined by the evaluation of the initial lumpectomy specimen including the tumor. Therefore, findings of frozen sections performed for intraoperative margin assessment, defined as surgically negative or positive margins, were compared with each corresponding finding in the permanent pathology. Sensitivity was defined as the proportion of patients with positive margins correctly identified by frozen section (true-positive findings/ true-positive findings and false negative findings). Specificity was defined as the proportion of patients who had negative margins that were correctly identified as such by frozen section (true-negative/true-negative findings and false positive findings). Accuracy was the proportion of patients correctly identified as either having positive margins or negative margins by frozen section as determined by the sum of true-positive and true-negative findings divided by the total number of specimens examined.

Furthermore, associations of final positive or close margins with patient and tumor characteristics were investigated by using Fisher’s exact or Pearson chi-square test as appropriate. The variables that were found to be statistically significant in univariate analyses were further evaluated by a multivariate analysis to identify the factors associated with final positive or close margins by using a forward logistic regression model. Moreover, IBTR-free survival was calculated to assess the outcome in patients with breast conservation. IBTR-free survival was measured from the date of definitive surgical therapy to the date of histologic diagnosis of the recurrent lesion or the last follow-up appointment. The Kaplan–Meier method was used to estimate IBTR-free survival.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient and Tumor Characteristics
The study group consisted of 264 women who were diagnosed with DCIS or invasive cancer between 1994 and 1996 and who underwent primary tumor excision at M.D. Anderson. Of the 264 patients, 13 patients underwent a completion mastectomy at the time of initial surgery (n = 3) or at a second surgery (n = 10) due to the finding of positive or close margins. Therefore, 251 patients were treated with breast conservation. Of these 251 patients, 10 (4%) patients required a second surgery for re-excision of positive or close margins seen on final pathology. The demographic, diagnostic, and treatment features of patients and tumor characteristics are shown in Tables 1Go and 2Go. Of the 264 patients, 200 had invasive cancer and 64 had DCIS with (n = 8) or without microinvasion (n = 56). The median age was 60 years (range 27–95 years) for women with invasive cancer and 58 years (range 32–81 years) for women with DCIS.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Demographic, diagnostic and treatment features of patients undergoing primary tumor excision between 1994 and 1996
 

View this table:
[in this window]
[in a new window]

  		TABLE 2. Pathologic characteristics of patients undergoing primary tumor excision
 
The majority of patients with invasive cancer (60%) underwent FNA or core biopsy (22.5%) for diagnosis. In contrast, most patients with DCIS (64.1%) underwent an excisional biopsy for diagnosis, usually performed with mammographically guided needle localization (Table 1Go). Patients with invasive cancer were less likely to have a primary tumor excision by mammographically guided-needle localization than patients with DCIS (invasive cancer, 23.3% vs DCIS, 81.3%). Preoperative ultrasound guided localization techniques were utilized more commonly for patients with invasive cancer (20.7%) than for those with DCIS (6.2%). Only five patients had tumor bracketing with more than one needle (three patients with DCIS, two with invasive carcinoma).

Intraoperative Margin Assessment
The algorithms utilized for intraoperative margin evaluation of palpable and nonpalpable lesions are described in Fig. 1Go. The procedures and findings on intraoperative margin assessment are tabulated according to histology (invasive vs DCIS) in Table 3Go. The majority of cases with invasive cancer (53.9%) were evaluated by frozen section with gross examination, whereas the majority of cases with DCIS (85.9%) were evaluated by specimen radiograph with or without frozen section. Ultrasound was seldom utilized for margin analysis (two cases with invasive cancer and one case with DCIS).


View this table:
[in this window]
[in a new window]

  		TABLE 3. Margin evaluation at first tumor excision
 
The majority of patients with invasive cancer (n = 145, 74.4%) underwent frozen section analysis of surgical margins after gross inspection or radiographic evaluation of the specimen. Among these, 58 (40%) patients were identified as having positive or close initial surgical margins. The specificity, sensitivity, and accuracy of frozen section analysis with 95% confidence intervals were 91.7% (81.6–97.4%), 77.8% (57.7–91.4%), and 87.4% (78.5–92.8%), respectively, for initial margin evaluation.

One hundred thirty-three patients, including 115 patients with invasive cancer (57.5%) and 18 patients with DCIS (28.1%), underwent additional re-excision of margins based on the intraoperative margin assessment. Of those 133 patients, 54 patients (40.6%) underwent re-excisions on radiographic specimen evaluation. Overall, 21 patients (15.8%; 19 patients with invasive cancer and 2 patients with DCIS) required a second additional margin re-excision during the same operation. Final intraoperative margins were still positive or close on permanent section analysis in ten patients (nine patients with invasive cancer and one patient with DCIS) of the total population, who had at least one re-excision during the initial surgery (10/133, 7.5%).

The margin status and the surgical outcome of the patients by intraoperative margin assessment are shown in Figs. 3Go, 4Go, and 5Go. Ninety-two patients (46%) with invasive cancer and 24 patients (38%) with DCIS had positive or close margins on permanent section analysis of their initial surgical specimen. Fifty-eight patients (29%) with invasive cancer and six patients (9%) with DCIS with initial positive or close margins were rendered margin-negative by intraoperative analysis and immediate re-excision of margins. The final margins were positive on permanent section analysis in 12 patients (6%), and close in 22 patients (11%) with invasive cancer. The final margins were positive in three patients (4.7%), and close in 15 patients (23.4%) with DCIS.


Figure 3
View larger version (18K):
[in this window]
[in a new window]

  		FIG. 3. Flow diagram for patients with invasive cancer. a The final numbers do not equal 100% due to missing data for a few patients. Initial and final margins represent the margin status by permanent pathology.

 

Figure 4
View larger version (17K):
[in this window]
[in a new window]

  		FIG. 4. Flow diagram for patients with DCIS. a The final totals do not equal 100% due to missing data for a few patients. Initial and final margins represent the margin status by permanent pathology.

 

Figure 5
View larger version (12K):
[in this window]
[in a new window]

  		FIG. 5. Management of close or positive margins. a Final margins were positive in 3 of 20 patients. No further surgery was performed due to the comorbidities, deep margin close/ positive in the setting of underlying fascia excised intraoperatively, due to patient refusal, or at the discretion of the surgeon. b Final margins were close in nine patients with no further surgery. A re-excision was not performed due to the patient’s choice or at the discretion of the surgeon.

 
Sixty-seven of 92 patients with initial positive/close margins and invasive cancer were found to have a tumor more than 2 cm. All of the 24 patients with initial positive/close margins and DCIS lesions underwent BCS by radiographic or ultrasound guided needle localization. Since the majority of those (21/24) underwent surgery for diagnosis of the lesion, achieving of negative margins was not the primary goal during the initial tumor excision, and this may have resulted in a high rate of positive/close initial margin status in patients with DCIS.

Of 264 patients, 14 (7%) of the 200 patients with invasive cancer underwent a second operation, re-excision, or mastectomy, whereas nine (14%) of the 64 patients with DCIS underwent a second operation due to positive or close margins on the final permanent pathology (Fig. 5Go). For patients with invasive cancer, final margins were positive in three patients. One patient did not undergo further surgery due to comorbidities, and another at the discretion of the surgeon. The third patient had a positive deep margin, where it was felt that the underlying pectoralis fascia had been excised intraoperatively. Final margins were close in 17 patients with invasive cancer. These patients did not undergo further surgery due to the comorbidities, at the discretion of the surgeon or due to the patient’s refusal (Fig. 5Go). None of the DCIS patients had final positive margins. The final margins were close in nine patients; patients were not re-excised due to the patients’ choice, or at the discretion of the surgeon (Fig. 5Go).

Factors Associated with Positive or Close Margins on Final Permanent Pathology
Factors associated with a finding of positive or close margins on final permanent pathology are shown in Table 4Go. Patients who had nonpalpable tumors, an excisional biopsy for diagnosis, a lumpectomy by needle localization techniques, DCIS with or without microinvasion, invasive cancer associated with extensive intraductal component (EIC), multifocality, or larger tumors were more likely to have positive or close margins on final pathology, compared with patients without these characteristics. When these factors found to be significant on univariate analysis were evaluated in a multivariate logistic regression model, excisional biopsy for diagnosis, larger tumor size (>2 cm), and multifocality remained significant at the P < 0.05 level (Table 5Go).


View this table:
[in this window]
[in a new window]

  		TABLE 4. Univariate analysis of variables associated with close or positive final margins in patients who underwent intraoperative margin evaluation for primary tumor excision (n = 264)
 

View this table:
[in this window]
[in a new window]

  		TABLE 5. Multivariate logistic regression analysis for factors associated with final positive or close margins in patients diagnosed with DCIS or invasive cancer who underwent intraoperative margin evaluation for primary tumor excision
 
Adjuvant Treatment and Outcome in Patients with Breast Conservation
The pathologic staging results for patients with invasive cancer were as follows: stage I, 72.6%; stage II, 23.3%, and stage III, 4.1% (Table 2Go). Adjuvant systemic therapy included hormonal therapy in 40.9% of patients with invasive cancer and chemotherapy in 24.7%. Out of 20 patients with invasive cancer and persistent positive/close margins after completion of all surgical treatment, 17 were ER (+), and nine of them received adjuvant tamoxifen. A minority of patients with DCIS received systemic therapy during the study period (Table 1Go).

One hundred and sixty-seven (87%) of 194 patients with invasive cancer who underwent BCS received adjuvant radiation therapy, whereas only 27 (48.2%) of 57 patients with DCIS who underwent BCS had radiation therapy. The data regarding boost radiation therapy are available for only 12 patients with invasive cancer (n = 20) or DCIS (n = 9) who had persistent positive/close margins after completion of all surgical treatment. Of those, eight patients with invasive cancer and two patients with DCIS received a boost while two patients with invasive cancer did not.

At a median follow-up of 6.4 years (range 0.6–9.4 years), eight patients (4.1%) with invasive cancer, and three patients (5.3%) with DCIS had an IBTR after BCS. The 5-year IBTR-free survival rates were higher in patients who underwent radiation therapy than in patients without radiation therapy for both invasive cancer and DCIS (invasive cancer, 99 vs 87%, respectively, P = 0.007; DCIS, 100 vs 91%, P = 0.07). Similarly, patients with DCIS and negative margins had better 5-year IBTR-free survival rates than patients with persistent positive/close margins after completion of all surgical treatment. (98 vs 86%, respectively, P = 0.017). No significant difference was observed in IBTR rates of patients with invasive cancer when stratified according to the margin status (96% for negative margins vs 96% for positive/close margins, P = 0.85). However, this analysis was somewhat limited due to the small number of patients who had persistent positive/ close final margins (n = 21). There were no second recurrences.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Intraoperative margin assessment of breast specimens is an evolving area in BCS, requiring multidisciplinary collaboration among surgeons, pathologists, and radiologists. At M.D. Anderson, our protocol for intraoperative margin analysis has been routinely used since 1994. In this study we reviewed our institutional approach in patients undergoing primary tumor excision between 1994 and 1996 to investigate the risk factors associated with positive or close margins as well as the outcome in patients with breast conservation.

The approaches we utilize to examine the surgical margins of the resection specimen during initial surgery, depend on the histologic type of the tumor (DCIS vs invasive cancer), size of the tumor, and whether the tumor is palpable or nonpalpable. In the current study, the majority of lumpectomy specimens from patients with invasive cancer were evaluated by gross inspection examination with or without frozen section analysis. More than half of the patients required an additional margin re-excision intraoperatively in order to achieve widely negative margins, and 55% of patients with initial positive or close margins on permanent section analysis were rendered margin-negative based on the final permanent pathology. The sensitivity (78%) and the specificity (92%) of frozen section analysis of initial margin evaluation were found to be consistent with previous studies reporting a sensitivity between 83 and 91% and a specificity between 86 and 100% for the evaluation of margins.26–29

Cytologic "touch prep" analysis and intraoperative analysis of shaved margins, have both been proposed as alternative approaches for immediate margin assessment. Touch prep examination of the lumpectomy margins is utilized by several institutions with expertise in this area.30–33 Although promising results have been reported by these studies, one important limitation of touch prep analysis is that it can detect only positive margins (i.e., tumor at the cut edge) and does not indicate when there are close margins, which may be undesirable from an oncologic perspective. With intraoperative shaved margin analysis, the tumor is excised with the goal of excising at least a 1-cm margin of normal breast parenchyma. Then, without intraoperative analysis of the excised specimen, additional breast tissue is sharply removed circumferentially36 and assessed by frozen section analysis. This approach has also been shown to significantly reduce re-excision rates.36 Although all of these approaches have been reported to demonstrate superiority over conventional margin analysis in achieving negative margins, it is important to note that intraoperative margin analysis, regardless of approach, requires additional time and multidisciplinary coordination. We believe the ability to convert over a quarter of patients from initial positive/ close margins to margin-negative with intraoperative re-excision, makes this effort worthwhile. However, further work is needed to determine the cost-effectiveness of intraoperative margin analysis, and to identify the most efficient approach.

Unlike invasive cancer, the majority of DCIS lesions do not form a mass, and therefore gross pathologic inspection of the specimen may not yield useful information to the surgeon.35,37 Therefore, specimen radiography is more crucial in DCIS or and patients presenting with nonpalpable lesions to evaluate the extent of the tumor and the proximity to margins.38–41 At our institution, we perform radiographs of both the whole specimen and sliced specimens to examine for calcifications as previously described (Fig. 2Go).39,40 In this study, the majority of patients with DCIS (n = 64) underwent a mammographically guided needle localization and the lumpectomy specimens were assessed by specimen radiography evaluation. Of the 24 patients with DCIS and initial positive or close margins, six (25%) patients were rendered margin-negative with intraoperative re-excision. However, this rate of converting patients with positive or close margins on initial excision to final margin-negative status was lower than that achieved in patients with invasive breast cancer (63%). This may be in part attributable to more of the patients with DCIS having undergone excisional diagnostic biopsies in this study. However, Chagpar et al.40 reviewed 109 patients diagnosed with DCIS by core biopsy at the M. D. Anderson Cancer Center, and found that with additional margin re-excision intraoperatively, 31 (54.3%) of 57 patients with initial positive or close margins were rendered margin-negative; yet a second operation was still required in 22% of the patients. This highlights the challenge of achieving widely negative margins for DCIS, even with a preoperative diagnosis of DCIS, and with intraoperative margin assessment.

Risk factors have been investigated in several previous studies to identify those patients with a high likelihood of having positive margins during BCS.42–47 Younger age,42,43 positive family history,43 histopathologic characteristics including DCIS,42 presence of EIC,42–44 larger tumor size,43–45 presence of lymphovascular invasion,44 multifocality,47 lobular histologic subtype45 axillary node positive disease43 have all been associated with positive margins. In the current study, we explored all patient and tumor characteristics associated with close and positive margins. Our findings were similar to those of the previous studies with patients with larger tumor size, DCIS histologic type, invasive cancer with EIC or multifocality and nonpalpable tumors being more likely to have close or positive margins during initial surgery for primary tumor excision. In addition, we found that patients with an excisional biopsy for diagnosis, or with a lumpectomy procedure guided by preoperative mammographic or sonographic localization techniques were more frequently found to have close or positive surgical margins. Only multifocality, larger tumor size (>2 cm), and diagnostic excisional biopsy remained significant in the multivariate analysis in the current study. Our data suggest that patients with larger tumor size, or multifocality, or those undergoing excisional biopsies for diagnosis require more meticulous intraoperative margin examination in order to avoid the need for reoperation. The majority of excisional biopsies were performed in patients with DCIS or nonpalpable invasive cancer by means of localization techniques. Our finding that excisional biopsies are associated with a greater risk of close or positive margins likely reflects the fact that the goal of intraoperative analysis of excisonal biopsies is primarily to confirm excision of the targeted lesion, rather than to confirm widely negative margins. Therefore, our current practice is to obtain a cancer diagnosis preoperatively with a core biopsy whenever possible, so that the patient can undergo a single definitive operation with intraoperative assessment of margins.

Whether intraoperative margin evaluation reduces IBTR rates by increasing the yield of negative margins has been of great interest to surgeons in recent years. The effect of negative margins on reducing the IBTR rates has been well established in previous studies14,17 and in reviews48 that summarize the published reports on the effect of margin status on IBTR rates in patients treated with BCT. Consistent with these studies, our recent study49 demonstrated that the presence of negative margins was associated with improved IBTR-free survival by multivariate analyses in 1355 patients diagnosed with invasive cancer (pathologic stages I–II) who underwent breast conservation with radiation therapy at M.D. Anderson. In that study, along with the decline in the 5-year cumulative IBTR rate from 5.7% before 1994 to 1.3% among patients treated in 1994–1996 (P = 0.001), it was also shown that the rates of unknown or positive margins declined from approximately 24% in the earlier time period to less than 3% after 1994 (P = 0.0001), which most likely reflects the establishment of the routine use of intraoperative margin analysis starting in 1994 at our institution. Similarly, Weinberg et al.50 compared the IBTR rates in 1,193 patients who underwent intraoperative imprint cytology evaluation during their initial BCS at the H. Lee Moffitt Cancer Center with the rates for 520 patients who had their surgery at an outside institution where conventional margin analysis was performed. They found that patients with imprint cytology evaluation had significantly lower overall 5-year IBTR rates compared with those patients with conventional histologic evaluation (2.8 vs 8.8%, P < 0.0001).

In this study, we report excellent local control in the current study population (stages 0–III) of women treated with breast conservation followed by radiation therapy. The 5-year IBTR-free survival rates were 99% for patients with invasive cancer and 100% for those with DCIS. Therefore, intraoperative margin evaluation techniques may play an important role in improving the IBTR rates by achieving widely negative margins. Our results suggest that achieving widely negative margins may be especially important for local control in patients with DCIS. This may in part reflect the use of systemic chemotherapy in patients with invasive cancer, which has been associated with lower IBTR rates.49,51 The use of radiation therapy was also associated with a significant improvement in the IBTR rates. This demonstrates that achieving negative margins with intraoperative margin analysis is not a substitute for radiation therapy, and that even further improvement in local control by potentially delaying or preventing local recurrence can be achieved with the use of radiation therapy after BCS. Whether there is a group of patients who are at a sufficiently low risk for IBTR that they can forego radiation therapy remains unknown.

In conclusion, intraoperative assessment of margins during the initial surgery can identify close or positive margins, and thereby avoid a second surgery. Excellent local control can be achieved for patients undergoing BCS when negative margins are obtained and radiation therapy is routinely employed.


   ACKNOWLEDGMENTS
 
We thank Kristine Broglio, Adriana Lopez and Nadeem Mirza for their help with statistical analyses.

Received for publication December 22, 2005. Accepted for publication August 23, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Fisher B, Anderson S, Bryant J, 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.[Abstract/Free Full Text]
  2. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347:1227–32.[Abstract/Free Full Text]
  3. Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr 1992; 11:19–25.
  4. Arriagada R, Le MG, Rochard F, Contesso G. Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol 1996; 14:1558–64.[Abstract/Free Full Text]
  5. van Dongen JA, Voogd AC, Fentiman IS, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000; 92:1143–50.[Abstract/Free Full Text]
  6. Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995; 332:907–11.[Abstract/Free Full Text]
  7. Haffty BG, Reiss M, Beinfield M, et al. Ipsilateral breast tumor recurrence as a predictor of distant disease: implications for systemic therapy at the time of local relapse. J Clin Oncol 1996; 14:52–7.[Abstract]
  8. Elkhuizen PH, van de Vijver MJ, Hermans J, et al. Local recurrence after breast-conserving therapy for invasive breast cancer: high incidence in young patients and association with poor survival. Int J Radiat Oncol Biol Phys 1998; 40:859–67.[CrossRef][Medline]
  9. Rouzier R, Extra JM, Carton M, et al. Primary chemotherapy for operable breast cancer: incidence and prognostic significance of ipsilateral breast tumor recurrence after breast-conserving surgery. J Clin Oncol 2001; 19:3828–35.[Abstract/Free Full Text]
  10. Fisher ER, Anderson S, Redmond C, Fisher B. Ipsilateral breast tumor recurrence and survival following lumpectomy and irradiation: pathological findings from NSABP protocol B-06. Semin Surg Oncol 1992; 8:161–6.[Medline]
  11. Meric F, Mirza NQ, Vlastos G, et al. Positive surgical margins and ipsilateral breast tumor recurrence predict disease-specific survival after breast-conserving therapy. Cancer 2003; 97:926–33.[CrossRef][Medline]
  12. Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96:115–21.[Abstract/Free Full Text]
  13. Group EBCTC Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:2087–106.[Medline]
  14. Schnitt SJ, Abner A, Gelman R, et al. The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy. Cancer 1994; 74:1746–51.[CrossRef][Medline]
  15. Smitt MC, Nowels KW, Zdeblick MJ, et al. The importance of the lumpectomy surgical margin status in long-term results of breast conservation. Cancer 1995; 76:259–67.[CrossRef][Medline]
  16. Smitt MC, Nowels K, Carlson RW, Jeffrey SS. Predictors of re-excision findings and recurrence after breast conservation. Int J Radiat Oncol Biol Phys 2003; 57:979–85.[CrossRef][Medline]
  17. Leong C, Boyages J, Jayasinghe UW, et al. Effect of margins on ipsilateral breast tumor recurrence after breast conservation therapy for lymph node-negative breast carcinoma. Cancer 2004; 100:1823–32.[CrossRef][Medline]
  18. Gwin JL, Eisenberg BL, Hoffman JP, et al. Incidence of gross and microscopic carcinoma in specimens from patients with breast cancer after re-excision lumpectomy. Ann Surg 1993; 218:729–34.[Medline]
  19. Kearney TJ, Morrow M. Effect of re-excision on the success of breast-conserving surgery. Ann Surg Oncol 1995; 2:303–7.[Abstract]
  20. Papa MZ, Zippel D, Koller M, et al. Positive margins of breast biopsy: is re-excision always necessary?. J Surg Oncol 1999; 70:167–71.[CrossRef][Medline]
  21. Ratanawichitrasin A, Rybicki LA, Steiger E, et al. Predicting the likelihood of residual disease in women treated for ductal carcinoma in situ. J Am Coll Surg 1999; 188:17–21.[CrossRef][Medline]
  22. Miller AR, Brandao G, Prihoda TJ, et al. Positive margins following surgical resection of breast carcinoma: analysis of pathologic correlates. J Surg Oncol 2004; 86:134–40.[CrossRef][Medline]
  23. Wazer DE, DiPetrillo T, Schmidt-Ullrich R, 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.[Abstract/Free Full Text]
  24. Ishida T, Furuta A, Moriya T, Ohuchi N. Pathological assessment of intraductal spread of carcinoma in relation to surgical margin state in breast-conserving surgery. Jpn J Clin Oncol 2003; 33:161–6.[Abstract/Free Full Text]
  25. Schnitt SJ, Connolly JL. Processing and evaluation of breast excision specimens. A clinically oriented approach. Am J Clin Pathol 1992; 98:125–37.[Medline]
  26. Weber S, Storm FK, Stitt J, Mahvi DM. The role of frozen section analysis of margins during breast conservation surgery. Cancer J Sci Am 1997; 3:273–7.[Medline]
  27. Noguchi M, Minami M, Earashi M, et al. Pathologic assessment of surgical margins on frozen and permanent sections in breast conserving surgery. Breast Cancer 1995; 2:27–33.[Medline]
  28. Sauter ER, Hoffman JP, Ottery FD, et al. Is frozen section analysis of re-excision lumpectomy margins worthwhile? Margin analysis in breast re-excisions. Cancer 1994; 73:2607–12.[CrossRef][Medline]
  29. Cendan JC, Coco D, Copeland EM III. Accuracy of intraoperative frozen-section analysis of breast cancer lumpectomy-bed margins. J Am Coll Surg 2005; 201:194–8.[CrossRef][Medline]
  30. Klimberg VS, Westbrook KC, Korourian S. Use of touch preps for diagnosis and evaluation of surgical margins in breast cancer. Ann Surg Oncol 1998; 5:220–6.[Abstract]
  31. Cox CE, Hyacinthe M, Gonzalez RJ, et al. Cytologic evaluation of lumpectomy margins in patients with ductal carcinoma in situ: clinical outcome. Ann Surg Oncol 1997; 4:644–9.[Abstract]
  32. Cox CE, Pendas S, Ku NN, et al. Local recurrence of breast cancer after cytological evaluation of lumpectomy margins. Am Surg 1998; 64:533–7; discussion 7–8.[Medline]
  33. Creager AJ, Shaw JA, Young PR, Geisinger KR. Intraoperative evaluation of lumpectomy margins by imprint cytology with histologic correlation: a community hospital experience. Arch Pathol Lab Med 2002; 126:846–8.[Medline]
  34. Greene FL, Page DL, Fleming ID, eds. et al. (2002) Breast. AJCC Cancer Staging Manual, 6th ed. New York: Springer pp 223–40.
  35. Sahin A. (2004) Surgical margin evaluation in patients treated with breast-conserving therapy. In: Singletary SE, Robb GL, Hortobagyi GN, eds. Advanced therapy of breast disease, 2nd edn. Ontario: BC Decker, Inc., pp 341–84.
  36. Camp ER, McAuliffe PF, Gilroy JS, 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.[CrossRef][Medline]
  37. Lagios MD. (2002) Practical pathology of ductal carcinoma in situ: how to derive optimal data from the pathologic examination. In: Silverstein MJ, Recht A, Lagios MD, eds. Ductal carcinoma in situ of the breast, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; pp 207–21.
  38. Oakley KL, Going JJ. Specimen slice radiography of cancer in breast conserving excisions. J Clin Pathol 1995; 48:1028–30.[Abstract/Free Full Text]
  39. Rubio IT, Mirza N, Sahin AA, et al. Role of specimen radiography in patients treated with skin-sparing mastectomy for ductal carcinoma in situ of the breast. Ann Surg Oncol 2000; 7:544–8.[Abstract]
  40. Chagpar A, Yen T, Sahin A, et al. Intraoperative margin assessment reduces re-excision rates in patients with ductal carcinoma in situ treated with breast-conserving surgery. Am J Surg 2003; 186:371–7.[CrossRef][Medline]
  41. McCormick JT, Keleher AJ, Tikhomirov VB, et al. Analysis of the use of specimen mammography in breast conservation therapy. Am J Surg 2004; 188:433–6.[CrossRef][Medline]
  42. Obedian E, Haffty BG. Negative margin status improves local control in conservatively managed breast cancer patients. Cancer J Sci Am 2000; 6:28–33.[Medline]
  43. Tartter PI, Kaplan J, Bleiweiss I, et al. Lumpectomy margins, re-excision, and local recurrence of breast cancer. Am J Surg 2000; 179:81–5.[CrossRef][Medline]
  44. Park CC, Mitsumori M, Nixon A, et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol 2000; 18:1668–75.[Abstract/Free Full Text]
  45. Luu HH, Otis CN, Reed WP Jr, et al. The unsatisfactory margin in breast cancer surgery. Am J Surg 1999; 178:362–6.[CrossRef][Medline]
  46. Chagpar AB, Martin RC II, Hagendoorn LJ, et al. Lumpectomy margins are affected by tumor size and histologic subtype but not by biopsy technique. Am J Surg 2004; 188:399–402.[CrossRef][Medline]
  47. Saarela AO, Rissanen TJ, Lahteenmaki KM, et al. Wire-guided excision of non-palpable breast cancer: determinants and correlations between radiologic and histologic margins and residual disease in re-excisions. Breast 2001; 10:28–34.[Medline]
  48. Singletary SE. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 2002; 184:383–93.[CrossRef][Medline]
  49. Cabioglu N, Hunt KK, Buchholz TA, et al. Improving local control with breast-conserving therapy: a 27-year single-institution experience. Cancer 2005; 104:20–9.[CrossRef][Medline]
  50. Weinberg E, Cox C, Dupont E, et al. Local recurrence in lumpectomy patients after imprint cytology margin evaluation. Am J Surg 2004; 188:349–54.[CrossRef][Medline]
  51. Buchholz TA, Tucker SL, Erwin J, et al. Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast-conservation therapy. J Oncol 2001; 19:2240–6.



This article has been cited by other articles:


Home page
 Ann. Surg. Oncol.Home page
L. Jacobs
Positive Margins: The Challenge Continues for Breast Surgeons
Ann. Surg. Oncol., May 1, 2008; 15(5): 1271 - 1272.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cabioglu, N.
Right arrow Articles by Meric-Bernstam, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cabioglu, N.
Right arrow Articles by Meric-Bernstam, F.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS