Intraoperative frozen section (FS) margin evaluation is not common practice for patients undergoing breast conservation therapy (BCT), but offers a significant reduction in reoperation. In this study, a technique to allow for more effective freezing of breast tissue was developed to perform FS evaluation of lumpectomy margins (FSM) for all patients undergoing BCT at an ambulatory surgery center. FS evaluation of sentinel lymph node biopsy specimens was performed concurrently. One hundred eighty-one study and 188 control patients, with and without FS evaluation, were compared. Reexcision was reduced 34% (from 48.9% to 14.9%) and reoperation was reduced 36% (from 55.3% to 19.3%) with FS evaluation. Most of the decrease in reoperative rate was because of a decrease in the need for margin reexcision. The number of patients requiring 1, 2, or 3 operations to complete therapy was 84, 92, and 12, respectively, in the control group, and 146, 33, and 2, respectively, in the study group. Lobular subtype, multifocal disease, and larger tumor size (≥2 cm) were significantly associated with failure of FSM to prevent reoperation, but reoperation rates were still significantly decreased in this subgroup of patients (from 75.5% to 43.8%) with FSM. This study highlights an innovative yet simple and adaptable FS approach that resulted in a nearly 3-fold reduction in reoperation for patients undergoing BCT.
Intraoperative frozen section
Breast conservation therapy
Patients undergoing breast conserving therapy (BCT) for early-stage breast carcinoma have outcomes comparable to patients undergoing mastectomy given adequate surgical margin status and appropriate radiation therapy.1-5 Factors influencing reoperation rates include axillary staging procedures, completion axillary lymph node dissection (cALND), and/or margin reexcision. Achieving acceptable margin status may be challenging because of nonpalpable or subtle breast disease, extent of disease, and the degree of commitment of the surgeon and patient to conservative therapy. These factors and variable definitions for inadequate (close) margins have resulted in variable but often high reexcision rates, ranging from 20% to 70%. Reoperation results in increased health care costs, inconvenience, and increased risks to the patient, and delays to subsequent radiation and other adjuvant therapy.1-20
Intraoperative pathology consultation for sentinel lymph node (SLN) and lumpectomy specimens can decrease the need for reoperation by allowing surgeons to resect additional breast tissue and/or perform cALND during the initial breast cancer operation. Many institutions offer intraoperative SLN assessment for patients undergoing BCT. Most, however, do not offer intraoperative analysis of lumpectomy specimens, and even fewer offer frozen section evaluation of margins (FSM) for these specimens, largely because of technical limitations when using standard frozen section (FS) techniques. Margin reexcision is the most common indication for reoperation in patients undergoing BCT.21 Reexcision for close or positive margins will likely increase in relative importance as cALND rates decline because of recent reports of the questionable significance of micrometastatic axillary disease.22-25 This report outlines the development of an intraoperative FS practice providing both SLN and FSM evaluation at a free-standing ambulatory care center and examines its effect on patient care during its first year.
Materials and Methods
Establishment of an FS Laboratory
The majority of breast surgical oncology services at the University of Michigan were relocated to an ambulatory surgical center (ASC) in April 2008. A pathology laboratory was designed to support pathology services at our ASC with a focus on developing FS practice to reduce reoperation rates for patients undergoing BCT. The pathology laboratory was designed and built according to Occupational Safety and Health Administration standards and was equipped with standard facilities for specimen storage; stations for accessioning, gross examination, and cryostat cutting; and a slide review area. The frozen section laboratory at the ASC opened in August 2009.
All patients undergoing BCT at our ASC between August 2008 and July 2010 were included. All of these patients had a previous pathologic diagnosis of invasive or in situ carcinoma and were considered BCT candidates based on clinical and radiographic evaluation.
The study group comprised all patients undergoing BCT who received FSM and/or SLN FS analysis from August 2009 through July 2010. The study group included patients who had undergone neoadjuvant therapy as well as patients undergoing a designed 2-step procedure because of either a need for axillary staging before chemotherapy or referral from an outside institution for inadequate margin status. Patients offered SLN FS were those with a previous diagnosis of invasive carcinoma or extensive high-grade ductal carcinoma in situ (DCIS) with unknown SLN status at the time of surgery. Patients with an invasive carcinoma 1 cm or larger routinely underwent preoperative axillary staging via ultrasound and fine-needle aspiration (FNA) of any suspicious lymph nodes. Any patient with positive FNA findings before surgery did not undergo SLN FS.
Patients included in the control group were all those who underwent BCT without FS analysis at the same ASC from August 2008 through July 2009, in the year before the opening of the FS laboratory.
SLN FS Analysis
SLNs were first dissected from adipose tissue, sectioned at 2-mm intervals, and entirely submitted for FS evaluation. Tissue sections were completely embedded and frozen within optimal cutting tissue (OCT) media and cut on a standard −20°C cryostat, creating sections 6 to 7 μm in thickness. At least 2 levels of each issue block were evaluated at the time of FS analysis. Any metastatic tumor larger than 0.2 mm was reported to the surgeon because at this time, any micrometastatic tumor deposit was considered clinically significant. If SLN FS analysis triggered cALND before completion of FS analysis of all SLN biopsy (SLNB) specimens, FS analysis on subsequent SLNB specimens was cancelled, and these were submitted for permanent section (PS) evaluation only.
All SLNB tissue blocks were then processed for PS evaluation via standard protocol which, at our institution, entailed pathologist evaluation of 4 H&E-stained levels.
FSM was performed on all lumpectomy and reexcision lumpectomy specimens, including those with and without wire localization. Mammographic films of the specimen (when applicable) were delivered to the pathology laboratory along with the specimen. The specimen was oriented using orienting sutures and/or with the assistance of the surgeon, and the margins were inked. The specimen was sectioned at 3- to 4-mm intervals along the long axis and examined by a pathology assistant and pathologist. Sections were submitted for FSM for all grossly suspicious margins. The number of sections varied from case to case but some tissue was submitted for FS evaluation in all cases. In general 2 to 3 radial sections were taken of highly suspicious margins in which tumor or fibrous tissue extending from the tumor were within 5 mm of the margin and at least 1 radial section was submitted if any suspicious tissue was present within 2 cm of the margin. Sections were not routinely submitted for FSM if the tissue at a margin was grossly unremarkable and more than 2 cm from any identifiable tumor, biopsy site, or other lesion. Areas of fibrous tissue adjacent to a margin not associated with an obvious tumor, biopsy site, or otherwise grossly suspicious lesion were sampled variably for FSM depending on pathologic findings in both the previous and current specimens. More sections were typically submitted for FSM in patients who had undergone previous excisional biopsy or lumpectomy, received prior chemotherapy, had extensive or exclusively intraductal disease, or were known to have multifocal disease (identified via preoperative imaging or pathology) in which potential neoplastic tissue was much more difficult to appreciate on gross examination. In patients with known multifocal disease, we correlated the specimen with prior radiologic and pathology reports and with accompanying specimen radiographs, attempted to grossly identify all tumors, and assess margins for each. For reexcision of individual margins in which the biopsy site was identified but no discrete tumor was identified, at least 3 radial sections of each margin were submitted for FS evaluation.
Once selected for FS, a tissue section was placed on a cryostat chuck with a minimal amount of OCT media (just enough OCT to adhere the tissue to the chuck) and immersed in liquid nitrogen (−196°C) for 10 to 15 seconds until the tissue was completely frozen. Because of the difficulty in sectioning fatty tissue, thicker sections than those typically used for FS (16- to 20-μm thick) were then cut on a standard cryostat (−20°C). At least 2 sections from each block were placed on plus slides, stained using a rapid H&E technique, coverslipped, and reviewed by the pathologist Image 1. Additional H&E-stained levels were cut and/or additional tissue sections were evaluated via FS based on communication of findings among the pathologist, pathology assistant, and histotechnologist.
Frozen section evaluation of margins. A, Sectioned lumpectomy specimen. B, Frozen tissue section with a minimal amount of optimal cutting tissue media on a chuck after immersion in liquid nitrogen. C, Tissue section cut directly on a standard cryostat. D, Example of frozen section slide. Arrows indicate margin (H&E, ×2).
A margin was considered positive if the tumor (either invasive carcinoma or DCIS) extended to the inked margin and close if DCIS extended to within 3 mm of the margin and/or invasive carcinoma extended to within 2 mm of the margin. In difficult cases in which the pathologist was uncertain whether atypical ductal hyperplasia or DCIS was extending to/close to a margin, atypical ducts extending to/close to the margin were reported, and the uncertainty was conveyed to the surgeon Image 2. In the majority of cases, a report of any positive or close margin prompted immediate surgical reexcision of that margin. Intraoperatively reexcised margin specimens were infrequently submitted for FSM at the discretion of the surgeon. Surgeons did not submit intraoperatively reexcised margins for FSM for various reasons, including time constraints, consideration of cosmetic outcome, and patient preference. Surgeons were more likely to send intraoperatively reexcised margins for FSM if the original FS diagnosis had indicated a positive as opposed to a close margin and if resection of additional tissue would not significantly compromise cosmetic outcome. Intraoperatively reexcised specimens were evaluated using a minimum of 3 representative radial sections for each margin. All FS blocks were then processed for PS evaluation. Additional tissue blocks from both the main lumpectomy specimen and any intraoperatively reexcised margin specimens were also submitted for PS evaluation.
Examples of frozen section slides. A, Invasive carcinoma extending to the inked margin (positive margin) (H&E, ×4) B, Invasive carcinoma and ductal carcinoma in situ (DCIS) extending to within 3 mm of the inked margin (close margin) (H&E, ×2). C, High nuclear grade DCIS extending to within 2 mm of the inked margin (close margins) (H&E, ×2). D, High-grade DCIS with comedonecrosis, punched out lumina, atypical monotonous cells, and readily identifiable mitotic figures (arrow [inset]) (H&E; ×10; inset ×40).
E, Example of a case reported as atypical ducts, either atypical ductal hyperplasia or low-grade DCIS, extending 3 mm from the inked margin (H&E, ×2). F, Higher power view of atypical ducts pictured in E showing epithelial bridges and low-grade but monotonous cytology (H&E ×10; inset ×40). Negative margins with fibrofatty (G; H&E, ×2) and predominantly fatty (H; H&E, ×2) breast parenchyma.
Clinicopathologic features were summarized for study and control groups using means, medians, and frequencies. The 2 groups were compared using 2-sample t tests for continuous factorsand χ2 tests for categorical factors. For tissue sections that were selected for FS, a false-negative (FN) result was defined as a negative margin in at least 1 of the 6 regions of the FS and a close or positive margin in the same region of the PS. Likewise, a true-negative (TN) or true-positive (TP) result was defined as either negative or positive margins on FS, respectively, which were confirmed on PS. A false-positive (FP) result was defined as any margin meeting all of the following criteria: (1) the margin was interpreted as close or positive at FS; (2) on review of correlative PS slides, the focus of carcinoma was more than 1 mm further from the margin than reported on FS; and (3) using the distance identified on PS slides and margin definitions previously outlined, the margin would be interpreted as negative. For SLN analysis, an FN result was defined as one that was deemed negative on FS and found to be positive on PS. SLN TP and TN results were FS results that were confirmed on PS. SLN FS and FSM TN, FN, TP, and FP results were described using counts and frequencies. Clinicopathologic features of patients with and without FSM FN results were compared similar to the study and control group analysis described before. The effect of FSM implementation on the outcome of additional surgery was analyzed using a multivariate logistic model controlling for clinicopathologic factors. Number of blocks submitted for FS was regressed on turnaround time using a linear regression model. All analyses were performed using SAS software version 9.2 (SAS Institute, Cary, NC).
SLN FS Analysis
One hundred seventy-eight patients underwent SLN FS analysis; 72 (40.4%) had SLN FS alone and 106 (59.6%) had both FSM and SLN FS during the same surgery. Thirty-one patients (17.4%) had TP results, 144 (80.9%) had TN results, and 3 (1.7%) had FN results; FP results were found in none. All 31 patients with TP results underwent immediate cALND. Among the TN cases, 5 had foci of isolated tumor cells (<0.2 mm) on PS not reported at the time of FS. No patients in this group later underwent cALND. The 3 FN cases consisted of 2 with micrometastases (0.2-2 mm) of ductal carcinoma, both present only in PS slides and not identified on rereview of the FS slides, and 1 patient with macrometastatic (>2 mm) lobular carcinoma that was present on FS slides on rereview. All 3 patients with FN results later underwent cALND, and none had additional metastatic axillary disease.
One hundred eighty-one patients underwent 189 surgical procedures using FSM, of whom 75 (41.4%) had FSM alone and 106 (58.6%) had both FSM and SLN FS analysis during the same surgery. Of 188 control patients who did not undergo FSM, 77 (41.0%) had lumpectomy alone and 111 (59.0%) had lumpectomy and SLNB. As is typical of patients deemed eligible for BCT, the majority in both study and control groups were more likely to have lower stage (T1 or T2) disease and an identifiable mass on preoperative imaging than noneligible patients. However, as demonstrated in Table 1, no statistically significant differences were found in clinicopathologic features between study and control groups and therefore there was no selection bias when comparing results between the 2 groups.
There were an average of 5.9 FS blocks per lumpectomy (range, 1-11), 8.3 FS blocks per case (range, 1-27), and 18.4 additional PS blocks per case (range 0-35). No significant association was found between close/positive margins and margin location. Close/positive margins were ultimately identified in 112 (59.3%) of 189 surgical specimens sent for FSM. One or more margins were reexcised in 133 (70.4%) of 189 cases. In the majority of cases, reexcision of margins was driven by an FS report of close/positive margins but was also influenced by specimen radiography findings and surgical judgment. Intraoperatively reexcised margins were sent for FSM in 28 (21.1%) of 133 cases.
The reoperation rate in the control group was 55.3%, with 92 (48.9%) requiring a second operation and 12 (6.4%) requiring a third operation to complete surgical therapy. Within this group, 72 (38.3%) required additional surgery for margin revision only, 6 (3.2%) for cALND only, 3 (1.6%) for SLNB only (because of unexpected invasive carcinoma present in the lumpectomy), and 23 (12.2%) for both margin revision and axillary surgery.
The reoperation rate in the study group was 19.3%, with 33 (18.2%) undergoing a second operation and 2 (1.1%) proceeding to a third operation to compete surgical therapy. Among those with indications for reoperation, 27 (14.9%) required margin revision only, 4 (2.2%) cALND only, and 3 (1.7%) SLNB only. One patient subsequently underwent elective mastectomy despite a negative margin status on lumpectomy; no residual carcinoma was identified in this specimen Figure 1, Figure 2, and Figure 3.
Rates of reoperation (patients who underwent additional breast or axillary surgery), reexcision (those who underwent reoperation for resection of additional breast tissue to achieve negative margin status), and conversion to mastectomy in control and study groups. FSM, frozen section evaluation of margins.
A, Surgeries required to complete therapy in control and study groups for all patients. Reoperation rates were 55.3% in controls and 19.3% in study patients (P < .0001). B, Surgeries in those with invasive lobular carcinoma subtype, multifocality, or tumor size of 2.0 cm or larger. Reoperation rates were 75.5% in controls and 43.8% in study patients (P < .0001).
Indications for reoperation in control (left) and study (right) groups. SLNB, sentinel lymph node biopsy; cALND, completion axillary lymph node dissection.
Among the 27 study group patients requiring margin revision, 16 (59.3%) underwent reexcision lumpectomy, and 11 (40.7%) proceeded directly to mastectomy. Of the 2 patients who required a third surgery to complete therapy, 1 underwent 2 additional reexcision lumpectomies, and the other a reexcision lumpectomy and ultimately mastectomy. In both of these cases, the initial reexcision lumpectomy was submitted for FSM, and both pathology sampling error and intraoperatively reexcised close/positive margins sent only for PS resulted in the need for a third surgery. Overall there were statistically significant declines in reoperation and reexcision rates between control and study groups (P < .0001). Rate of conversion to mastectomy was also reduced but did not reach statistical significance (P = .0961) (Figures 1-3).
The decrease in reoperative rates was largely attributed to the addition of FSM, not FS SLN, because most of the decrease in reoperation rate was because of a large decrease in number of patients who had to undergo reexcision of margins, alone or jointly with other procedures (95 patients in the control group vs 27 patients in the study group). In fact, the number of patients who needed to undergo reoperation for additional axillary surgery alone was similar in the study and control groups (9 patients in the control group vs 7 patients in the study group) (Figure 3). Most of the patients in both control and study groups with positive SLNB findings also had close/positive margins (15/21 in the control group, 17/21 in the study group). Among patients who underwent both FSM and FS SLN, only 5 of 106 (4.7%) study patients benefited from and only 7 of 111 (6.3%) control patients would have benefited from SLN FS analysis alone (assuming perfect pathology performance). This is likely influenced by stringent preoperative evaluation with axillary ultrasound and FNA which identifies many node-positive patients who would have otherwise been identified on SLNB.
Reasons for failure of FSM to prevent reoperation (FN cases) were divided into the following categories: (1) final close/positive margins limited to the intraoperatively reexcised specimens sent for PS evaluation only; (2) pathologist analytic errors; (3) cessation of the procedure because the extent of the disease was greater than anticipated; and (4) a combination of multiple factors.
The majority of FN cases had close/positive intraoperatively reexcised margins that were submitted for PS only, and/or had close/positive margins that were not adequately sampled at the time of FS. Sampling errors included close/positive margins seen only on deeper PS and not present on FS slides, as well as close/positive margins that were not sampled at the time of FS (gross sampling error). Only 1 FN case was the result of interpretation error. In this case, in situ carcinoma that appeared to be classic lobular carcinoma in situ on FS was identified close to the margins and on PS was interpreted as pleomorphic lobular carcinoma in situ, prompting reexcision. Of note, 4 FN cases did not require reexcision because of anatomic reasons (the close margin represented the limit of resection at the deep margin) and 1 patient did not elect to undergo advised reoperation despite a final close margin Figure 4.
Reasons for reoperation in study cases (35/181). * Of the 4 patients who underwent completion axillary lymph node dissection (cALND), 3 were sentinel lymph node (SLN) frozen section (FS) false-negative cases and 1 was an SLN FS true-positive case, but the focus of metastatic tumor became larger in permanent section (PS) slides than was seen in FS slides. FSM, frozen section evaluation of margins; SLNB, sentinel lymph node biopsy.
Multivariate logistic regression revealed invasive lobular carcinoma subtype, tumor multifocality, and larger tumor size to be significantly associated with increased likelihood for reoperation Table 2. Univariate analysis found that disease multifocality and larger tumor size were factors significantly associated with FN cases. In addition, FN cases were also associated with lobular subtype and the presence of both mass and microcalcifications on mammography Table 3.
Seventy-three (40.3%) study cases and 94 (50%) control cases had multifocal disease, invasive lobular carcinoma, and/or largest tumor focus of 2.0 cm or larger. When any of these factors were present, reoperation rates were higher but significantly reduced with FSM (75.5% and 43.8% in control and study groups, respectively) (Figure 2B).
Assessment of FP margins proved challenging in some cases because the foci would occasionally change between the FS and deeper, correlative PS slides (eg, the foci became smaller or larger or would be closer or further away from the margin[s] than reported at the time of FS). Thus we believed that the criteria used to define FP margin (outlined previously) would best identify true FP cases. Using this definition, we found only 6 cases with FP margins (6/189; 3.2%), 5 of which had 1 FP margin and 1 of which had 2 FP margins. In 3 cases, the FP margins were likely because of pathologist overinterpretation, in which the biopsy site was seen at the margin but no identifiable tumor was seen close to the margin on rereviewed FS or correlative PS slides. In the other 3 cases, the FP margins were likely because of a combination of the focus changing on deeper sectioning for PS and possible FS artifact (eg, folding or fragmentation of adipose tissue) making the margin appear closer than it may have been. In all 6 cases, additional breast tissue, with a mean volume of 25.5 cm3 (range, 15.3-44 cm3), was excised.
Mean turnaround time from receipt of specimen to final reporting of FS results was 24 minutes for all specimens and 27 minutes for lumpectomy specimens alone. Turnaround time was directly proportional to number of blocks sampled, on average adding 2 minutes for each additional block submitted for FS. Turnaround time was significantly increased when multiple specimens were submitted concurrently; however, this was directly related to increased FS block volume Figure 5.
Turnaround time (TAT) vs number of blocks sampled for frozen section.
Intraoperative FSM significantly decreases reoperation rates in patients undergoing BCT. In our series, the largest case-control study of its kind, nearly a 3-fold decrease in reoperation rates was seen after the implementation of our FSM practice. Reexcision rates were reduced from 48.9% to 14.9% in just the first year of practice. Similar results were also observed by others using a similar approach; however, many of these studies are limited by lack of a comparable control group, small study size, differing definitions of close/positive margins, and lack of a clear outline of the technique used.26-30
Different approaches for intraoperative evaluation of lumpectomy margins have included cytologic methods, gross evaluation, and FS analysis.26-40 Bakhshandeh et al31 and Ku et al38 reported imprint cytology as a rapid and reliable method that offers high sensitivity in the detection of neoplasia. However, imprint cytology does not allow for the distinction between carcinoma in situ and invasive carcinoma. Cytologic evaluation also has the significant limitation of only allowing interpretation of positive and not close margins, which also require reexcision.
Gross evaluation is crucial in the examination of a lumpectomy specimen and guides sampling for microscopic assessment. However, gross evaluation is best at identifying the boundaries of easily identifiable solid masses. When fibrous septae extend from or surround a mass, the distinction between neoplasia and benign breast tissue or biopsy site changes is less certain. When there is no clear mass but only fibrous tissue, calcifications, and/or biopsy site changes, differentiation of neoplastic from benign tissue is impractical using gross evaluation alone. For example, Balch et al32 identified 141 of 255 cases with grossly suspicious margins which prompted reexcision, ultimately resulting in a reexcision rate of 25%. However, 20% (51/255) had FN margins compared with only 10.5% (19/181) FN cases in our study using FSM.
The importance of gross evaluation of lumpectomy specimens should not be understated; however, the addition of FSM dramatically reduces rates of reexcision beyond what can be accomplished with gross examination alone. Camp et al34 and Fukamachi et al37 found that FS of shaved margins and FS of total cavity circumference excisions led to reductions in reexcision rates from 33.3% to 5.8% and 27% to 9.8%, respectively. Cabioglu et al33 also used intraoperative gross examination not for margin assessment but rather as a guide for selective radiographic and FS analysis and found that this prevented reexcision in 29% of patients with invasive cancer and 9% of patients with DCIS. Radiologic examination of the sliced gross specimen further reduced the reexcision rate to 22% in patients with DCIS in another study by the same group.35
Although effective at reducing reexcision, FS analysis on breast specimens has historically been controversial and many pathologists continue to worry that in challenging cases FP FS results may prompt unnecessary resection of breast tissue. In our study, the FP rate was low (3.2%) and resulted in excision of a relatively low volume of additional tissue (mean, 25.5 cm3). Historically, FP in FS analysis posed a more significant risk because diagnostic excisional biopsies sent for FS diagnosis could result in conversion to mastectomy during the same procedure.41 However, today most breast lesions are amenable to preoperative histologic diagnosis, often made via core biopsy, which has high sensitivity and improved specificity compared with FNA biopsy.42-44 In our breast FS practice, FSM is only performed on patients undergoing BCT with a histologically confirmed diagnosis of malignancy, greatly reducing uncertainty about the targeted lesion. Breast oncology surgeons at our institution generally will not convert to mastectomy during an attempt at BCT because of lack of patient preparedness. Instead, a best attempt at margin clearance is carried out while balancing the risks of poor cosmetic outcome and the likelihood of attaining negative final margins via intraoperative reexcision.
Perhaps the main reason why FSM is not routinely provided at most institutions is technical challenges in freezing breast tissue. Specifically, lumpectomy specimens with high adipose content do not freeze or section adequately using standard FS techniques, making microscopic measurements difficult to assess. We have found that liquid nitrogen provides lower temperatures that allow freezing and solidification of breast tissue and increased ease in sectioning for FS. In our experience, using just a minimal amount of OCT media for mounting tissue to the chuck was also crucial for freezing tissue samples uniformly and significantly reducing frozen section artifact seen with OCT-embedded tissue. These sections are easily interpretable as evidenced by the fact that we had only 1 pathologist interpretation error in 181 cases.
We acknowledge that before implementing this unique FS practice our institutional reoperation rates were near the high end of the published range, which varies widely because of factors such as varying institutional practices in selection of patients for BCT as well as varying definitions of close margins. We attribute our relatively high reexcision rate in part to being a referral center with increased willingness to attempt BCT in more complex cases. In addition, a previous study at our institution showed that close margins (as defined before) result in residual disease in reexcision specimens comparable to positive margins.45 This has driven our relatively strict definitions of close margins as well as our strict practice of margin reexcision in patients with close margins. In fact, other studies with similar definitions of close margins report equivalent reexcision rates.2,7,11,16,20
Despite a significant reduction in reoperation and reexcision with FSM, a number of patients still required additional procedures to complete surgical therapy. Many of these patients, however, had risk factors known to be associated with an increased likelihood of margin positivity including tumor multifocality, lobular subtype, and larger tumor size.14,15,45-47 Despite this, FSM was effective in reducing reoperation rates even when these features were present. Efforts at process improvement may further reduce reexcision and reoperation rates in these challenging cases; however, disease biology will likely still result in a number of patients who continue to require multiple reexcisions and/or have failed attempts at BCT despite FSM. Preoperative evaluation will be important in identifying these patients for whom BCT, even with the assistance of FSM, will be more difficult. This is supported by previous findings reported by Morrow et al48 who observed that reexcision and conversion to mastectomy were highest for those patients who underwent BCT despite initial surgical recommendation to undergo mastectomy.
FS analysis does require greater resources and more operating room time than evaluation via imprint cytology or gross evaluation only. Despite this, we have shown that FSM can be performed with very reasonable turnaround times. We have also observed that it does not significantly increase overall operating room times and is cost-effective.49 With proper resources it is an easy adaptation because the technique is simple, easy to learn and perform, and uses materials that are typically already present in an FS laboratory.
Reoperation in patients undergoing BCT is also driven by the need to stage and treat metastatic axillary disease via SLNB and/or cALND. Until recently patients with macrometastatic (>2 mm) and micrometastatic (0.2-2 mm) positive SLNs would typically undergo cALND. However, recent evidence shows that many patients with limited micrometastases only, especially those with early stage breast cancer, may not derive clinical benefit from cALND.22-25,50 In this study, new guidelines for cALND had not yet been adopted. Specifically, cALND was still being performed for micrometastatic disease in both study and control groups. Despite this, only a few patients (4%-5%) would have benefited from SLN FS analysis alone because of the additional need for reexcision of margins in the majority of patients with positive SLNs. Similarly, McLaughlin et al21 identified only 6% of clinically node-negative patients (n = 1,218) who would have avoided reoperation with SLN FS analysis alone. Both studies have a selection bias toward patients who are more likely to lack axillary disease because of preoperative axillary staging. However, with changing surgical practices, these numbers would be expected to be reduced even further.
In conclusion, reoperation rates will vary depending on patient population and patient and surgeon preferences regarding BCT. However, reexcision of margins is becoming increasingly important in dictating the need for reoperation in patients undergoing BCT. Surgeons tread a fine line between achieving negative margins and removing more tissue than necessary; therefore, reexcision rates will remain high without intraoperative evaluation. Our FSM practice is an example of a simple yet effective approach that has resulted in approximately two thirds of patients avoiding additional breast cancer surgery.
We thank Christine Rigney, HT(ASCP), Tiffany Vail, PA(ASCP), and Misty Wideman, HT(ASCP), for their tireless effort in the development of this unique frozen section method and laboratory. We also thank Debbie Laubach, MBA, CPC, CPC-H, Norah Naughton, MD, Craig Newman, MS, MBA, MT(ASCP), and John Perrin, M(ASCP), for their administrative efforts in establishing the frozen section laboratory.
Presented in part at the United States and Canadian Academy of Pathology (USCAP) Annual Meeting; San Antonio, TX; February 26 to March 4, 2011.
. 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;44:1005-1015.
. The effect of timing of radiotherapy after breast-conserving surgery in patients with positive or close resection margins, young age, and node-negative disease, with long term follow-up. Int J Radiat Oncol Biol Phys. 2006;66:687-690.
. Local relapse and contralateral tumor rates in patients with breast cancer treated with conservative surgery and radiotherapy (Institut Gustave Roussy 1970-1982): IGR Breast Cancer Group. Cancer. 1995;76:2260-2265.
. 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;18:1668-1675.
. Axillary lymph node dissection for sentinel lymph node micrometastases may be safely omitted in early-stage breast cancer patients: long-term outcomes of a prospective study. Ann Surg Oncol. 2009;16:3366-3374.
. Development of an intraoperative pathology consultation service at a free standing ambulatory surgical center: clinical and economic impact for patients undergoing breast cancer surgery. Am J Surg. 2012;204:66-77.