Is Intraoperative Frozen Section Analysis of Reexcision Specimens of Value in Preventing Reoperation in Breast-Conserving Therapy?

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1 AJCP / Original Article Is Intraoperative Frozen Section Analysis of Reexcision Specimens of Value in Preventing Reoperation in Breast-Conserving Therapy? Julie M. Jorns, MD, 1 Stephanie Daignault, MS, 2 Michael S. Sabel, MD, 3 and Angela J. Wu, MD 1 From the 1 Department of Pathology, 2 Center for Cancer Biostatistics, School of Public Health, and 3 Department of Surgery, University of Michigan, Ann Arbor. Key Words: Intraoperative frozen section; Breast conservation therapy; Frozen section; Lumpectomy margins; Reexcision Am J Clin Pathol November 2014;142: ABSTRACT Objectives: A prior study at our institution showed a marked reduction in reoperation for margin reexcision following the development of an intraoperative frozen section evaluation of margins (FSM) practice on lumpectomy specimens from patients undergoing breast-conserving therapy (BCT). This study aimed to examine the frequency of FSM utilization, FSM pathology performance, and outcomes for BCT patients undergoing margin reexcision only. Methods: Consecutive reexcision-only specimens were reviewed from a 40-month period following the development of the FSM practice. Clinicopathologic features and patient outcomes were assessed. Results: FSM was performed in 46 (30.7%) of 150 reexcision-only operations. Of the 46 operations with FSM, there were 28 (60.9%) true-negative, 12 (26.1%) truepositive, six (13.0%) false-negative, and no false-positive cases. There was no difference in further reexcision, total operations, or conversion to mastectomy among patients with and without FSM. Need for further reexcision was significantly associated with tumor multifocality (P =.008). Conclusions: Despite overall good pathology performance for FSM in reexcision-only specimens, use of FSM did not affect patient outcome. Rather, underlying disease biology appeared most significant in predicting whether adequate surgical margins could be attained. Breast-conserving therapy (BCT), or lumpectomy plus radiation, is the most common mode of treatment for women with early stage breast cancer, 1 since previous studies have shown similar survival to mastectomy, given adequate surgical margin status is attained. 2-6 However, achieving acceptable margin status is often challenging due to the subtle and infiltrative nature of breast cancer, as well as a lack of standard definitions for acceptable margin status. As a result, rates of reoperation for margin reexcision are variable but often high for women undergoing BCT, ranging from 20% to 70% in the published literature. Reoperation results in increased utilization of health care resources, increased risks and inconveniences to the patient, and delays to subsequent steps in patient care. 2,3,5-21 Many methods of intraoperative evaluation have been employed to reduce reexcision for patients undergoing BCT In August 2009, our institution developed a pathology laboratory and a specialized frozen section evaluation of margins (FSM) practice at an ambulatory surgery center (ASC). In the year following the initiation of this FSM practice, there was a 34% reduction in the need for reoperation for margin reexcision in patients undergoing lumpectomy. Invasive lobular subtype, disease multifocality (histologically discrete tumors at least 2 cm apart), and larger tumor size (>2 cm) were identified as high-risk features that resulted in higher rates of reoperation. For patients with these features, FSM offered a significant but reduced benefit compared with when they were absent. 37 This study aimed to examine the use and utility of FSM for BCT patients who previously underwent excision and required reexcision for margin control. Am J Clin Pathol 2014;142:

2 Jorns et al / FSM of Reexcision Specimens Materials and Methods Case Selection Patients undergoing BCT operations for margin reexcision as the only procedure were identified via an electronic database search between August 2009 (coinciding with the opening of the ASC pathology laboratory) and November Twenty-seven cases were excluded due to surgery being performed at sites at which FSM was unavailable (all sites except the ASC). All patients had a previous pathologic diagnosis of invasive breast carcinoma or ductal carcinoma in situ (DCIS) and were considered BCT candidates based on clinical and radiographic evaluation. In addition, all patients had undergone a primary excisional procedure (either a previous lumpectomy or excisional biopsy). All patients undergoing margin reexcision only operations, regardless of whether one or multiple margins or the entire lumpectomy cavity were being reexcised, were included. FSM Intraoperative evaluation was performed when requested by the surgeon. The decision for FSM was influenced by the extent of disease at and/or close to margins in the previous specimen, surgeon and patient preference, and ability to achieve acceptable cosmesis with further tissue resection. Intraoperative evaluation included performing a rapid gross assessment by the pathology assistant and pathologist, with or without assistance from the surgeon, and then submitting tissue blocks for FSM. FSM was performed via the technique outlined in detail in our previous publication. 37 Briefly, a radial tissue section selected for FSM is mounted on a chuck with minimal optimal cutting temperature media, immersed in liquid nitrogen ( 196 C) for 10 to 15 seconds, and then cut on a standard cryostat ( 20 C) by a histotechnologist, cutting sections at 16 to 20 µm thick (approximately three times thicker than standard frozen section [FS]). The slides are then rapidly H&E stained, coverslipped, and evaluated by the pathologist. Standard policy at our institution is to cut at least two sections from each block, placing them on plus slides, and to submit a minimum of three tissue blocks per reexcision specimen for FSM evaluation. Submission of additional blocks and cutting of additional levels for evaluation are based on communication of findings among the surgeon, pathologist, pathology assistant, and histotechnologist. In this study, a margin was considered positive if the tumor (either invasive carcinoma or DCIS) extended to the inked margin, close if it extended within 0.2 cm of the margin, and negative if the tumor was greater than 0.2 cm from the margin. Examples of positive, close, and negative FS margins are shown in Image 1. In difficult cases in which the pathologist was uncertain whether atypical ductal hyperplasia (ADH) or DCIS was extending to or close to a margin, atypical ducts were reported, and the uncertainty and/or favored diagnosis (ADH vs DCIS) was reported to the surgeon. In most cases, a report of a positive or close margin prompted immediate surgical reexcision, with exceptions being location at the surgical limit of resection and inability to achieve acceptable cosmetic outcome with further reexcision of breast tissue. Additional intraoperatively reexcised specimens were infrequently submitted for FSM, largely due to surgical time constraints; in these rare cases, the intraoperatively reexcised margins were evaluated identically to the methods outlined above. All FS blocks were processed for permanent section (PS) evaluation. Additional tissue blocks from the main intraoperatively evaluated reexcision specimens as well as sections from any additional intraoperatively reexcised specimens were also submitted for PS evaluation; in most cases, the main intraoperatively evaluated reexcision specimens as well as any additional intraoperatively reexcised specimens were submitted in their entirety for PS evaluation. In some cases in which the margins were large, at least half of all the tissue was submitted for PS evaluation. Statistical Analysis Clinicopathologic features for patients undergoing margin reexcision operations were compared between groups with and without FSM. Categorical and ordinal variables were tested between groups using appropriate c 2 tests. Continuous variables were tested using t tests or Wilcoxon rank sum tests as appropriate based on the distribution. A multivariable logistic model was used to determine associations between covariates and the need for further reexcision. For tissue sections selected for FS, true-negative (TN), true-positive (TP), false-negative (FN), and false-positive (FP) margins were defined identically to those described in our previous publication. 37 Specifically, an FN result was defined as a negative margin in FS slides and a close or positive margin in the same region of the correlative PS. Similarly, a TN or TP was defined as either negative or positive margins on FS, respectively, which were confirmed on PS. An FP was defined as any margin in which (1) the margin was interpreted as close or positive at FS; (2) on review of the PS slides, the focus of carcinoma was more than 0.1 cm 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. 602 Am J Clin Pathol 2014;142:

3 AJCP / Original Article A Results Patients In total, 142 BCT patients underwent 150 margin reexcision operations. FSM was performed in 46 (30.7%) of 150 operations. Patients with and without FSM had similar clinicopathologic features, as outlined in Table 1. Specifically, patients in both groups had similar rates of further reexcision (P =.83), total number of operations (P =.23), and rates of conversion to mastectomy (P =.81). This is in contrast to our previous publication examining FSM utility in primary lumpectomy specimens in BCT patients, in which there were reductions in all of these metrics with the use of FSM.37 FSM Utilization Use of FSM was not associated with any measured clinicopathologic features, including high-risk features such as tumor multifocality (Table 1). However, there was Image 1 Examples of frozen section slides from reexcision specimens. A, Ductal carcinoma in situ extending to the inked margin (positive margin). B, Invasive lobular carcinoma (lower left) extending close (<0.2 cm) to the inked margin. C, Negative margin with biopsy site changes. (H&E; 4) variability in the request for FSM for reexcision-only specimens, ranging from 3% to 75% utilization among the seven breast surgeons. Specimen Sampling Overall, there was no significant difference in total tissue blocks submitted per case between those who had FSM (median, 14; range, 3-84) and those who did not (median, 12; range, 2-31) (P =.09). The wider range of blocks submitted in cases with FSM was influenced by the outcome of FS, with negative FS margins resulting in lower numbers of additional PS blocks submitted and cases with positive or close FS margins resulting in higher numbers of total specimens and additional PS blocks submitted. FSM Turnaround Time Turnaround time (TAT) data were available for 43 (93.5%) of 46 patients who underwent FSM. Median and Am J Clin Pathol 2014;142: C B

4 Jorns et al / FSM of Reexcision Specimens Table 1 Clinicopathologic Features of BCT Patients Undergoing Margin Reexcision-Only Surgery With and Without FSM Characteristic FSM (n = 46) No FSM (n = 104) P Value Age at diagnosis, mean (range), y 57.4 ( ) 56.3 ( ).60 a Histologic subtype, No. (%).76 b DCIS only 20 (43.5) 38 (36.5) IDC 23 (50.0) 53 (51.0) ILC 2 (4.3) 8 (7.7) Other 1 (2.2) 5 (4.8) Tumor grade, No. (%).35 c Low/mBR 1 11 (23.9) 31 (29.8) Intermediate/mBR 2 20 (43.5) 46 (44.2) High/mBR 3 15 (32.6) 27 (26.0) Largest tumor size, mean (range), cm 1.1 ( ) 1.4 ( ).41 d Multifocality, e No. (%).45 c None 23 (50.0) 47 (45.2) DCIS only 18 (39.1) 40 (38.5) Invasive ± DCIS 5 (10.9) 17 (16.3) Previous surgery, No. (%).09 b Excisional biopsy 23 (50.0) 45 (43.3) Lumpectomy 15 (32.6) 51 (49) Reexcision 8 (17.4) 8 (7.7) Previous margin status, No. (%).62 c Negative f 2 (4.4) 1 (1) Close (<0.2 cm) 29 (63.0) 67 (64.4) Positive 15 (32.6) 36 (34.6) FSM previously performed, No. (%) 12 (26.1) 26 (25.0).99 b Previous margin(s) multifocally close/positive, No. (%) 26 (56.5) 54 (51.9).72 b Linear extent of previous close/positive margin(s), No. (%) n = 44 n = c <0.1 cm 4 (9.1) 16 (15.5) cm 14 (31.8) 33 (32) >0.3 cm 26 (59.1) 54 (52.4) Total tissue blocks, median (range) 14 (3-84) 12 (2-31).09 d Reexcision margin status, No. (%).36 b No residual disease 26 (56.5) 70 (67.3) Negative ( 0.2 cm) 8 (17.4) 9 (8.7) Close (<0.2 cm) 9 (19.6) 16 (15.4) Positive (at ink) 3 (6.5) 9 (8.7) Reexcision margin(s) multifocally close/positive, No. (%) 9 (19.6) 17 (16.3).64 b Linear extent of close/positive reexcision margin(s), No. (%) n = 12 n = c <0.1 cm 3 (25.0) 3 (12.0) cm 2 (16.7) 8 (32.0) >0.3 cm 7 (58.3) 14 (56.0) Further reexcision performed, No. (%) 11 (23.9) 23 (22.1).83 b Total operations, No. (%).23 d 1 20 (43.5) 36 (34.6) 2 20 (43.5) 46 (44.2) 3 4 (8.7) 21 (20.2) 4 2 (4.3) 1 (1.0) Final surgery, No. (%).81 b BCT 38 (82.6) 88 (84.6) Mastectomy 8 (17.4) 16 (15.4) BCT, breast-conserving therapy; DCIS, ductal carcinoma in situ; FSM, frozen section evaluation of margins; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; mbr, modified Bloom-Richardson. a t test. b Fisher exact test. c Jonckheere-Terpstra test. d Wilcoxon rank sum test. e Multifocality was defined as histologically discrete tumors at least 2 cm apart. f Three cases with histologically negative margins underwent reexcision due to suspicious postsurgical mammography. 604 Am J Clin Pathol 2014;142:

5 AJCP / Original Article mean TAT were 20 and 24 min/case (range, 5-74). High TAT outliers had proportionately increased specimen parts sent for FSM and higher FS block volumes per case. FSM (11/46) No FSM (23/104) FSM Pathology Performance Of patients undergoing FSM, 28 (60.9%) of 46 had TN margins and 12 (26.1%) of 46 had TP margins. Of note, one case had a small focus of carcinoma seen at FS and later confirmed by rereview of FS slides; however, this focus disappeared in the deeper sections cut to produce the correlative PS slide. This case was deemed a TP. There were no FP cases by criteria defined previously. The remaining six cases (13.0%) had FN margins. All FS FN cases were attributable to gross sampling error in which tumor was not present in FS slides but was present at or close to a margin in a section or sections submitted for PS only. All cases with positive or close margins identified intraoperatively (TP cases) underwent immediate reexcision. FSM was requested on the additional intraoperatively reexcised specimen in three (25%) of 12 cases. All three of these cases had only one additional specimen sent to pathology in which the final margin was called negative, both at the time of FS and later confirmed on PS. FSM was not requested in the intraoperatively excised specimens in the remaining nine (75%) TP cases; these cases had a median number of three additional specimens sent to pathology (range, 1-6). Cases Requiring Further Reexcision in a Later Operative Procedure Further reexcision was performed in 11 (23.9%) of 46 and 23 (22.1%) of 104 patients with and without FSM, respectively. Reasons for further reexcision for patients with and without FSM are shown in Figure 1. In patients who had FSM, the most common factor influencing the need for reexcision was inadequate margins due to the tumor at or close to a margin in additional reexcision specimens sent for PS only (five [55.6%] of nine). In patients who underwent FSM, five (41.7%) of 12 TP and four (66.7%) of six FN FSM cases underwent further reexcision in a later procedure due to residual disease at or close to final margin(s) (Figure 1). Of the remaining seven TP FSM patients, three had margin clearance via use of additional intraoperative FSM for their single reexcised margin, and four had final negative margins in their reexcised specimens sent for PS only. The two FN FSM cases that did not undergo additional surgery for further reexcision were due to extreme focality of the tumor close to a margin (n = 1) and limit of anatomic resection (n = 1). Multivariate logistic regression showed that need for further reexcision was significantly associated with tumor multifocality (P =.008) but was not associated with larger tumor size, histologic subtype, or use of FSM Table 2. Imaging findings 2/11 (18.2%) Intraoperatively close/positive reexcised margins sent for PS only 5/9 (55.6%) Figure 1 Reasons for further reexcision in a later operative procedure in patients following reexcision-only surgery with and without frozen section evaluation of margins (FSM). PS, permanent section. We theorized that FSM might have more impact on patients who had a prior excisional biopsy vs all other patients. We noted significantly lower multifocality in patients with a prior procedure of excisional biopsy (27 [39.7%] of 68) vs lumpectomy or reexcision (54 [65.9%] of 82) (P =.001); however, when we compared these cohorts, there was no significant difference in the need for a later reoperation, whether or not FSM was provided. Discussion Inadequate margins 9/11 (81.8%) Focus present in additional PS slides only (pathology gross sampling error) 3/9 (33.3%) Imaging findings 3/23 (13.0%) Inadequate margins 20/23 (87.0%) Combination of intraoperatively close/positive reexcised margins sent for PS only and pathology gross sampling error 1/9 (11.1%) Table 2 Multivariate Logistic Regression for Features Associated With Need for Further Reexcision Following Reexcision-Only Surgery (34 of 150) Characteristic Odds Ratio (95% CI) P Value Largest tumor size ( 0.2 vs 1.33 ( ).733 <0.2 cm) Histologic subtype (vs IDC).369 DCIS 0.75 ( ) ILC 2.29 ( ) Multifocality (invasive 3.41 ( ).008 carcinoma or DCIS) (vs none) FSM (vs no FSM) 0.89 ( ).808 DCIS, ductal carcinoma in situ; FSM, frozen section evaluation of margins; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma. During the interval between lumpectomy and reexcision, regional breast tissue undergoes a series of reparative changes, which can even include destruction of remaining cancerous tissue. 38 Despite this, several studies have shown that BCT patients with close or positive Am J Clin Pathol 2014;142:

6 Jorns et al / FSM of Reexcision Specimens margins have an increased risk of local recurrence, 3,11,19 and thus these patients have typically undergone reexcision to achieve acceptable final margin status before proceeding to adjuvant therapies. In a previous publication, we showed that our relatively unique FSM practice resulted in a marked (nearly 3-fold) reduction in the need for reoperation for margin reexcision for close or positive margins in patients undergoing lumpectomy. 37 In contrast, the current study shows that use of FSM for reexcision specimens, although requested in only 30.7% of cases, resulted in no difference in the need for further reexcision or ultimate conversion to mastectomy. In this study, pathology FSM performance did not seem to be an influential factor in the need for further reexcision. In fact, FSM of reexcision specimens showed a similar FN percentage compared with that previously described in our lumpectomy series (13.0% vs 10.5%). 37 This occurred despite the inherently challenging nature of gross examination of these specimens, in which, several weeks after an excisional procedure, abundant surgical site alteration easily obscures small foci of residual disease. Most commonly, FSM was able to identify residual disease, prompting immediate tissue excision for all patients intraoperatively found to have close or positive margins. However, many of these patients had additional foci in their additional, intraoperatively reexcised tissue sent for PS and not evaluated by FSM (five [55.6%] of nine). One could speculate that using FSM for additional, intraoperatively reexcised specimens may have spared other patients from additional surgery. However, reexcision-only operations are otherwise quite short surgical procedures due to the relative simplicity of the procedure and lack of other accompanying procedures that have been previously performed (ie, concurrent sentinel lymph node biopsy). Thus, the surgeon must also weigh patient risk of prolonged anesthesia time and impact on operating room (OR) scheduling (ie, delay of subsequent patient operations) with additional time spent performing FSM. Concerns over proper use of OR time, coupled with the generally low frequency of disease in reexcision specimens (36% in this study), make a plausible argument for the observed infrequent use of FSM for BCT patients undergoing reexcision only (30.7%) and the uncommon use of FSM for further intraoperatively reexcised specimens (2% of all patients, 6.5% of patients undergoing FSM). In this subset of patients, the need for further reexcision was only significantly associated with disease multifocality. Interestingly, compared with our prior lumpectomy series, there was a difference in disease distribution, with a 14.6% increase in DCIS-only patients in the reexcision-only group (38.7%) compared with the lumpectomy group (24.1%). Not surprisingly, there was an even higher increase (20.8%) in patients with multifocal DCIS and/or invasive carcinoma in the reexcision series (53.3%) compared with lumpectomy (32.5%). Correspondingly, there was a higher rate of eventual conversion to mastectomy in this reexcision study (16%) compared with the prior lumpectomy one, in which 11.7% and 7.2% of patients without and with FSM, respectively, ultimately underwent mastectomy (overall rate 9.5%). 37 Overall, these findings point to a selection bias in which cases necessitating reexcision seem to have features that result in greater difficulty in achieving negative margin status via BCT alone. Previous studies such as those by Saarela et al 39 and Luu et al 40 have also shown that certain histopathologic features, including tumor multifocality as seen in this study, were associated with reduced ability to attain acceptable margin status. Findings from ours and other studies further predicate the need for careful preoperative evaluation to identify patients for whom BCT will prove more challenging, even with the assistance of intraoperative evaluation methods, including FSM. Challenge in the achievement of adequate margin status is of course influenced by the definition of adequate. In the past, many institutions have used cutoffs for tumor distance from the margin of 0.1 cm or greater, 3,11,19 while others have defined adequate as no tumor at the inked margin. 10,15,16 Shortly after this study was completed, a consensus statement by the Society of Surgical Oncology and American Society for Radiation Oncology was published that proposed guidelines for the management of surgical margins in BCT patients. 41 They conclude that with current improved, multidisciplinary management of breast cancer, the standard of an adequate margin should be defined as no tumor on ink. They state that only positive margin(s), or tumor on ink, pose a significant risk for ipsilateral breast recurrence and thus warrant reexcision. Applying these guidelines to our study, just 51 (34%) of 150 patients in this study would have undergone reexcision based on these criteria (ie, had positive margins in their prior excision). Furthermore, only nine (75%) of 12 patients who had final positive margins in their reexcision-only surgery would have been selected to undergo reexcision based on these guidelines. The remaining three (25%) patients previously had close lumpectomy margins. We agree with the authors of the consensus statement that application of their guidelines may result in a decrease in overall tissue excision and a significant reduction in reexcision-only operations. However, we feel that continued use of intraoperative evaluation, including FSM, may be warranted for primary lumpectomy specimens due to its benefit in detecting margin involvement by subtle and multifocal breast cancers such as DCIS and invasive lobular carcinoma. 606 Am J Clin Pathol 2014;142:

7 AJCP / Original Article In conclusion, this study supports that BCT patients undergoing reexcision only likely represent a subgroup with more difficult-to-control disease in which disease biology appears to be the most influential factor affecting final margin status and thus the need for reoperation. Despite relatively good pathology performance, FSM appears to be of limited value in BCT patients undergoing reexcision only due to greater extent of disease than anticipated in some cases and the balance currently struck between time allocation for FSM and extension of surgery. It is difficult to predict future benefits of FSM for reexcision-only specimens in light of recently published margin recommendations. Although the number of reexcision-only operations may decrease, it is possible that FSM may have increased utility since there may be a higher incidence of clinically significant residual disease in these specimens following adoption of new margin criteria. 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