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Journal of Breast Disease > Volume 9(2); 2021 > Article
Na, Ryu, Lim, Lee, Cho, Yoon, and Park: Atypical Hyperplasia at the Margin of Frozen Sections from Breast-Conserving Surgery

Abstract

Purpose

Intraoperative frozen section analysis to assess margin status during breast-conserving surgery is often performed to reduce the rate of re-excision. Whether additional resection is required if atypical cells are found at the margin during breast-conserving surgery is controversial. The aim of this study was to evaluate the accuracy of intraoperative frozen section analysis and investigate the feasibility of additional resection in cases of atypical hyperplasia on frozen sections from breast-conserving surgery.

Methods

A retrospective analysis was performed on 1,411 patients with invasive breast cancer who underwent breast-conserving surgery between July 2004 and June 2012. The microscopic margins of the intraoperative frozen sections and permanent sections were examined. Overall events (locoregional recurrence and distant metastasis) were analyzed between the negative margin group and the other margin group (including atypical hyperplasia, carcinoma in situ [CIS], and invasive carcinoma).

Results

Of the 1,411 patients, 1,201 had negative margins and 210 had other margin types in the first frozen section. 68 patients had atypical hyperplasia on frozen section analysis. This atypical hyperplasia included atypical cells, atypical ductal hyperplasia, and atypical lobular hyperplasia. Of these 68 patients, the final findings on the permanent section were negative (n=32, 47.1%), atypical cells (n=16, 23.5%), and CIS (n=20, 29.4%). The rate of overall events and distant metastases were higher in the other margin group (9.5% vs. 5.4%, p=0.021) and (5.7% vs. 3.0%, p=0.045). Of the 1,411 patients, 44 (3.1%) had false-positive findings, and 15 (1.1%) had false-negative findings in the frozen sections, with an accuracy of 95.8%.

Conclusion

The accuracy of intraoperative frozen section analysis was 95.8%, with 91.7% sensitivity and 96.4% specificity. Atypical hyperplasia on frozen section analysis requires additional resection at the time of breast-conserving surgery because of the possibility of CIS, but excessive resection may be performed in other cases. Therefore, sufficient consultation with patients is required.

INTRODUCTION

Cancer is the leading cause of death in South Korea, and breast cancer is the second most common cancer in women [1]. Many randomized control trials have shown that breast-conserving surgery has better cosmetic benefits and similar long-term survival rates to total mastectomy. Consequently, breast-conserving surgery followed by adjuvant radiation therapy has become the standard treatment for early stage invasive breast carcinoma or carcinoma in situ (CIS) [2-4]. However, since there is a possibility of local recurrence in the remnant breast tissue in the case of breast-conserving surgery, radiation therapy is required after surgery, and it is therefore important to confirm gross and microscopic clear margins during surgery [5-7]. Intraoperative frozen section analysis to assess the margin status during breast-conserving surgery reduces the rate of re-excision. Re-excision is associated with morbidity and adverse cosmetic effects. Therefore, it is important for surgeons to obtain appropriate resection margins and confirm negative margins using frozen section analysis [8,9].
When frozen section analysis is performed during surgery, various margin statuses can be reported. One of these is atypical hyperplasia, which is defined as a borderline lesion between benign ductal hyperplasia and carcinoma. However, whether additional resection is required if atypical cells are found in frozen section analysis is controversial [10].
The aim of this study was therefore to evaluate the accuracy of intraoperative frozen section analysis and to investigate the feasibility of obtaining a negative margin at the primary resection and additional resection in cases of atypical hyperplasia on frozen sections.

METHODS

Patients and data analysis

We performed a retrospective analysis based on the medical records of 1,411 patients diagnosed with invasive carcinoma who underwent breast-conserving surgery with intraoperative frozen section analysis between July 2004 and June 2012 at Chonnam National University Hwasun Hospital. Core needle biopsy, fine needle aspiration, excisional biopsy, incisional biopsy and vacuum-assisted breast biopsy procedures were used to diagnose invasive carcinoma prior to surgery.
To compare events according to the first margin status, we divided patients into a negative margin group and an other margin group (including atypical hyperplasia, CIS, and invasive carcinoma). Event analysis included local recurrence in the ipsilateral skin, breast, and chest wall and regional recurrence in the axillary lymph nodes and internal mammary lymph nodes, and distant metastasis in the bone, liver, brain, lung, pleura, distant lymph nodes, and others. Overall, events included all of these events and death. The first margin atypia group and the CIS and invasive carcinoma margin groups were also analyzed. The difference between the frozen section and permanent biopsy was investigated in the atypia, carcinoma in situ, and invasive carcinoma groups. In addition, false-positive and false-negative rates were analyzed to test the accuracy of the frozen section analysis. This study was approved by the Institutional Review Board at Chonnam National University Hwasun Hospital, with the reference number HTMP-2021-020. Informed consent was waived owing to the retrospective nature of the study.

Surgical procedure and frozen section analysis

Preoperative mammography-guided wire localization or ultrasonography-guided staining was performed in cases of nonpalpable microcalcification or small-sized lesions. During the surgery, we aimed to achieve a safe margin of 1 cm grossly at the first excision. When microcalcification was present, the surgeon performed specimen mammography to confirm precise excision. Sentinel lymph node biopsy was performed using indigo carmine blue dye for axillary lymph node staging. After the first lumpectomy specimen resection, the upper, lower, inner, and outer margins were excised from the breast tissue and sent to the pathology department for frozen section analysis. The surgical defect was repaired with a glandular interposition. If tumor or atypical cells were observed in the frozen section analysis, additional resection was performed to obtain a negative margin.

Statistical analysis

The Student’s t-test was used to compare continuous variables, and the chi-squared or Fisher’s exact test were used to compare categorical variables. All data analyses were performed using SPSS version 25.0 (SPSS Inc., Chicago, IL, USA). Two-sided p-values of < 0.050 were considered statistically significant.

RESULTS

Baseline characteristics

We divided patients into the negative margin group and the other margin group based on the frozen margin status. There were 1,201 patients in the negative group and 210 patients in the other margin group. The median follow-up duration was 60 months. Table 1 lists the baseline characteristics of the patients. The proportion of pathologic T1 stage was slightly higher in the negative group than in the other margin group (72.0% vs. 70.9%, p= 0.049), and the proportion of progesterone receptor-positive samples was higher in the other margin group (76.2% vs. 68.9%, p= 0.034). There were no significant differences in other variables between the two groups. In both groups, core needle biopsy was the most commonly used diagnostic method, and the upper-outer quadrant was the most common tumor location. Pathologic T1 and N0 stages were the most common.

Events according to margin status on the first frozen section

Table 2 shows the difference in events between the negative group and the other margin group (including atypical hyperplasia, CIS, and invasive carcinoma) in the frozen sections. Local and regional recurrences were not significantly different between the two groups, but the rate of distant metastasis was higher in the other group (5.7% vs. 3.0%, p= 0.045), and the overall events were higher in the other group than in the negative group (9.5% vs. 5.4%, p= 0.021). When events were compared by subdividing the other group into the atypical hyperplasia group and the CIS and invasive carcinoma groups, there was no significant difference in locoregional recurrence, distant metastasis, or overall events between the two groups (Table 3).

Correlation between frozen section and permanent biopsy for margin assessment

Figure 1 shows the difference between the frozen section analysis and the permanent section in each group. In the group with atypical hyperplasia on frozen sections, 32 (47.1%) were negative, 16 (23.5%) were found to have atypical cells, and 20 (29.4%) margins were CIS in the permanent section.

Accuracy of frozen section analysis

To assess the accuracy of frozen section analysis, we excluded atypical hyperplasia groups that had borderline and undetermined features. Of the 1,201 patients with negative margins on the frozen section, 15 patients had positive margins in the permanent section and were defined as false-negative cases (1.1%). Of the 142 patients with CIS or carcinoma in the margin of the frozen section, 12 patients were found to have negative margins in the final permanent section and were defined as false-positive cases (3.1%). The accuracy of the frozen section analysis was 95.8%, with 91.7% sensitivity and 96.4% specificity (Table 4).

DISCUSSION

Many randomized control trials have shown that breast-conserving surgery has better cosmetic benefits and a similar long-term survival rates to total mastectomy [2-4]. For this reason, breast-conserving surgery for breast cancer treatment has increased worldwide. Likewise, in Korea, breast-conserving surgery accounted for 65% of surgeries for newly diagnosed breast carcinoma, which is significantly higher than the total mastectomy rate (34%) [11]. Many studies have reported that intraoperative frozen section analysis during breast-conserving surgery reduces the rate of re-excision [8,12,13]. Whether frozen section analysis reduces local recurrence is controversial, but it is important to confirm negative margins for local control after breast-conserving surgery [7,14]. There is also controversy over the local recurrence rate when additional resection is performed. In two previous studies, patients with resection margins noted as positive on the final diagnosis after surgery, required re-excision to obtain negative margins after surgery and were comparable to those who had a negative margin at the time of primary surgery with no significant difference in the local recurrence rates [15,16]. In contrast, other studies have reported higher local recurrence rates in re-excision cases [17,18]. However, it is feasible to confirm negative resection margins by performing frozen section analysis during breast-conserving surgery, since re-excision has a costly mental and physical burden on the patient. For this reason, many surgeons employ frozen section analysis during breast-conserving surgery to confirm a clean resection margin status [8,19].
To compare the baseline characteristics and overall events including locoregional recurrence and distant metastasis, we divided the patients into two groups, the negative group and the other group, based on the frozen section. Overall events and distant metastases were significantly higher in the other margin groups.
The need for additional resection is controversial when atypical hyperplasia is reported in frozen sections, but it is feasible for several reasons. First, atypical hyperplasia has a relatively high risk of developing cancer [20-23]. Second, atypical cells are difficult to identify because they are at the morphological boundary between benign lesions and CIS. Therefore, it is possible to downstage diagnosis [24,25]. In addition, the margin could be insufficient for diagnosis. In our study, of the 68 patients who had atypical hyperplasia on the first frozen section, 20 (29.4%) patients were diagnosed with ductal carcinoma in situ and 16 (23.5%) patients were diagnosed with atypical cells in the permanent section. If additional resection was not performed during the surgery, 20 patients would have required reoperation. Because CIS is a premalignant lesion, it has a high risk of invasive breast cancer [26,27]. In a comparison of the overall events, the frozen atypical hyperplasia and carcinoma groups showed no difference in locoregional recurrence or distant metastasis. In addition, in a previous study, because atypical cells found at the margin are associated with a high rate of residual atypical ductal hyperplasia and carcinoma, re-excision was recommended [10]. In contrast, Li et al. [28] reported that there is a lack of evidence for re-excision because there was no significant difference in the ipsilateral recurrence rate and distant metastasis-free 5-year survival rate between the group with atypical hyperplasia and the non-atypical hyperplasia group. However, since 29.4% of patients who noted atypical hyperplasia on frozen section were diagnosed with CIS in the permanent section, it is important to confirm a negative margin through additional resection during surgery.
In our study, we found frozen section analysis to have an accuracy of 95.8%. The sensitivity and specificity were 91.7% and 96.4%, respectively. In other studies, the false-negative rate reached up to 18.6%, but in this study, it was as low as 1.1% [8,9,19,29]. Despite the effectiveness of this method in reducing re-excision, frozen section analysis is controversial among many pathologists because it can sometime lead to unnecessary resection due to false positives. However, in our study of a large number of cases, it had important implications with high accuracy (95.8%) and a low false-positive rate (3.1%).
Our study has some limitations. First, this was a retrospective study. Since only patients who underwent breast-conserving surgery for invasive carcinoma were included, the margins of other types of surgery were not evaluated. Second, because all of the atypical hyperplasia margin groups underwent an additional resection, comparison with the non-resected case was not possible. Third, it was not possible to compare how radiotherapy or medical treatment affected progression after breast-conserving surgery.
In conclusion, the accuracy of intraoperative frozen section analysis was 95.8%, with 91.7% sensitivity and 96.4% specificity. Intraoperative frozen section analysis with a negative margin can decrease the rate of overall events and distant metastases. For atypical hyperplasia on frozen section analysis, additional resection is required at the time of breast-conserving surgery because of possibility of CIS, but excessive resection may be performed in other cases. Therefore, sufficient consultation with patients is required.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

Figure 1.
Correlation between frozen sections and permanent biopsies for margin assessment.
N=negative; AH=atypical hyperplasia; CIS=carcinoma in situ; IC=invasive carcinoma.
jbd-9-2-71f1.jpg
Table 1.
Baseline characteristics
Characteristic Negative margin (n = 1,201) Other margin (n = 210) p-value
No. (%) No. (%)
Mean age (yr) 48.8 48.1 0.307
Diagnostic method 0.472
 CNB 980 (81.6) 164 (78.1)
 FNA 76 (6.3) 14 (6.7)
 Excision 96 (8.0) 25 (11.9)
 Incision 2 (0.2) 0 (0.0)
 VABB 47 (3.9) 7 (3.3)
Side 0.657
 Right 592 (49.3) 107 (51.0)
 Left 609 (50.7) 103 (49.0)
Tumor Location 0.728
 UOQ 588 (49.0) 101 (48.1)
 UIQ 346 (28.8) 57 (27.1)
 LOQ 167 (13.9) 32 (15.2)
 LIQ 85 (7.1) 15 (7.1)
 Central 15 (1.2) 5 (2.4)
Tumor size (mm) 16.1 15.3 0.160
pTstage* 0.049
 pT1 865 (72.0) 149 (70.9)
 pT2 328 (27.3) 59 (28.1)
 pT3 8 (0.7) 1 (0.5)
 pT4 0 (0.0) 1 (0.5)
pNstage* 0.245
 pN0 852 (70.9) 140 (66.7)
 pN1 269 (22.3) 55 (26.2)
 pN2 59 (4.9) 8 (3.8)
 pN3 21 (1.8) 7 (3.3)
pSTAGE* 0.544
 1 678 (56.5) 110 (52.4)
 2 442 (36.8) 85 (40.5)
 3 81 (6.7) 15 (7.1)
ER 0.084
 Positive 863 (71.9) 163 (77.6)
 Negative 338 (28.1) 47 (22.4)
PR 0.034
 Positive 828 (68.9) 160 (76.2)
 Negative 373 (31.1) 50 (23.8)
HER2 0.076
 Positive 187 (15.6) 43 (20.5)
 Negative 1,014 (84.4) 167 (79.5)
LVI 0.238
 Present 239 (19.9) 52 (24.8)
 Absent 944 (78.6) 154 (73.3)
 Unknown 18 (1.5) 4 (1.9)
Histologic grade 0.219
 1 302 (25.1) 48 (22.9)
 2 465 (38.7) 97 (46.2)
 3 407 (33.9) 60 (28.6)
 Unknown 27 (2.2) 5 (2.4)

Values are presented as number (%) or number only and percentages have been rounded and may not total to 100%.

CNB=core needle biopsy; FNA=fine needle aspiration; VABB=vacuum assisted breast biopsy; UOQ=upper-outer quadrant; UIQ=upper-inner quadrant; LOQ=lower-outer quadrant; LIQ=lower-inner quadrant; ER=estrogen receptor; PR=progesterone receptor; HER2=human epidermal growth factor receptor 2; LVI=lymph node invasion.

* The 8th edition of AJCC (American Joint Committee on Cancer) TNM (tumor-node-metastasis) classification.

Table 2.
Events according to margin status on frozen section
Variable Negative margin (n = 1,201) Other margin (n = 210) p-value
No. (%) No. (%)
Local recurrence 0.371
 Present 18 (1.5) 5 (2.4)
 Absent 1,183 (98.5) 205 (97.6)
Regional recurrence 1.000
 Present 7 (0.6) 1 (0.5)
 Absent 1,194 (99.4) 209 (99.5)
Distant metastasis 0.045
 Present 36 (3.0) 12 (5.7)
 Absent 1,165 (97.0) 198 (94.3)
Overall event 0.021
 Present 65 (5.4) 20 (9.5)
 Absent 1,136 (94.6) 190 (90.5)
Table 3.
Comparison of events between atypia margins and CIS and carcinoma margin
Variable Atypia margin (n = 68) CIS and carcinoma margin (n = 142) p-value
No. (%) No. (%)
Local recurrence 1.000
 Present 1 (1.5) 4 (2.8)
 Absent 67 (98.5) 138 (97.2)
Regional recurrence 1.000
 Present 0 1 (0.7)
 Absent 68 (100.0) 141 (99.3)
Distant metastasis 0.755
 Present 3 (4.4) 9 (6.3)
 Absent 65 (95.6) 133 (93.7)
Overall event 0.458
 Present 5 (7.4) 15 (10.6)
 Absent 63 (92.6) 127 (89.4)

CIS=carcinoma in situ.

Table 4.
Table assessing the accuracy of frozen section analysis
Frozen section Permanent biopsy
Total
Negative Other
No. (%) No. (%)
Negative 1,186 (84.0)* 15 (1.1) 1,201
Other 44 (3.1) 166 (11.8)§ 210
Total 1,230 181 1,411

* True negative margin;

False negative margin;

False positive margin;

§ True positive margin.

REFERENCES

1. Hong S, Won YJ, Park YR, Jung KW, Kong HJ, Lee ES, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2017. Cancer Res Treat 2020;52:335-50.
crossref pmid pmc
2. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41.
crossref pmid
3. Jacobson JA, Danforth DN, Cowan KH, d’Angelo T, Steinberg SM, Pierce L, 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.
crossref pmid
4. Poggi MM, Danforth DN, Sciuto LC, Smith SL, Steinberg SM, Liewehr DJ, et al. Eighteen‐year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the national cancer institute randomized trial. Cancer 2003;98:697-702.
crossref pmid
5. Gage I, Schnitt SJ, Nixon AJ, Silver B, Recht A, Troyan SL, et al. Pathologic margin involvement and the risk of recurrence in patients treated with breast-conserving therapy. Cancer 1996;78:1921-8.
crossref pmid
6. Obedian E, Haffty BG. Negative margin status improves local control in conservatively managed breast cancer patients. Cancer J Sci Am 2000;6:28-33.
pmid
7. Schnitt SJ, Abner A, Gelman R, Connolly JL, Recht A, Duda RB, 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 pmid
8. Olson T, Harter J, Munoz A, Mahvi D, Breslin T. Frozen section analysis for intraoperative margin assessment during breast-conserving surgery results in low rates of re-excision and local recurrence. Ann Surg Oncol 2007;14:2953.
crossref pmid
9. Cendán JC, Coco D, Copeland III. Accuracy of intraoperative frozen-section analysis of breast cancer lumpectomy-bed margins. J Am Coll Surg 2005;201:194-8.
crossref pmid
10. Arora S, Menes TS, Moung C, Nagi C, Bleiweiss I, Jaffer S. Atypical ductal hyperplasia at margin of breast biopsy—is re-excision indicated? Ann Surg Oncol 2008;15:843-7.
crossref pmid
11. Park EH, Min SY, Kim Z, Yoon CS, Jung KW, Nam SJ, et al. Basic facts of breast cancer in Korea in 2014: the 10-year overall survival progress. J Breast Cancer 2017;20:1-11.
crossref pmid pmc
12. Cabioglu N, Hunt KK, Sahin AA, Kuerer HM, Babiera GV, Singletary SE, et al. Role for intraoperative margin assessment in patients undergoing breast-conserving surgery. Ann Surg Oncol 2007;14:1458-71.
crossref pmid
13. Racz JM, Glasgow AE, Keeney GL, Degnim AC, Hieken TJ, Jakub JW, et al. Intraoperative pathologic margin analysis and re-excision to minimize reoperation for patients undergoing breast-conserving surgery. Ann Surg Oncol 2020;27:5303-11.
crossref pmid
14. Smitt MC, Nowels KW, Zdeblick MJ, Jeffrey S, Carlson RW, Stockdale FE, et al. The importance of the lumpectomy surgical margin status in long term results of breast conservation. Cancer 1995;76:259-67.
crossref pmid
15. Aziz D, Rawlinson E, Narod SA, Sun P, Lickley HLA, McCready DR, et al. The role of reexcision for positive margins in optimizing local disease control after breast‐conserving surgery for cancer. Breast J 2006;12:331-7.
crossref pmid
16. O’sullivan MJ, Li T, Freedman G, Morrow M. The effect of multiple reexcisions on the risk of local recurrence after breast conserving surgery. Ann Surg Oncol 2007;14:3133-40.
crossref pmid
17. Ali AN, Vapiwala N, Guo M, Hwang WT, Harris EE, Solin LJ. The impact of re-excision and residual disease on local recurrence after breast conservation treatment for patients with early stage breast cancer. Clin Breast Cancer 2011;11:400-5.
crossref pmid
18. Kouzminova NB, Aggarwal S, Aggarwal A, Allo MD, Lin AY. Impact of initial surgical margins and residual cancer upon re-excision on outcome of patients with localized breast cancer. Am J Surg 2009;198:771-80.
crossref pmid
19. 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.
pmid
20. Page DL, Dupont WD, Rogers LW, Rados MS. Atypical hyperplastic lesions of the female breast. A long‐term follow‐up study. Cancer 1985;55:2698-708.
crossref pmid
21. Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield AC, Worrell JA, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer 1993;71:1258-65.
crossref pmid
22. Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, et al. Benign breast disease and the risk of breast cancer. N Engl J Med 2005;353:229-37.
crossref pmid
23. Kader T, Hill P, Zethoven M, Goode DL, Elder K, Thio N, et al. Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma. J Pathol 2019;248:326-38.
crossref pmid
24. McGhan LJ, Pockaj BA, Wasif N, Giurescu ME, McCullough AE, Gray RJ. Atypical ductal hyperplasia on core biopsy: an automatic trigger for excisional biopsy? Ann Surg Oncol 2012;19:3264-9. Ann Surg Oncol 2012;19:3264-9.
crossref pmid
25. Polat AK, Andacoglu O, Polat AV, Johnson R, Bonaventura M, Soran A, et al. Atypical hyperplasia on core biopsy: is further surgery needed? Am J Med Sci 2012;344:28-31. Am J Med Sci 2012;344:28-31.
pmid
26. Cowell CF, Weigelt B, Sakr RA, Ng CKY, Hicks J, King TA, et al. Progression from ductal carcinoma in situ to invasive breast cancer: revisited. Mol Oncol 2013;7:859-69.
crossref pmid pmc
27. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst 2010;102:170-8.
pmid
28. Li S, Liu J, Yang Y, Zeng Y, Deng H, Jia H, et al. Impact of atypical hyperplasia at margins of breast-conserving surgery on the recurrence of breast cancer. J Cancer Res Clin Oncol 2014;140:599-605.
crossref pmid
29. Ko SS, Chun YK, Kang SS, Hur MH. The usefulness of intraoperative circumferential frozen-section analysis of lumpectomy margins in breast-conserving surgery. J Breast Cancer 2017;20:176-82.
crossref pmid pmc
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