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Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management
The Breast xxx (2016) 1e7
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The Breast journal homepage: www.elsevier.com/brst
Original article
Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management Alana R. Donaldson a, Leah Sieck b, Christine N. Booth a, Benjamin C. Calhoun a, * a b
Robert J. Tomsich Pathology and Laboratory Medicine Institute, Department of Pathology, Cleveland Clinic, Cleveland, OH, USA Imaging Institute, Department of Breast Imaging, Cleveland Clinic, Cleveland, OH, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 March 2016 Received in revised form 3 June 2016 Accepted 4 June 2016 Available online xxx
Aims: The risk of finding carcinoma in excisions following a core needle biopsy diagnosis of radial scar is not well defined and clinical management is variable. The aim of this study is to determine the frequency of high-risk lesions, ductal carcinoma in situ, and invasive carcinoma in excisions following a core biopsy diagnosis of radial scar. Methods and results: Dedicated breast pathologists and radiologists correlated the histologic and radiologic findings and categorized radial scars as the target lesion or an incidental finding. High-risk lesions were defined as atypical hyperplasia or classical lobular carcinoma in situ. Of the 79 radial scars identified over a 14-year period, 22 were associated with atypia or carcinoma in the core biopsy. Thirty-seven (37) of the 57 benign radial scars underwent excision with benign findings in 30 (81%), high-risk lesions in six (16%), and flat epithelial atypia in one (3%). There were no upgrades to carcinoma. One patient with a benign radial scar developed a 3-mm focus of intermediate-grade estrogen receptor-positive ductal carcinoma in situ in the same quadrant of the ipsilateral breast 72 months after excision. One patient with an incidental un-excised benign radial scar was diagnosed with ductal carcinoma in situ at a separate site of suspicious calcifications. Conclusions: In this series, none of the benign radial scars was upgraded to carcinoma. Radial scar was the targeted lesion in all cases with high-risk lesions on excision. Surgical excision may not be mandatory for patients with benign incidental radial scars on core biopsy. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Breast Screening Diagnosis Core biopsy Radial scar Pathology
Introduction Radial scars of the breast are uncommon findings in breast biopsies and are characterized by a central focus of fibroelastotic stroma with adenotic epithelial elements radiating outward [1]. The stellate appearance of radial scars may mimic carcinoma mammographically and histologically [2,3]. Some early studies suggested that radial scars were more common in women with breast cancer [4], while subsequent studies found no significant difference in the frequency of radial scars in women with and without breast cancer [5,6]. The observation that radial scars may
* Corresponding author. Robert J. Tomsich Pathology and Laboratory Medicine Institute, Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Mail Code L25, Cleveland, OH 44195, USA. Tel.: þ1 (216) 636 9914; fax: þ1 (216) 445 3707. E-mail addresses: [email protected] (A.R. Donaldson), [email protected] (L. Sieck), [email protected] (C.N. Booth), [email protected] (B.C. Calhoun).
contain carcinoma also suggested a relationship between radial scars and breast cancer [7e10]. An initial report from the Nurses' Health Study provided evidence that radial scars were an independent risk factor for the development of carcinoma [11]. Subsequent studies from the Nashville (Sanders et al. [12]) and Mayo cohorts (Berg et al. [13]) failed to confirm this finding. In an updated analysis of the Nurses' Health Study, the risk associated with radial scars in proliferative disease categories was attenuated but remained statistically significant [14]. In the Nashville cohort, the risk of developing invasive carcinoma after a diagnosis of radial scars was 3.4% in the first 10 years, compared with 1.6% for patients without a radial scar [12]. The long-term follow-up studies of the Nashville cohort, the Mayo cohort, and the Nurse's Health Study included patients with open biopsies, many of which were performed in the premammographic era. With the widespread use of percutaneous core needle biopsy (CNB) of the breast, attention has shifted to the risk of finding carcinoma in an excision specimen following a core biopsy diagnosis of radial scar. Studies correlating core biopsy
http://dx.doi.org/10.1016/j.breast.2016.06.007 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
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diagnoses of radial scar with final pathology after surgery have shown variable results with the frequency of invasive mammary carcinoma and ductal carcinoma in situ on excision ranging from 0% to 40% [8,15e23]. However, recent studies with careful radiologyepathology correlation suggest that upgrade to carcinoma occurs in 2% of cases with radial scars on core biopsy [24,25]. The objective of this study was to determine the frequency of high-risk lesions (defined as atypical ductal hyperplasia or atypical lobular hyperplasia/classical lobular carcinoma in situ) and carcinoma in a series of excision specimens following a diagnosis of radial scar on core biopsy. Materials and methods This study was approved by the Cleveland Clinic Institutional Review Board. Breast core biopsies with a diagnosis of radial scar or complex sclerosing lesion from January 1, 2000, to March 26, 2014, were retrieved from the Anatomic Pathology information system CoPathPlus (Cerner Corporation, Kansas City, MO) using the search terms “radial scar,” “complex sclerosing lesion,” and “breast.” For the purposes of this study, radial scars and complex sclerosing lesions were combined and referred to as radial scar. At low power, lesions were characterized by a stellate appearance (Fig. 1A) with a central focus of fibroelastotic stroma containing entrapped benign epithelial elements apparent at higher magnification (Fig. 1B). A total of 79 core biopsies with radial scars were initially identified. Thirty-five (35) of the 79 cases had no excision/no correlation with the site of core biopsy (19), missing slides (11), or missing core biopsy slides and were not excised (5). The data were analyzed for the entire group of 79 patients as well as for the 44 patients with excisions and available slides for both the core biopsy and the corresponding excision. Statistical analysis (Fischer's exact test and Pearson's correlation coefficient) was performed using JMP® software version 10.0.2 (SAS Statistical Institute, Inc., Cary, NC, USA). The indications for core biopsy and patient age at biopsy were recorded for all cases. Biopsies of mammographic findings such as asymmetry (a finding only seen on one mammographic projection), calcifications, or architectural distortion without a corresponding sonographic finding were performed with a stereotactic technique using a dedicated prone stereotactic biopsy table and a Suros ATEC (Hologic, Inc., Marlborough, MA) or an Eviva (Hologic, Inc., Marlborough, MA, USA) 12-gauge core biopsy device. Routinely, at least six to 12 core specimens were obtained, with additional specimens obtained at the discretion of the radiologist. Biopsies of sonographic findings such as masses were performed free hand with a 14-gauge core biopsy device (C. R. Bard, Inc., Tempe, AZ). Biopsy specimens of magnetic resonance imaging (MRI) findings were
obtained using a nine-gauge vacuum assisted core biopsy device (Suros ATEC, Hologic, Inc., Marlborough, MA, USA) with a 1.5T magnet (Siemens Symphony, Siemens Medical Solutions, Malvern, PA, USA). Specimen radiography was completed on all CNBs performed for calcifications. Clips were placed after the core specimens were obtained and post-clip mammography was performed for all biopsies. Radial scars were classified as incidental if they were not a part of the targeted lesion as determined from the radiology report or patient's imaging. Radial scars were considered the targeted lesion if pre-biopsy imaging showed a spiculated mass or architectural distortion and there was no separate coexisting mass-forming lesion in the core biopsy or excision specimen. If the targeted lesion was a calcification and the radial scar was not reported to contain calcification, the radial scar was regarded as incidental. According to the protocol at our institution, all radial scars found on core biopsy, whether they were the targeted lesion or incidental, were referred for evaluation by a surgeon. The patients who underwent surgery had a wire localization of the biopsy site prior to surgery and the biopsy site was identified in the excision specimens. The surgical pathology findings were correlated with the imaging findings and the largest size of the radial scar in either the core biopsy or the excision specimen was recorded. All available surgical pathology reports for excision specimens following a core biopsy diagnosis of radial scar alone were reviewed. The presence and location of calcifications were included in the pathology reports for the core biopsy and the excisions. The submitted sections for all of the excision specimens included biopsy sites. Each core biopsy was individually correlated with a corresponding excision specimen when possible. The presence of atypical ductal hyperplasia, atypical lobular hyperplasia, classical lobular carcinoma in situ, flat epithelial atypia, ductal carcinoma in situ, and invasive mammary carcinoma in the core biopsy and excisions was recorded. For all cases, the presence and type of coexisting (in the same core) or concurrent (in a concurrent ipsilateral core biopsy) atypia or carcinoma was recorded. High-risk lesions were defined as atypical ductal hyperplasia or atypical lobular hyperplasia/classical lobular carcinoma in situ. An upgrade to carcinoma was defined as invasive mammary carcinoma or ductal carcinoma in situ in the excision specimen. Clinical follow-up and chemoprevention data were obtained from the electronic medical record. For patients who underwent immediate surgical excision, the follow-up interval was calculated from the date of excision to the date of the most recent mammogram or progress note from a breast oncologist or primary care physician. For patients who did not have surgery, the follow-up interval was calculated from the date of core biopsy to the date of
Fig. 1. Representative images of a radial scar diagnosed on core biopsy, hematoxylin and eosin stain (a and b at 40 and 100 magnification, respectively).
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
A.R. Donaldson et al. / The Breast xxx (2016) 1e7
the most recent mammogram or progress note from a breast oncologist or primary care physician. Results A total of 79 core biopsies with radial scars were initially identified (Table 1). For the entire cohort, the mean and median ages were 52 and 54 years, respectively (range 34e79). The indications for biopsy were mass or architectural distortion in 45 (57%), calcifications in 22 (28%), and MRI findings in 12 (15%). There were 49 (62%) ultrasound-guided, 25 (32%) stereotactic, and five (6%) MRIguided core biopsies. The radial scar was the targeted lesion in 64 (81%) cases. Of the 79 core biopsies with radial scars, 22 (28%) had atypia or carcinoma in the same core and 57 (72%) did not (Fig. 2). Patients with atypia or carcinoma on core biopsy with radial scars tended to be older and more likely to undergo excision (Table 1). There were no significant differences in the indication for core biopsy, type of core biopsy, or history of concurrent ipsilateral or contralateral breast cancer. Thirty-seven (65%) of the benign radial scars underwent excision with benign findings in 30 (81%),
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high-risk lesions in six (16%), and flat epithelial atypia in one (3%). None of the benign radial scars, targeted or incidental, was upgraded to carcinoma on excision. Twenty-one (95%) of the radial scars with atypia or carcinoma underwent excision with the following results: benign findings in nine (43%), high-risk lesions in five (24%), ductal carcinoma in situ in five (24%), and invasive carcinoma in two (9%). The radial scar was the targeted lesion in all the cases with a high-risk lesion on excision. A subset of 44 (56%) core biopsies with available slides for both the core biopsy and the corresponding excision was also analyzed (Fig. 3). The findings were similar to those for the entire cohort of 79 patients. This subset excludes 35 (44%) of the 79 cases that had no excision/no correlation with the site of core biopsy (19, 24%), missing slides (11, 14%), or missing core biopsy slides and were not excised (5, 6%). Of these 44 cases, 10 (23%) radial scars were associated with atypia and four (9%) were associated with carcinoma. Surgical excision of the 10 core biopsies with atypia revealed ductal carcinoma in situ in 1/10 (10%), high-risk lesions in 3/10 (30%), and benign findings in 6/10 (60%). Surgical excision of the 30 (68%) benign radial scars revealed high-risk lesions in five (17%) and
Table 1 Clinicopathologic features of patients with RS on breast core biopsy, as median (range) or n (%). Total cohort n ¼ 79 (100%) Patient characteristics Age, yearsb Concurrent ipsilateral breast cancer Concurrent contralateral breast cancer Indication for core biopsy Architectural distortion/mass Calcifications MRI enhancement Type of core biopsy Stereotactic Ultrasound MRI-guided Correlation with imaging Targeted RS Surgical excisions HRL IMC or DCIS
RS e no atypia or carcinoma 57 (72%)
RS e atypia or carcinoma 22 (28%)
P valuea
50 (34e71) 2 (4%) 7 (12%)
58 (40e79) 1 (4%) 1 (4%)
P ¼ 0.01* P > 0.99 P ¼ 0.43
31 (55%) 15 (26%) 11 (19%)
14 (64%) 7 (32%) 1 (4%)
P ¼ 0.61 P ¼ 0.78 P ¼ 0.16
16 (28%) 37 (65%) 4 (7%)
9 (41%) 12 (55%) 1 (4%)
P ¼ 0.29 P ¼ 0.44 P > 0.99
47 (82%) 37 (65%) 6 (11%) 0 (0%)
17 (77%) 21 (95%) 5 (23%) 7 (32%)
P P P P
¼ 0.75 ¼ 0.005* ¼ 0.50 < 0.001*
Abbreviations: MRI, magnetic resonance imaging; RS, radial scar; HRL, high-risk lesion; DCIS, ductal carcinoma in situ; IMC, invasive mammary carcinoma. *Statistically significant P < 0.05. a Fisher's exact test for categorical variables. b Analyzed as a continuous variable.
RS Core Biopsies (79)
No Atypia or Carcinoma on Core (57)
No excision (20)
Atypia or Carcinoma on Core (22)
Excision (37)
No excision (1)
Excision (21)
Benign (30)
Benign (9)
HRL (6)
HRL (5)
FEA (1)
DCIS (5)
IMC or DCIS (0)
IMC (2)
Fig. 2. Outcomes of patients with radial scars diagnosed on breast core biopsy. Abbreviations: RS, radial scar; HRL, high-risk lesion; FEA, flat epithelial atypia; DCIS, ductal carcinoma in situ; IMC, invasive mammary carcinoma.
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
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RS Core Biopsies (79)
Not Excised or Slides Unavailable (35)
Complete Pathology Slide Review (44)
No Atypia or Carcinoma on Core (30)
Atypia or Carcinoma Present on Core (14)
Excision
Excision
Benign (25)
Benign (6)
HRL (5)
HRL (3)
IMC or DCIS (0)
DCIS (4)
IMC (1) Fig. 3. Outcomes of patients with radial scars diagnosed on breast core biopsy with a complete pathology slide review. Abbreviations: RS, radial scar; HRL, high-risk lesion; DCIS, ductal carcinoma in situ; IMC, invasive mammary carcinoma.
benign findings in 25 (83%). None of the benign radial scars, targeted or incidental, was upgraded to carcinoma on excision. The radial scar was the targeted lesion in all cases with high-risk lesions on excision. Clinical, pathologic, and radiologic data for patients with benign radial scars on core biopsy, who had high-risk lesions on excision, are listed in Table 2. The indication for core biopsy in all of the patients with high-risk lesions was the presence of a mass on imaging studies and all of those patients had 14-gauge ultrasound core biopsies. None of the patients with a benign radial scar on a stereotactic (12-gauge) or MRI-guided (nine-gauge) core biopsy was upgraded to a high-risk lesion. For the 30 benign radial scars on CNB, the mean and median sizes were 7.2 and 6 mm, respectively (range 3e12 mm). The benign radial scars on CNB with high-risk lesions on excision were measured to be 4, 5, 9, 10, and 11 mm each. The patient with a 5-mm benign radial scar on CNB and a high-risk lesion on excision had concurrent ipsilateral ductal carcinoma in situ (DCIS) with microinvasion. The patient with a 4-mm benign radial scar on CNB and a high-risk lesion on excision also had extensive sclerosing adenosis in the excision specimen. Clinical follow-up information was available for 39 of the 44 cases with excisions and complete slide reviews with a mean and median of 54 and 68 months, respectively (range 14e166). Follow-
up was unavailable for three patients, and two patients died of other causes 57 and 72 months after excision of the radial scar. No patients developed invasive carcinoma over this follow-up period. One patient (3%) with a benign radial scar on core biopsy developed a 3-mm focus of intermediate-grade estrogen receptor-positive ductal carcinoma in situ 72 months after excision. This patient did not have a history of concurrent ipsilateral or contralateral breast cancer. The ductal carcinoma in situ was located in the same quadrant of the ipsilateral breast as the core biopsy site. A total of eight out of 44 (18%) patients received selective estrogen receptor modulators for chemoprevention. Two of these patients were placed on chemoprevention solely on the basis of high-risk lesion found on excision of a benign radial scar: one received tamoxifen for a diagnosis of atypical ductal hyperplasia and the other received raloxifene for atypical lobular hyperplasia. Clinical follow-up was available for 23 out of 27 patients who did not undergo surgery (20 patients) or whose benign radial scar slides were not available for review (7 patients) with a median and mean of 29 and 53 months, respectively (range 3e165). None of these patients developed invasive carcinoma. One patient (4%) with an un-excised benign radial scar was diagnosed with high-grade ductal carcinoma in situ in the same breast 16 months later. The
Table 2 Clinical, pathologic, and radiologic data for patients with benign RS on core biopsy and HRL on excision. Patient
Indication for biopsy
Type of core biopsy
Surgical excision pathology
Concurrent ipsilateral/contralateral breast cancer
1 2 3 4 5
Mass Mass Mass Mass Mass
Ultrasound-guided Ultrasound-guided Ultrasound-guided Ultrasound-guided Ultrasound-guided
ADH ADH ALH LCIS LCIS
No Concurrent ipsilateral DCIS with microinvasion No Concurrent contralateral IMC No
Abbreviations: RS, radial scar; HRL, high-risk lesion; ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ; IMC, invasive mammary carcinoma.
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
A.R. Donaldson et al. / The Breast xxx (2016) 1e7 Table 3 Selected studies: Benign radial scars on core biopsy with outcomes on excision. Core biopsies
Pathology on excision HRL
Miller et al., 2014 [24] Conlon et al., 2015 [25] Matrai et al., 2014 [28] This study Total
102 48 77 37 264
22 12 9 6 49/264
Carcinoma (22%) (25%)a (12%) (16%) (19%)
1 1 0 0 2/264
(1%) (2%) (0%) (0%) (1%)
Abbreviations: HRL, high-risk lesions: atypical hyperplasia or lobular carcinoma in situ. a A combined category of epithelial atypia (atypical hyperplasia, lobular carcinoma in situ, flat epithelial atypia, and atypical apocrine adenosis) was reported in 23%.
initial core biopsy was performed for indeterminate calcifications, and based on the association of calcifications with other findings in the excision specimen, the radial scar was regarded as incidental. Suspicious calcifications in other locations in the same breast were followed up with mammography and a subsequent core biopsy at another site revealed high-grade ductal carcinoma in situ. The patient underwent a unilateral mastectomy and was placed on tamoxifen. This patient very likely did not undergo immediate excision because the radial scar was incidental and other foci of calcifications required clinical and radiologic surveillance. Discussion In this single-institutional review over a 14-year period, we identified 79 cases of radial scar diagnosed on core biopsy, corresponding to <1% of core biopsies. The expected frequency of radial scars on core biopsies specifically is not well established. In the largest caseecontrol studies of open biopsies, approximately 5e9% of patients had radial scars [12e14]. In the series reported by Miller et al., 1.5% of core biopsies over a 16-year period had radial scars [24]. Despite being uncommon, radial scars remain important in the management of breast disease because of their association with breast cancer risk [14] and the potential for misinterpretation by pathologists as low-grade invasive ductal or tubular carcinoma [3]. The use of immunohistochemical markers for myoepithelial cells can be helpful in differentiating radial scars from invasive carcinoma [26,27]. None of the benign radial scars in this series with follow-up excisions had carcinoma when core biopsies with atypia or carcinoma were excluded. Of a total of 37 benign radial scars on core biopsy, six (16%) showed high-risk lesions on excision. These findings are similar to other recent studies with detailed radiologicepathologic correlation (Table 3). In a recent series of 102 benign radial scars on core biopsy, 1% of cases were upgraded to carcinoma and 21.6% had high-risk lesions on excision [24]. In a series of 77 incidental radial scars measuring 5 mm, as reported by Matrai et al., none was upgraded to carcinoma and nine (12%)
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had high-risk lesions on excision [28]. Conlon et al. reported that one out of 48 cases (2%) was upgraded to carcinoma on excision and 12 cases (25%) contained high-risk lesions or other types of epithelial atypia [25]. The single upgraded case was a 2-mm focus of low-grade ductal carcinoma in situ in a background of atypical ductal hyperplasia in a patient who had a separate focus of ductal carcinoma in situ (excised separately) in the ipsilateral breast. In a meta-analysis including their data and 20 published studies of radial scars diagnosed on core biopsy, Conlon et al. found an overall upgrade rate of 7.5% for radial without high-risk lesions or flat epithelial atypia [25]. Importantly, most of the upgrades in these series were ductal carcinoma in situ and the invasive carcinomas tended to be low-grade ductal or tubular type. The lower upgrade rates observed in this and other recent studies (Table 3) are presumably related to careful radiologyepathology correlation. The mean size of the benign radial scar in our series (6 mm) also may have contributed to the lower rate of upgrade to carcinoma. Two distinct, but presumably related, categories of risk require consideration in patients with high-risk lesions. In the largest caseecontrol studies, the risk associated with various types of benign breast disease was defined as the relative risk of the patient developing a subsequent carcinoma (in either breast, usually 10e15 years after an open biopsy) [29e31]. With the routine use of percutaneous CNB, the risk of finding a carcinoma on excision has become a more immediate concern. Patients with a core biopsy diagnosis of radial scar are often offered surgery based on concerns regarding the risk of finding carcinoma in adjacent tissue, but recommendations and clinical management are quite variable [32,33]. Unfortunately, there are no large long-term studies of radial scar diagnosed on core biopsy with follow-up comparable to the prior studies of open biopsies. The risk associated with radial scars in the larger caseecontrol studies applies equally to both breasts [11], and the effect of surgical excision on the risk associated with radial scar is unknown. In our series, one patient (3%) developed a 3-mm focus of intermediate-grade DCIS, strongly estrogen receptor-positive, in the same quadrant of the ipsilateral breast 72 months after excision of a benign radial scar. Miller et al. reported three breast cancers (3%) within 30e62 months of follow-up after excision of radial scar [24]. The two invasive carcinomas in that study developed in patients with concurrent contralateral invasive carcinoma or ductal carcinoma at the time of the core biopsy diagnosis of radial scar. Another limitation of many breast core biopsy studies is the lack of follow-up for patients who did not undergo surgery. In this series, one (4%) patient with an un-excised benign radial scar on core biopsy was diagnosed with high-grade ductal carcinoma in situ 16 months later. However, this patient was followed up for suspicious calcifications elsewhere in the same breast and the subsequent core biopsy with ductal carcinoma was from a separate area of calcifications. Conlon et al. reported one case (2%) of ductal carcinoma in situ 78 months after the core biopsy diagnosis of a benign radial scar in a patient who did not undergo immediate excision [25]. In
Table 4 Clinical and radiologic follow-up for radial scars diagnosed on core biopsy that were not immediately excised.
Brenner et al., 2002 [15] Becker et al., 2006 [16] Resetkova et al., 2011 [19] Miller et al., 2014 [24] This study
Core biopsies
Follow-up period
Carcinoma (%)
DCIS
IMC
55 47 61 25 23
38 47 32 79 53
0 0 0 1 1
0 0 0 1 1
0 0 0 0 0
months months months months months
(median) (mean) (mean) (median) (median)
(0%) (0%) (0%) (4%)a (4%)b
Abbreviations: DCIS, ductal carcinoma in situ; IMC, invasive mammary carcinoma. a 3-mm DCIS in a patient with a radial scar and a high-risk lesion, no upgrade in benign radial scars. b DCIS developed at a separate site of suspicious calcifications.
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
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that case, the ductal carcinoma in situ occurred in an area distant from the radial scar core biopsy site. With a median follow-up period of 79 months, Miller et al. reported that one out of 25 patients who did not undergo excision had a 3-mm focus of low-grade ductal carcinoma in situ in a later excision [24]. However, that patient had a high-risk lesion associated with the radial scar. Other studies with short-term follow-up of radial scars that have not been excised have shown no upgrades (Table 4). The exact nature of the relationship between radial scar and neoplasia remains poorly understood. Molecular studies of radial scars have demonstrated some features that are similar to invasive carcinomas [34,35]. Data from the Nurses' Health Study suggested the carcinomas that develop in patients with radial scar may be more likely to be hormone receptor-negative [14]. However, a recent study identified gene mutations in radial scars that are particularly prevalent in luminal-type, hormone receptor-positive breast cancers [36]. Further studies are required to more clearly establish the link between radial scar and carcinoma. The data from our series and others [19,25,28,37] suggest that a subset of patients with radial scars may safely forego excision, especially in the absence of coexisting high-risk lesions or other indications for excision. The detection of high-risk lesions in 16% of the cases of excised benign radial scar in our series could have implications for risk stratification and chemoprevention with selective estrogen receptor modulators or aromatase inhibitors. However, the available data indicate that selective estrogen receptor modulators may be infrequently prescribed and taken by patients in this setting [38e41] and there is no proven survival benefit from chemoprevention [42]. Our findings would support the emerging consensus that patients diagnosed with benign radial scars on core biopsy, especially if they are incidental, may not require immediate surgical excision and could continue routine clinical and mammographic follow-up [43,44]. In the future, it may be possible to tailor the management of patients with radial scars to the most relevant clinical, radiologic, and histologic features of the lesion. Patients with non-palpable, screen-detected, small (5mm) [28] radial scars that are not associated with a formal pattern of atypia could be offered surveillance if they are likely to be compliant with clinical and radiologic follow-up. Immediate surgical excision could be recommended for most patients with palpable and/or larger lesions could be offered immediate surgical excision for a more thorough evaluation of the lesion. Surgery remains the recommended management for patients with discordant imaging studies or limited sampling of the radiographic abnormality on core biopsy. Conflict of interest statement The authors declare that they have no conflict of interest. Acknowledgments This study was approved by the Cleveland Clinic Institutional Review Board with a waiver of consent. No specific funding or financial support was provided for this study. Drs. Donaldson, Booth, and Calhoun were involved in the study conception, design, and review of the pathology. Dr. Sieck was involved in the study conception, design, and review of the imaging studies. Dr. Donaldson collected the clinical follow-up data. References [1] Linell F, Ljungberg O, Andersson I. Breast carcinoma. Aspects of early stages, progression and related problems. Acta Pathol Microbiol Scand Suppl 1980: 1e233.
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Breast cancer risk in women with radial scars in benign breast biopsies. Breast Cancer Res Treat 2008;108:167e74. [14] Aroner SA, Collins LC, Connolly JL, Colditz GA, Schnitt SJ, Rosner BA, et al. Radial scars and subsequent breast cancer risk: results from the nurses' health studies. Breast Cancer Res Treat 2013;139:277e85. [15] Brenner RJ, Jackman RJ, Parker SH, Evans 3rd WP, Philpotts L, Deutch BM, et al. Percutaneous core needle biopsy of radial scars of the breast: when is excision necessary? AJR Am J Roentgenol 2002;179:1179e84. [16] Becker L, Trop I, David J, Latour M, Ouimet-Oliva D, Gaboury L, et al. Management of radial scars found at percutaneous breast biopsy. Can Assoc Radiol J 2006;57:72e8. [17] Cawson JN, Malara F, Kavanagh A, Hill P, Balasubramanium G, Henderson M. Fourteen-gauge needle core biopsy of mammographically evident radial scars: is excision necessary? Cancer 2003;97:345e51. pez-Medina A, Cintora E, Múgica B, Opere E, Vela AC, Iban ~ ez T. 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[22] Bianchi S, Giannotti E, Vanzi E, Marziali M, Abdulcadir D, Boeri C, et al. Radial scar without associated atypical epithelial proliferation on image-guided 14gauge needle core biopsy: analysis of 49 cases from a single-centre and review of the literature. Breast 2012;21:159e64. [23] Osborn G, Wilton F, Stevens G, Vaughan-Williams E, Gower-Thomas K. A review of needle core biopsy diagnosed radial scars in the welsh breast screening programme. Ann R Coll Surg Engl 2011;93:123e6. [24] Miller CL, West JA, Bettini AC, Koerner FC, Gudewicz TM, Freer PE, et al. Surgical excision of radial scars diagnosed by core biopsy may help predict future risk of breast cancer. Breast Cancer Res Treat 2014;145:331e8. [25] Conlon N, D'Arcy C, Kaplan JB, Bowser ZL, Cordero A, Brogi E, et al. Radial scar at image-guided needle biopsy: is excision necessary? Am J Surg Pathol 2015;39:779e85. [26] Hilson JB, Schnitt SJ, Collins LC. Phenotypic alterations in myoepithelial cells associated with benign sclerosing lesions of the breast. Am J Surg Pathol 2010;34:896e900. [27] de Moraes Schenka NG, Schenka AA, de Souza Queiroz L, de Almeida Matsura M, Alvarenga M, Vassallo J. P63 and cd10: reliable markers in discriminating benign sclerosing lesions from tubular carcinoma of the breast? Appl Immunohistochem Mol Morphol 2006;14:71e7. [28] Matrai C, D'Alfonso TM, Pharmer L, Drotman MB, Simmons RM, Shin SJ. Advocating nonsurgical management of patients with small, incidental radial scars at the time of needle core biopsy: a study of 77 cases. Arch Pathol Lab Med 2015;139:1137e42.
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A.R. Donaldson et al. / The Breast xxx (2016) 1e7 [29] Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146e51. [30] London SJ, Connolly JL, Schnitt SJ, Colditz GA. A prospective study of benign breast disease and the risk of breast cancer. Jama 1992;267:941e4. [31] 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: 229e37. [32] Nizri E, Schneebaum S, Klausner JM, Menes TS. Current management practice of breast borderline lesionseneed for further research and guidelines. Am J Surg 2012;203:721e5. [33] Georgian-Smith D, Lawton TJ. Variations in physician recommendations for surgery after diagnosis of a high-risk lesion on breast core needle biopsy. AJR Am J Roentgenol 2012;198:256e63. [34] Jacobs TW, Schnitt SJ, Tan X, Brown LF. Radial scars of the breast and breast carcinomas have similar alterations in expression of factors involved in vascular stroma formation. Hum Pathol 2002;33:29e38. [35] Iqbal M, Shoker BS, Foster CS, Jarvis C, Sibson DR, Davies MP. Molecular and genetic abnormalities in radial scar. Hum Pathol 2002;33:715e22. [36] Wolters KL, Ang D, Warrick A, Beadling C, Corless CL, Troxell ML. Frequent pik3ca mutations in radial scars. Diagn Mol Pathol 2013;22:210e4. [37] Sohn VY, Causey MW, Steele SR, Keylock JB, Brown TA. The treatment of radial scars in the modern eraesurgical excision is not required. Am Surg 2010;76: 522e5.
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[38] Ropka ME, Keim J, Philbrick JT. Patient decisions about breast cancer chemoprevention: a systematic review and meta-analysis. J Clin Oncol 2010;28: 3090e5. [39] Waters EA, McNeel TS, Stevens WM, Freedman AN. Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010. Breast Cancer Res Treat 2012;134:875e80. [40] Taylor R, Taguchi K. Tamoxifen for breast cancer chemoprevention: low uptake by high-risk women after evaluation of a breast lump. Ann Fam Med 2005;3:242e7. [41] Port ER, Montgomery LL, Heerdt AS, Borgen PI. Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol 2001;8: 580e5. [42] Cuzick J, Sestak I, Cawthorn S, Hamed H, Holli K, Howell A, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the ibis-i breast cancer prevention trial. Lancet Oncol 2015;16:67e75. [43] Degnim AC, King TA. Surgical management of high-risk breast lesions. Surg Clin North Am 2013;93:329e40. [44] Neal L, Sandhu NP, Hieken TJ, Glazebrook KN, Mac Bride MB, Dilaveri CA, et al. Diagnosis and management of benign, atypical, and indeterminate breast lesions detected on core needle biopsy. Mayo Clin Proc 2014;89:536e47.
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Original article
Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management Alana R. Donaldson a, Leah Sieck b, Christine N. Booth a, Benjamin C. Calhoun a, * a b
Robert J. Tomsich Pathology and Laboratory Medicine Institute, Department of Pathology, Cleveland Clinic, Cleveland, OH, USA Imaging Institute, Department of Breast Imaging, Cleveland Clinic, Cleveland, OH, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 March 2016 Received in revised form 3 June 2016 Accepted 4 June 2016 Available online xxx
Aims: The risk of finding carcinoma in excisions following a core needle biopsy diagnosis of radial scar is not well defined and clinical management is variable. The aim of this study is to determine the frequency of high-risk lesions, ductal carcinoma in situ, and invasive carcinoma in excisions following a core biopsy diagnosis of radial scar. Methods and results: Dedicated breast pathologists and radiologists correlated the histologic and radiologic findings and categorized radial scars as the target lesion or an incidental finding. High-risk lesions were defined as atypical hyperplasia or classical lobular carcinoma in situ. Of the 79 radial scars identified over a 14-year period, 22 were associated with atypia or carcinoma in the core biopsy. Thirty-seven (37) of the 57 benign radial scars underwent excision with benign findings in 30 (81%), high-risk lesions in six (16%), and flat epithelial atypia in one (3%). There were no upgrades to carcinoma. One patient with a benign radial scar developed a 3-mm focus of intermediate-grade estrogen receptor-positive ductal carcinoma in situ in the same quadrant of the ipsilateral breast 72 months after excision. One patient with an incidental un-excised benign radial scar was diagnosed with ductal carcinoma in situ at a separate site of suspicious calcifications. Conclusions: In this series, none of the benign radial scars was upgraded to carcinoma. Radial scar was the targeted lesion in all cases with high-risk lesions on excision. Surgical excision may not be mandatory for patients with benign incidental radial scars on core biopsy. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Breast Screening Diagnosis Core biopsy Radial scar Pathology
Introduction Radial scars of the breast are uncommon findings in breast biopsies and are characterized by a central focus of fibroelastotic stroma with adenotic epithelial elements radiating outward [1]. The stellate appearance of radial scars may mimic carcinoma mammographically and histologically [2,3]. Some early studies suggested that radial scars were more common in women with breast cancer [4], while subsequent studies found no significant difference in the frequency of radial scars in women with and without breast cancer [5,6]. The observation that radial scars may
* Corresponding author. Robert J. Tomsich Pathology and Laboratory Medicine Institute, Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Mail Code L25, Cleveland, OH 44195, USA. Tel.: þ1 (216) 636 9914; fax: þ1 (216) 445 3707. E-mail addresses: [email protected] (A.R. Donaldson), [email protected] (L. Sieck), [email protected] (C.N. Booth), [email protected] (B.C. Calhoun).
contain carcinoma also suggested a relationship between radial scars and breast cancer [7e10]. An initial report from the Nurses' Health Study provided evidence that radial scars were an independent risk factor for the development of carcinoma [11]. Subsequent studies from the Nashville (Sanders et al. [12]) and Mayo cohorts (Berg et al. [13]) failed to confirm this finding. In an updated analysis of the Nurses' Health Study, the risk associated with radial scars in proliferative disease categories was attenuated but remained statistically significant [14]. In the Nashville cohort, the risk of developing invasive carcinoma after a diagnosis of radial scars was 3.4% in the first 10 years, compared with 1.6% for patients without a radial scar [12]. The long-term follow-up studies of the Nashville cohort, the Mayo cohort, and the Nurse's Health Study included patients with open biopsies, many of which were performed in the premammographic era. With the widespread use of percutaneous core needle biopsy (CNB) of the breast, attention has shifted to the risk of finding carcinoma in an excision specimen following a core biopsy diagnosis of radial scar. Studies correlating core biopsy
http://dx.doi.org/10.1016/j.breast.2016.06.007 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
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A.R. Donaldson et al. / The Breast xxx (2016) 1e7
diagnoses of radial scar with final pathology after surgery have shown variable results with the frequency of invasive mammary carcinoma and ductal carcinoma in situ on excision ranging from 0% to 40% [8,15e23]. However, recent studies with careful radiologyepathology correlation suggest that upgrade to carcinoma occurs in 2% of cases with radial scars on core biopsy [24,25]. The objective of this study was to determine the frequency of high-risk lesions (defined as atypical ductal hyperplasia or atypical lobular hyperplasia/classical lobular carcinoma in situ) and carcinoma in a series of excision specimens following a diagnosis of radial scar on core biopsy. Materials and methods This study was approved by the Cleveland Clinic Institutional Review Board. Breast core biopsies with a diagnosis of radial scar or complex sclerosing lesion from January 1, 2000, to March 26, 2014, were retrieved from the Anatomic Pathology information system CoPathPlus (Cerner Corporation, Kansas City, MO) using the search terms “radial scar,” “complex sclerosing lesion,” and “breast.” For the purposes of this study, radial scars and complex sclerosing lesions were combined and referred to as radial scar. At low power, lesions were characterized by a stellate appearance (Fig. 1A) with a central focus of fibroelastotic stroma containing entrapped benign epithelial elements apparent at higher magnification (Fig. 1B). A total of 79 core biopsies with radial scars were initially identified. Thirty-five (35) of the 79 cases had no excision/no correlation with the site of core biopsy (19), missing slides (11), or missing core biopsy slides and were not excised (5). The data were analyzed for the entire group of 79 patients as well as for the 44 patients with excisions and available slides for both the core biopsy and the corresponding excision. Statistical analysis (Fischer's exact test and Pearson's correlation coefficient) was performed using JMP® software version 10.0.2 (SAS Statistical Institute, Inc., Cary, NC, USA). The indications for core biopsy and patient age at biopsy were recorded for all cases. Biopsies of mammographic findings such as asymmetry (a finding only seen on one mammographic projection), calcifications, or architectural distortion without a corresponding sonographic finding were performed with a stereotactic technique using a dedicated prone stereotactic biopsy table and a Suros ATEC (Hologic, Inc., Marlborough, MA) or an Eviva (Hologic, Inc., Marlborough, MA, USA) 12-gauge core biopsy device. Routinely, at least six to 12 core specimens were obtained, with additional specimens obtained at the discretion of the radiologist. Biopsies of sonographic findings such as masses were performed free hand with a 14-gauge core biopsy device (C. R. Bard, Inc., Tempe, AZ). Biopsy specimens of magnetic resonance imaging (MRI) findings were
obtained using a nine-gauge vacuum assisted core biopsy device (Suros ATEC, Hologic, Inc., Marlborough, MA, USA) with a 1.5T magnet (Siemens Symphony, Siemens Medical Solutions, Malvern, PA, USA). Specimen radiography was completed on all CNBs performed for calcifications. Clips were placed after the core specimens were obtained and post-clip mammography was performed for all biopsies. Radial scars were classified as incidental if they were not a part of the targeted lesion as determined from the radiology report or patient's imaging. Radial scars were considered the targeted lesion if pre-biopsy imaging showed a spiculated mass or architectural distortion and there was no separate coexisting mass-forming lesion in the core biopsy or excision specimen. If the targeted lesion was a calcification and the radial scar was not reported to contain calcification, the radial scar was regarded as incidental. According to the protocol at our institution, all radial scars found on core biopsy, whether they were the targeted lesion or incidental, were referred for evaluation by a surgeon. The patients who underwent surgery had a wire localization of the biopsy site prior to surgery and the biopsy site was identified in the excision specimens. The surgical pathology findings were correlated with the imaging findings and the largest size of the radial scar in either the core biopsy or the excision specimen was recorded. All available surgical pathology reports for excision specimens following a core biopsy diagnosis of radial scar alone were reviewed. The presence and location of calcifications were included in the pathology reports for the core biopsy and the excisions. The submitted sections for all of the excision specimens included biopsy sites. Each core biopsy was individually correlated with a corresponding excision specimen when possible. The presence of atypical ductal hyperplasia, atypical lobular hyperplasia, classical lobular carcinoma in situ, flat epithelial atypia, ductal carcinoma in situ, and invasive mammary carcinoma in the core biopsy and excisions was recorded. For all cases, the presence and type of coexisting (in the same core) or concurrent (in a concurrent ipsilateral core biopsy) atypia or carcinoma was recorded. High-risk lesions were defined as atypical ductal hyperplasia or atypical lobular hyperplasia/classical lobular carcinoma in situ. An upgrade to carcinoma was defined as invasive mammary carcinoma or ductal carcinoma in situ in the excision specimen. Clinical follow-up and chemoprevention data were obtained from the electronic medical record. For patients who underwent immediate surgical excision, the follow-up interval was calculated from the date of excision to the date of the most recent mammogram or progress note from a breast oncologist or primary care physician. For patients who did not have surgery, the follow-up interval was calculated from the date of core biopsy to the date of
Fig. 1. Representative images of a radial scar diagnosed on core biopsy, hematoxylin and eosin stain (a and b at 40 and 100 magnification, respectively).
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
A.R. Donaldson et al. / The Breast xxx (2016) 1e7
the most recent mammogram or progress note from a breast oncologist or primary care physician. Results A total of 79 core biopsies with radial scars were initially identified (Table 1). For the entire cohort, the mean and median ages were 52 and 54 years, respectively (range 34e79). The indications for biopsy were mass or architectural distortion in 45 (57%), calcifications in 22 (28%), and MRI findings in 12 (15%). There were 49 (62%) ultrasound-guided, 25 (32%) stereotactic, and five (6%) MRIguided core biopsies. The radial scar was the targeted lesion in 64 (81%) cases. Of the 79 core biopsies with radial scars, 22 (28%) had atypia or carcinoma in the same core and 57 (72%) did not (Fig. 2). Patients with atypia or carcinoma on core biopsy with radial scars tended to be older and more likely to undergo excision (Table 1). There were no significant differences in the indication for core biopsy, type of core biopsy, or history of concurrent ipsilateral or contralateral breast cancer. Thirty-seven (65%) of the benign radial scars underwent excision with benign findings in 30 (81%),
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high-risk lesions in six (16%), and flat epithelial atypia in one (3%). None of the benign radial scars, targeted or incidental, was upgraded to carcinoma on excision. Twenty-one (95%) of the radial scars with atypia or carcinoma underwent excision with the following results: benign findings in nine (43%), high-risk lesions in five (24%), ductal carcinoma in situ in five (24%), and invasive carcinoma in two (9%). The radial scar was the targeted lesion in all the cases with a high-risk lesion on excision. A subset of 44 (56%) core biopsies with available slides for both the core biopsy and the corresponding excision was also analyzed (Fig. 3). The findings were similar to those for the entire cohort of 79 patients. This subset excludes 35 (44%) of the 79 cases that had no excision/no correlation with the site of core biopsy (19, 24%), missing slides (11, 14%), or missing core biopsy slides and were not excised (5, 6%). Of these 44 cases, 10 (23%) radial scars were associated with atypia and four (9%) were associated with carcinoma. Surgical excision of the 10 core biopsies with atypia revealed ductal carcinoma in situ in 1/10 (10%), high-risk lesions in 3/10 (30%), and benign findings in 6/10 (60%). Surgical excision of the 30 (68%) benign radial scars revealed high-risk lesions in five (17%) and
Table 1 Clinicopathologic features of patients with RS on breast core biopsy, as median (range) or n (%). Total cohort n ¼ 79 (100%) Patient characteristics Age, yearsb Concurrent ipsilateral breast cancer Concurrent contralateral breast cancer Indication for core biopsy Architectural distortion/mass Calcifications MRI enhancement Type of core biopsy Stereotactic Ultrasound MRI-guided Correlation with imaging Targeted RS Surgical excisions HRL IMC or DCIS
RS e no atypia or carcinoma 57 (72%)
RS e atypia or carcinoma 22 (28%)
P valuea
50 (34e71) 2 (4%) 7 (12%)
58 (40e79) 1 (4%) 1 (4%)
P ¼ 0.01* P > 0.99 P ¼ 0.43
31 (55%) 15 (26%) 11 (19%)
14 (64%) 7 (32%) 1 (4%)
P ¼ 0.61 P ¼ 0.78 P ¼ 0.16
16 (28%) 37 (65%) 4 (7%)
9 (41%) 12 (55%) 1 (4%)
P ¼ 0.29 P ¼ 0.44 P > 0.99
47 (82%) 37 (65%) 6 (11%) 0 (0%)
17 (77%) 21 (95%) 5 (23%) 7 (32%)
P P P P
¼ 0.75 ¼ 0.005* ¼ 0.50 < 0.001*
Abbreviations: MRI, magnetic resonance imaging; RS, radial scar; HRL, high-risk lesion; DCIS, ductal carcinoma in situ; IMC, invasive mammary carcinoma. *Statistically significant P < 0.05. a Fisher's exact test for categorical variables. b Analyzed as a continuous variable.
RS Core Biopsies (79)
No Atypia or Carcinoma on Core (57)
No excision (20)
Atypia or Carcinoma on Core (22)
Excision (37)
No excision (1)
Excision (21)
Benign (30)
Benign (9)
HRL (6)
HRL (5)
FEA (1)
DCIS (5)
IMC or DCIS (0)
IMC (2)
Fig. 2. Outcomes of patients with radial scars diagnosed on breast core biopsy. Abbreviations: RS, radial scar; HRL, high-risk lesion; FEA, flat epithelial atypia; DCIS, ductal carcinoma in situ; IMC, invasive mammary carcinoma.
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
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A.R. Donaldson et al. / The Breast xxx (2016) 1e7
RS Core Biopsies (79)
Not Excised or Slides Unavailable (35)
Complete Pathology Slide Review (44)
No Atypia or Carcinoma on Core (30)
Atypia or Carcinoma Present on Core (14)
Excision
Excision
Benign (25)
Benign (6)
HRL (5)
HRL (3)
IMC or DCIS (0)
DCIS (4)
IMC (1) Fig. 3. Outcomes of patients with radial scars diagnosed on breast core biopsy with a complete pathology slide review. Abbreviations: RS, radial scar; HRL, high-risk lesion; DCIS, ductal carcinoma in situ; IMC, invasive mammary carcinoma.
benign findings in 25 (83%). None of the benign radial scars, targeted or incidental, was upgraded to carcinoma on excision. The radial scar was the targeted lesion in all cases with high-risk lesions on excision. Clinical, pathologic, and radiologic data for patients with benign radial scars on core biopsy, who had high-risk lesions on excision, are listed in Table 2. The indication for core biopsy in all of the patients with high-risk lesions was the presence of a mass on imaging studies and all of those patients had 14-gauge ultrasound core biopsies. None of the patients with a benign radial scar on a stereotactic (12-gauge) or MRI-guided (nine-gauge) core biopsy was upgraded to a high-risk lesion. For the 30 benign radial scars on CNB, the mean and median sizes were 7.2 and 6 mm, respectively (range 3e12 mm). The benign radial scars on CNB with high-risk lesions on excision were measured to be 4, 5, 9, 10, and 11 mm each. The patient with a 5-mm benign radial scar on CNB and a high-risk lesion on excision had concurrent ipsilateral ductal carcinoma in situ (DCIS) with microinvasion. The patient with a 4-mm benign radial scar on CNB and a high-risk lesion on excision also had extensive sclerosing adenosis in the excision specimen. Clinical follow-up information was available for 39 of the 44 cases with excisions and complete slide reviews with a mean and median of 54 and 68 months, respectively (range 14e166). Follow-
up was unavailable for three patients, and two patients died of other causes 57 and 72 months after excision of the radial scar. No patients developed invasive carcinoma over this follow-up period. One patient (3%) with a benign radial scar on core biopsy developed a 3-mm focus of intermediate-grade estrogen receptor-positive ductal carcinoma in situ 72 months after excision. This patient did not have a history of concurrent ipsilateral or contralateral breast cancer. The ductal carcinoma in situ was located in the same quadrant of the ipsilateral breast as the core biopsy site. A total of eight out of 44 (18%) patients received selective estrogen receptor modulators for chemoprevention. Two of these patients were placed on chemoprevention solely on the basis of high-risk lesion found on excision of a benign radial scar: one received tamoxifen for a diagnosis of atypical ductal hyperplasia and the other received raloxifene for atypical lobular hyperplasia. Clinical follow-up was available for 23 out of 27 patients who did not undergo surgery (20 patients) or whose benign radial scar slides were not available for review (7 patients) with a median and mean of 29 and 53 months, respectively (range 3e165). None of these patients developed invasive carcinoma. One patient (4%) with an un-excised benign radial scar was diagnosed with high-grade ductal carcinoma in situ in the same breast 16 months later. The
Table 2 Clinical, pathologic, and radiologic data for patients with benign RS on core biopsy and HRL on excision. Patient
Indication for biopsy
Type of core biopsy
Surgical excision pathology
Concurrent ipsilateral/contralateral breast cancer
1 2 3 4 5
Mass Mass Mass Mass Mass
Ultrasound-guided Ultrasound-guided Ultrasound-guided Ultrasound-guided Ultrasound-guided
ADH ADH ALH LCIS LCIS
No Concurrent ipsilateral DCIS with microinvasion No Concurrent contralateral IMC No
Abbreviations: RS, radial scar; HRL, high-risk lesion; ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ; IMC, invasive mammary carcinoma.
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
A.R. Donaldson et al. / The Breast xxx (2016) 1e7 Table 3 Selected studies: Benign radial scars on core biopsy with outcomes on excision. Core biopsies
Pathology on excision HRL
Miller et al., 2014 [24] Conlon et al., 2015 [25] Matrai et al., 2014 [28] This study Total
102 48 77 37 264
22 12 9 6 49/264
Carcinoma (22%) (25%)a (12%) (16%) (19%)
1 1 0 0 2/264
(1%) (2%) (0%) (0%) (1%)
Abbreviations: HRL, high-risk lesions: atypical hyperplasia or lobular carcinoma in situ. a A combined category of epithelial atypia (atypical hyperplasia, lobular carcinoma in situ, flat epithelial atypia, and atypical apocrine adenosis) was reported in 23%.
initial core biopsy was performed for indeterminate calcifications, and based on the association of calcifications with other findings in the excision specimen, the radial scar was regarded as incidental. Suspicious calcifications in other locations in the same breast were followed up with mammography and a subsequent core biopsy at another site revealed high-grade ductal carcinoma in situ. The patient underwent a unilateral mastectomy and was placed on tamoxifen. This patient very likely did not undergo immediate excision because the radial scar was incidental and other foci of calcifications required clinical and radiologic surveillance. Discussion In this single-institutional review over a 14-year period, we identified 79 cases of radial scar diagnosed on core biopsy, corresponding to <1% of core biopsies. The expected frequency of radial scars on core biopsies specifically is not well established. In the largest caseecontrol studies of open biopsies, approximately 5e9% of patients had radial scars [12e14]. In the series reported by Miller et al., 1.5% of core biopsies over a 16-year period had radial scars [24]. Despite being uncommon, radial scars remain important in the management of breast disease because of their association with breast cancer risk [14] and the potential for misinterpretation by pathologists as low-grade invasive ductal or tubular carcinoma [3]. The use of immunohistochemical markers for myoepithelial cells can be helpful in differentiating radial scars from invasive carcinoma [26,27]. None of the benign radial scars in this series with follow-up excisions had carcinoma when core biopsies with atypia or carcinoma were excluded. Of a total of 37 benign radial scars on core biopsy, six (16%) showed high-risk lesions on excision. These findings are similar to other recent studies with detailed radiologicepathologic correlation (Table 3). In a recent series of 102 benign radial scars on core biopsy, 1% of cases were upgraded to carcinoma and 21.6% had high-risk lesions on excision [24]. In a series of 77 incidental radial scars measuring 5 mm, as reported by Matrai et al., none was upgraded to carcinoma and nine (12%)
5
had high-risk lesions on excision [28]. Conlon et al. reported that one out of 48 cases (2%) was upgraded to carcinoma on excision and 12 cases (25%) contained high-risk lesions or other types of epithelial atypia [25]. The single upgraded case was a 2-mm focus of low-grade ductal carcinoma in situ in a background of atypical ductal hyperplasia in a patient who had a separate focus of ductal carcinoma in situ (excised separately) in the ipsilateral breast. In a meta-analysis including their data and 20 published studies of radial scars diagnosed on core biopsy, Conlon et al. found an overall upgrade rate of 7.5% for radial without high-risk lesions or flat epithelial atypia [25]. Importantly, most of the upgrades in these series were ductal carcinoma in situ and the invasive carcinomas tended to be low-grade ductal or tubular type. The lower upgrade rates observed in this and other recent studies (Table 3) are presumably related to careful radiologyepathology correlation. The mean size of the benign radial scar in our series (6 mm) also may have contributed to the lower rate of upgrade to carcinoma. Two distinct, but presumably related, categories of risk require consideration in patients with high-risk lesions. In the largest caseecontrol studies, the risk associated with various types of benign breast disease was defined as the relative risk of the patient developing a subsequent carcinoma (in either breast, usually 10e15 years after an open biopsy) [29e31]. With the routine use of percutaneous CNB, the risk of finding a carcinoma on excision has become a more immediate concern. Patients with a core biopsy diagnosis of radial scar are often offered surgery based on concerns regarding the risk of finding carcinoma in adjacent tissue, but recommendations and clinical management are quite variable [32,33]. Unfortunately, there are no large long-term studies of radial scar diagnosed on core biopsy with follow-up comparable to the prior studies of open biopsies. The risk associated with radial scars in the larger caseecontrol studies applies equally to both breasts [11], and the effect of surgical excision on the risk associated with radial scar is unknown. In our series, one patient (3%) developed a 3-mm focus of intermediate-grade DCIS, strongly estrogen receptor-positive, in the same quadrant of the ipsilateral breast 72 months after excision of a benign radial scar. Miller et al. reported three breast cancers (3%) within 30e62 months of follow-up after excision of radial scar [24]. The two invasive carcinomas in that study developed in patients with concurrent contralateral invasive carcinoma or ductal carcinoma at the time of the core biopsy diagnosis of radial scar. Another limitation of many breast core biopsy studies is the lack of follow-up for patients who did not undergo surgery. In this series, one (4%) patient with an un-excised benign radial scar on core biopsy was diagnosed with high-grade ductal carcinoma in situ 16 months later. However, this patient was followed up for suspicious calcifications elsewhere in the same breast and the subsequent core biopsy with ductal carcinoma was from a separate area of calcifications. Conlon et al. reported one case (2%) of ductal carcinoma in situ 78 months after the core biopsy diagnosis of a benign radial scar in a patient who did not undergo immediate excision [25]. In
Table 4 Clinical and radiologic follow-up for radial scars diagnosed on core biopsy that were not immediately excised.
Brenner et al., 2002 [15] Becker et al., 2006 [16] Resetkova et al., 2011 [19] Miller et al., 2014 [24] This study
Core biopsies
Follow-up period
Carcinoma (%)
DCIS
IMC
55 47 61 25 23
38 47 32 79 53
0 0 0 1 1
0 0 0 1 1
0 0 0 0 0
months months months months months
(median) (mean) (mean) (median) (median)
(0%) (0%) (0%) (4%)a (4%)b
Abbreviations: DCIS, ductal carcinoma in situ; IMC, invasive mammary carcinoma. a 3-mm DCIS in a patient with a radial scar and a high-risk lesion, no upgrade in benign radial scars. b DCIS developed at a separate site of suspicious calcifications.
Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007
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A.R. Donaldson et al. / The Breast xxx (2016) 1e7
that case, the ductal carcinoma in situ occurred in an area distant from the radial scar core biopsy site. With a median follow-up period of 79 months, Miller et al. reported that one out of 25 patients who did not undergo excision had a 3-mm focus of low-grade ductal carcinoma in situ in a later excision [24]. However, that patient had a high-risk lesion associated with the radial scar. Other studies with short-term follow-up of radial scars that have not been excised have shown no upgrades (Table 4). The exact nature of the relationship between radial scar and neoplasia remains poorly understood. Molecular studies of radial scars have demonstrated some features that are similar to invasive carcinomas [34,35]. Data from the Nurses' Health Study suggested the carcinomas that develop in patients with radial scar may be more likely to be hormone receptor-negative [14]. However, a recent study identified gene mutations in radial scars that are particularly prevalent in luminal-type, hormone receptor-positive breast cancers [36]. Further studies are required to more clearly establish the link between radial scar and carcinoma. The data from our series and others [19,25,28,37] suggest that a subset of patients with radial scars may safely forego excision, especially in the absence of coexisting high-risk lesions or other indications for excision. The detection of high-risk lesions in 16% of the cases of excised benign radial scar in our series could have implications for risk stratification and chemoprevention with selective estrogen receptor modulators or aromatase inhibitors. However, the available data indicate that selective estrogen receptor modulators may be infrequently prescribed and taken by patients in this setting [38e41] and there is no proven survival benefit from chemoprevention [42]. Our findings would support the emerging consensus that patients diagnosed with benign radial scars on core biopsy, especially if they are incidental, may not require immediate surgical excision and could continue routine clinical and mammographic follow-up [43,44]. In the future, it may be possible to tailor the management of patients with radial scars to the most relevant clinical, radiologic, and histologic features of the lesion. Patients with non-palpable, screen-detected, small (5mm) [28] radial scars that are not associated with a formal pattern of atypia could be offered surveillance if they are likely to be compliant with clinical and radiologic follow-up. Immediate surgical excision could be recommended for most patients with palpable and/or larger lesions could be offered immediate surgical excision for a more thorough evaluation of the lesion. Surgery remains the recommended management for patients with discordant imaging studies or limited sampling of the radiographic abnormality on core biopsy. Conflict of interest statement The authors declare that they have no conflict of interest. Acknowledgments This study was approved by the Cleveland Clinic Institutional Review Board with a waiver of consent. No specific funding or financial support was provided for this study. Drs. Donaldson, Booth, and Calhoun were involved in the study conception, design, and review of the pathology. Dr. Sieck was involved in the study conception, design, and review of the imaging studies. Dr. Donaldson collected the clinical follow-up data. References [1] Linell F, Ljungberg O, Andersson I. Breast carcinoma. Aspects of early stages, progression and related problems. Acta Pathol Microbiol Scand Suppl 1980: 1e233.
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Please cite this article in press as: Donaldson AR, et al., Radial scars diagnosed on breast core biopsy: Frequency of atypia and carcinoma on excision and implications for management, The Breast (2016), http://dx.doi.org/10.1016/j.breast.2016.06.007