complex sclerosing lesions: a clinicopathologic correlation study from a single institution

Annals of Diagnostic Pathology 19 (2015) 24–28

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Annals of Diagnostic Pathology

Radial scar/complex sclerosing lesions: a clinicopathologic correlation study from a single institution☆,☆☆ Aziza Nassar, MD a,⁎, Amy L. Conners, MD b, Betul Celik, MD a, Sarah M. Jenkins, MS c, Carin Y. Smith, BS c, Tina J. Hieken, MD d a

Department of Pathology and Laboratory Medicine, Mayo Clinic, Jacksonville, FL Department of Radiology, Mayo Clinic, Rochester, MN Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN d Division of Subspecialty General Surgery, Mayo Clinic, Rochester, MN b c

a r t i c l e

i n f o

Keywords: Breast cancer Core needle biopsy Excisional biopsy Radial scar Upstage

a b s t r a c t Radial scars (RSs) or complex sclerosing lesions (CSLs) of the breast are benign radiologic and histologic entities. With the introduction of population-based screening programs, their incidence has increased to 0.03% to 0.09% of all core needle biopsies (CNBs). They can pose diagnostic difficulty because their radiologic and histologic appearances mimic carcinoma. We retrospectively searched for and reviewed all cases of RS/CSL diagnosed on image-guided CNB from January 1, 1994, to August 31, 2013, at a single institution. We also assessed the pathologic reports from excisional biopsies to identify cases upstaged to atypia or neoplasm. After exclusions, 100 CNBs were identified from 97 women, which showed RS/CSL without concomitant atypia. Mean age of the women was 52.9 years. Thirty-five women (38/100 CNBs, 38%) had follow-up excision. The median size of the excised RS/CSLs was 1.2 cm; 69% were larger than 1.0 cm. Almost all excised cases (92%) showed radiologic and pathologic concordance, and 79% were designated as suspicious for malignancy (Breast Imaging Reporting and Data System level 4). The most common findings of 38 follow-up excisional biopsies were residual RS (22 [58%]), atypical lobular hyperplasia (5 [13%]), and no residual lesion (5 [13%]). Eleven excisional biopsies (29%) were upstaged to invasive or in situ carcinoma or to atypical hyperplasia. Follow-up excisional biopsy is warranted for RS/CSLs, specifically those larger than 1.0 cm with worrisome radiographic findings or with radiologic and pathologic discordance. Approximately 29% of cases were upstaged to in situ or invasive carcinomas or other high-risk lesions in our study. © 2014 Elsevier Inc. All rights reserved.

1. Introduction A radial scar (RS) or complex sclerosing lesion (CSL) is a pathologic entity characterized by a fibroelastotic core with entrapped ducts [1]. Radiologically, it has a radiolucent central core and radiating spicules; it is indistinguishable from invasive carcinoma both mammographically and histopathologically [2,3]. It may be associated with atypical and typical usual epithelial hyperplasia, adenosis, papillomatosis, ductal carcinoma in situ (DCIS), or even invasive carcinoma within or adjacent to RS [2,4]. The incidence of RS is reported as 0.03% to 0.07% [5]. The pathogenesis of RS is uncertain. Reaction to an unknown trauma, which results in scarring with elastosis or inflammation, has been hypothesized [3]. It has been suggested that RS is a premalignant lesion for the development

☆ Portions of this manuscript have been presented and published in abstract form: Mod Pathol. 2014 Feb; 27(S2):70A. ☆☆ Conflict of interest: None. ⁎ Corresponding author. Department of Pathology and Laboratory Medicine, 4500 San Pablo Rd, Jacksonville, FL 32224. Tel.: +1 904 956 3318; fax: +1 904 956 3336. E-mail address: [email protected] (A. Nassar). http://dx.doi.org/10.1016/j.anndiagpath.2014.12.003 1092-9134/© 2014 Elsevier Inc. All rights reserved.

of breast cancer (BC), but coexistent proliferative epithelial lesions have also been proposed to be the underlying causative factors for BC [6,7]. Some groups advocate that all RSs diagnosed on core needle biopsy (CNB) should be excised [2,5,8-13], whereas others do not support surgical excision [14-18]. This study was initiated to characterize RSs and CSLs diagnosed at a single medical center and to define the clinical, mammographic, and histopathologic characteristics in correlation with performance of and findings on follow-up excisional biopsies. 2. Materials and methods Institutional review board approval was obtained to perform the study. We retrospectively searched our anatomical pathology database for the records of patients with a diagnosis of RS or CSL made from CNB findings at our academic medical center between January 1, 1994, and August 31, 2013. We also identified those who had excisional biopsy of the RS/CSL. Cases were excluded if the pathologic diagnosis from CNB was RS/CSL associated with atypical epithelial hyperplasia, lobular neoplasia, DCIS, or malignancy. Patient demographic and clinical characteristics were retrieved from the hospital records. All CNB and excisional biopsy specimens as well as radiologic images were retrieved

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Table 1 Patients' clinical and lesion pathologic characteristics RS/CSL CNBs Characteristic

Total (N = 100)a

No excision (n = 62)

Excision (n = 38)b

P

Age at CNB, y Oral contraceptive use Lesion presentation Mammographic screening Palpable mass Focal breast pain Screening MRI Other Imaging method for RS/CSL measurement MBI MRI Mammography Ultrasonography Mammography findings Architectural distortion + calcifications Architectural distortion Calcifications Mass Mass with calcifications Mass with distortion Occult Other BI-RADS level 3 (probably benign) 4 (suspicious) 5 (highly suggestive of malignancy) Ultrasonography findings Hypoechoic area Hypoechoic area with shadowing Isoechoic/hyperechoic Mass with no shadowing Mass with shadowing Occult Other MRI findings Enhancing mass Nonmass enhancement Occult Other MBI findings Mass moderate uptake Mass shadowing Nonmass marked uptake Nonmass mild uptake Nonmass moderate uptake Occult Laterality Left Right Lesion size, cm CNB needle gauge 9g 11 14 16 No. of cores ≤4 N4

52.9 (11.9) 44/75 (59) n = 96 70 (73) 11 (12) 3 (3) 6 (6) 6 (6) n = 93 1 (1) 12 (13) 30 (32) 50 (54) n = 89 12 (14) 19 (21) 26 (29) 6 (7) 1 (1) 7 (8) 14 (16) 4 (5) n = 30 5 (17) 24 (80) 1 (3) n = 70 9 (13) 12 (17) 1 (1) 23 (33) 13 (19) 10 (14) 2 (3) n = 16 8 (50) 4 (25) 3 (19) 1 (6) n = 11 1 (9) 1 (9) 1 (9) 1 (9) 3 (27) 4 (36) n = 34 19 (56) 15 (44) 1.1 (0.6-1.6) (n = 93) n = 95 20 (21) 28 (30) 41 (43) 6 (6) n = 93 18 (19) 75 (81)

54.6 (11.7) 24/41 (59) n = 62 51 (82) 5 (8) 1 (2) 2 (3) 3 (5) n = 58 0 (0) 4 (7) 26 (45) 28 (48) n = 57 5 (9) 9 (16) 21 (37) 6 (11) 1 (2) 4 (7) 8 (14) 3 (5) n=1 0 (0) 1 (100) 0 (0) n = 37 4 (11) 5 (14) 1 (3) 13 (35) 6 (16) 6 (16) 2 (5) n=6 1 (17) 3 (50) 2 (33) 0 (0) n=2 0 (0) 0 (0) 0 (0) 1 (50) 1 (50) 0 (0) ND

50.2 (11.8) 20/34 (59) n = 34 19 (56) 6 (18) 2 (6) 4 (12) 3 (9) n = 35 1 (3) 8 (23) 4 (11) 22 (63) n = 32 7 (22) 10 (31) 5 (16) 0 (0) 0 (0) 3 (9) 6 (19) 1 (3) n = 29 5 (17) 23 (79) 1 (3) n = 33 5 (15) 7 (21) 0 (0) 10 (30) 7 (21) 4 (12) 0 (0) n = 10 7 (70) 1 (10) 1 (10) 1 (10) n=9 1 (11) 1 (11) 1 (11) 0 (0) 2 (22) 4 (44) n = 34 19 (56) 15 (44) 1.2 (0.7-1.7) (n = 35) n = 36 3 (8) 6 (17) 25 (69) 2 (6) n = 36 6 (17) 30 (83)

.07c .98d .05e

0.9 (0.5-1.5) (n = 58) n = 59 17 (29) 22 (37) 16 (27) 4 (7) n = 57 12 (21) 45 (79)

NA

NA

NA

NA

NA

NA

.04f b.001f

.60d

Values are expressed as mean (SD), number of patients (%), number of patients/number with data available (%), or median (interquartile range). Abbreviations: MBI, molecular breast imaging; MRI, magnetic resonance imaging; NA, not analyzed; ND, no data available. a In 97 women. b In 35 women. c Unequal variance t test. d χ2 Test. e Fisher exact test. f Wilcoxon rank sum test. g Gauges 1 and 2 combined with 9.

and re-evaluated by 2 pathologists (BC and AN) and a radiologist (ALC), respectively. Radiologic results of ultrasonography, mammography, and magnetic resonance imaging were captured and evaluated with the Breast

Imaging Reporting and Data System (BI-RADS) score. Size of the mass was noted from the radiology report, with RS defined as a mass of 1.0 cm or smaller and CSL defined as a mass larger than 1.0 cm. The needle gauge and number of cores obtained during sampling

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A. Nassar et al. / Annals of Diagnostic Pathology 19 (2015) 24–28

were recorded. Core needle biopsy and follow-up excisional biopsy findings were correlated with the diagnosis. Per the histologic criteria developed by Sanders et al [6], findings on follow-up biopsy were classified as residual RS/CSL or associated fibrocystic disease, papillary lesion, atypical epithelial hyperplasia (ductal or lobular), in situ carcinoma (DCIS or lobular carcinoma in situ [LCIS]), or invasive carcinoma and its subtype; the presence of any calcifications was also noted. Patient and lesion characteristics were summarized using number and percentage for categorical variables and mean (SD) or median and range or interquartile range for continuous variables. Characteristics were compared between lesions that did and did not proceed to excision using the t test or Wilcoxon rank sum test for continuous variables and the χ 2 or Fisher exact text for categorical variables. All analyses were performed using SAS software version 9.3 (SAS Institute Inc, Cary, NC). P b .05 was considered statistically significant. 3. Results 3.1. Demographic analysis A total of 109 women were identified with a diagnosis of RS/CSL, without concomitant atypia, on CNB during the study period. Patients were excluded because the excision was done at a site different from the initial CNB (n = 3; 2 had invasive carcinoma at the excised site) or because the patient had known invasive carcinoma 1 week before the biopsy (n = 2), had concurrent cancer (n = 5), or declined the use of their medical records for research purposes (n = 2). The remaining 97 women included in the study had a total of 100 CNBs (3 women had 2 sites examined). Of the 100 CNB samples, 38 cases had follow-up excision (Table 1). Seventy CNBs (73%) were identified through mammographic screening, and 11 (12%) presented as a palpable mass (Table 1). The median size of RS was significantly larger for those with than without follow-up excision (1.2 vs 0.9 cm; P= .04). Core needle biopsy needle gauge also was larger among those with excision (Pb .001) (Table 1). Mean age at CNB of the 35 patients with follow-up excision was 50.2 years (range, 23.0-74.0 years) (Table 1). The median time to surgical excision was 25.5 days, and the median time from excision to follow-up was 4.2 years (range, 26 days to 10.2 years). The median size of the excised RS/CSL was 1.2 cm (range, 0.4-3.3 cm), and approximately two-thirds of excised lesions (24/35) were larger than 1.0 cm. More patients had an RS on the left breast (19 [56%]). 3.2. Pathologic analysis All CNBs showed pure RS/CSL, except 1 with associated flat epithelial atypia. Residual RS/CSL was present in 22 (58%) of 38 patients with follow-up excisional biopsy. There was no residual RS/CSL in 5 patients (13%). Most cases were macroscopic (N5.0 mm) RS (24/32 [75%]), were surrounded by fat (26/32 [81%]), and had stellate shape (29/32 [91%]).

Fig. 1. Low-grade metaplastic adenosquamous carcinoma with infiltrating glands showing squamous differentiation (hematoxylin-eosin, original magnification ×10). On mammography, it appeared as a mass with distortion, and on ultrasonography, it was detected as a mass with shadowing.

Microcalcifications were present in 17 RS (53%), detected on either CNB or excision. Fibrocystic disease was present in 28 (88%) of 32 patients with RS. Of 30 women, 13 (43%) had papilloma associated with RS. Of 30, 12 (40%) had associated flat epithelial atypia/columnar cell change (1 with carcinoma and 3 with high-risk lesions). Of 30 women, 5 (17%) had atypical lobular hyperplasia. A total of 4 (11%) of 38 lesions were upstaged to cancer (DCIS and invasive carcinoma) at excision, and 7 (18%) were upstaged to high-risk lesions (LCIS, atypical lobular hyperplasia, and atypical ductal hyperplasia) at excision (Table 2). The cancerous lesions included 2 (5%) that were characterized as invasive carcinoma (metaplastic and adenoid cystic carcinoma) (Fig. 1) and 2 (5%) characterized as DCIS (Fig. 2). For the high-risk lesions, 1 (3%) was characterized as LCIS; 1 (3%), as atypical ductal hyperplasia; and 5 (13%), as isolated atypical lobular hyperplasia. A total of 9 cases of RS/CSL had equivocal imaging findings, but none of these cases were upstaged on follow-up excisional biopsy. 3.3. Radiologic analysis The pathologic diagnosis had radiologic concordance in 33 (92%) of 36 cases and discordance in only 3 cases (8%). Among those with concordance, 79% (23/29) were designated as BI-RADS level 4 (suspicious for malignancy). The average size of RSs detected by mammographic imaging was 1.31 cm (range, 0.40-3.30 cm). Mean lesion size for cases in which a high-risk lesion was detected was 1.39 cm (range, 0.402.70 cm) and for malignancy was 1.45 cm (range, 1.20-1.90 cm). Almost

Table 2 Clinical, radiologic, and histologic data for RS/CSL cases upstaged at excision Case

Mammographic findings

Sonographic findings

Size, mm

Type of guidance

No. of cores

Needle gauge

Vacuum assistance

Malignancy associated with RS/CSL on excision

1 2 3 4 5 6 7 8 9 10 11

Mass with distortion Architectural distortion Architectural distortion Architectural distortion with calcifications Architectural distortion with calcifications Calcifications Occult Mass with distortion Architectural distortion with calcifications Architectural distortion Occult

Mass with shadowing Mass with no shadowing Hypoechoic area Mass with shadowing Mass with shadowing Not available Mass with shadowing Mass with shadowing Mass with no shadowing Hypoechoic area Mass with no shadowing

23 14 13 20 17 4 10 12 27 25 17

US US MRI US US Mam US US US US US

4 4 12 5 7 4 6 8 8 6 5

16 14 9 14 14 11 14 9 14 9 14

No No Yes No No No No Yes No Yes No

Metaplastic adenosquamous carcinoma Adenoid cystic carcinoma Low-grade apocrine DCIS Low-grade DCIS ALH ALH ALH ALH ALH LCIS ADH

Abbreviations: ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; Mam, mammography; US, ultrasonography.

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Fig. 2. Low-grade apocrine ductal carcinoma in situ showing several duct units with solid proliferation of atypical neoplastic cells with apocrine differentiation (hematoxylin-eosin, original magnification ×10). It appeared as a hypoechoic area on ultrasonography and as an architectural distortion on mammography.

half of the women (51%; 36/70) had a mass with or without shadowing on ultrasound imaging. The mammographic and ultrasonographic imaging features were listed as architectural distortion in 53% (17/32) and hypoechoic nodules with irregular margins in 36% (12/33). 4. Discussion Our study showed that the overall rate of upstaging of RS/CSL was 29% (11/38), with in situ and invasive ductal carcinoma in 11% (4/38). Upstaging was noted more often in women with RS lesions larger than 1.0 cm and in women with worrisome radiologic features. Radial scar was first described by Hamperl [19] in 1975 and later by Eusebi et al [20] in 1976. The incidence rates of RS have been reported as 0.03% and 0.09% in screening populations [3,12]. Lesions smaller than 1.0 cm have been referred to as RS, whereas those larger than 1.0 cm are described as CSL [3]. Radial scar poses diagnostic challenges because of its mammographic similarity to BC and its association with cancer on further excision [2]. In some cohort studies of benign breast disease, RS was not found to be independently associated with an increased risk of BC, and the mild increase in cancer risk was attributed to the frequent association of RS with other proliferative diseases [6,7,21]. In some cases, however, RS has been independently associated with increased risk of BC [7]. Radial scar has been associated with BC [6] and with metaplastic carcinoma in particular [10,22]. This association was also noted in our patients, with 2 of the women with invasive cancer at follow-up having metaplastic carcinoma. Several risk factors have been found to be associated with cancer upstaging of RS, including older age (N50 years), postmenopausal status, larger size of RS on radiography, and presence of atypical hyperplasia within the RS [4,7,9]. The average reported size of RSs associated with cancer is 1.4 cm [2,10,23]. When RS is the targeted lesion, there may be an association with atypical hyperplasia and carcinoma in situ [2,4,7,11]. However, when RS is an incidental microscopic finding, cancer may not be present [2,23]. On follow-up excisional biopsy, RS has been shown to be associated with high-risk lesions such as atypical hyperplasia and in situ and invasive carcinoma [9,15], but the risk of malignancy on follow-up excisional biopsy is not always increased [15]. The rate of upstaging to high-risk lesions and cancer on follow-up excisional biopsies ranges from 3% to 46% in the literature [2,5,6,8-10,12,13,17,18,24]. The rate of atypical hyperplasia in RS ranges from as low as 8% (8/99) [7] to 11% (8/74) [4] to as high as 18.9% (33/175) [11] to 31% (5/16) [2]. The rate of carcinoma in situ in RS ranges from 6% (1/16) [2] to 10% (7/74)

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[4] or higher (10.9% [19/175]) [11]. Invasive carcinoma has been found in 9.1% (16/275) of women with follow-up excisional biopsy [11]. Notably, a survey of members of the American Society of Breast Surgeons revealed that only 50% of respondents would recommend routine excision of RS [25]. In 1 study [14] using a larger gauge needle [8,11] with adequate sampling of RSs, no lesions were upstaged on follow-up surgical excision [15]. Some investigators, therefore, believe that excisional biopsy of RS is not required if the initial CNB is obtained using a large-gauge needle with vacuum-assisted biopsy, specifically if the RS is not associated with atypia on prior needle biopsy and if radiologic and histologic findings are concordant [3,15,17,18]. Sampling a larger number of cores (12 or more) may also result in a lower likelihood of upstaging to cancer [18]. Although some investigators recommend no additional follow-up of women with RS (beyond routine mammographic screening) [26], we believe that the 29% rate of upstaging to high-risk lesions in our patients indicates that follow-up is warranted, specifically if the RS is larger than 1.0 cm and is associated with worrisome radiologic features. This study had several limitations. Our sample size was small, and the study was retrospective. In addition, almost two-thirds of the patients did not have a follow-up excisional biopsy, which precluded the evaluation of outcome in those women. In conclusion, our data support the use of follow-up excisional biopsy to detect or rule out more significant lesions in women with larger RSs (N1.0 cm) and in women with worrisome radiologic findings. Acknowledgment The authors received no financial support for this study. References [1] Eusebi V, Millis RR. Epitheliosis, infiltrating epitheliosis, and radial scar. Semin Diagn Pathol 2010;27(1):5–12. [2] King TA, Scharfenberg JC, Smetherman DH, Farkas EA, Bolton JS, Fuhrman GM. A better understanding of the term radial scar. Am J Surg 2000;180(6):428–32. [3] Loane J. Benign sclerosing lesions of the breast. Diagn Histopathol 2009;15(8): 395–401. [4] Sloane JP, Mayers MM. Carcinoma and atypical hyperplasia in radial scars and complex sclerosing lesions: importance of lesion size and patient age. Histopathology 1993;23(3):225–31. [5] 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(2):123–6 [Epub 2010 Nov 12]. [6] Sanders ME, Page DL, Simpson JF, Schuyler PA, Dale Plummer W, Dupont WD. Interdependence of radial scar and proliferative disease with respect to invasive breast carcinoma risk in patients with benign breast biopsies. Cancer 2006;106(7): 1453–61. [7] Jacobs TW, Byrne C, Colditz G, Connolly JL, Schnitt SJ. Radial scars in benign breastbiopsy specimens and the risk of breast cancer. N Engl J Med 1999;340(6):430–6. [8] Linda A, Zuiani C, Furlan A, Londero V, Girometti R, Machin P, et al. Radial scars without atypia diagnosed at imaging-guided needle biopsy: how often is associated malignancy found at subsequent surgical excision, and do mammography and sonography predict which lesions are malignant? AJR Am J Roentgenol 2010;194 (4):1146–51. [9] Andacoglu O, Kanbour-Shakir A, Teh YC, Bonaventura M, Ozbek U, Anello M, et al. Rationale of excisional biopsy after the diagnosis of benign radial scar on core biopsy: a single institutional outcome analysis. Am J Clin Oncol 2013;36(1):7–11. [10] Morgan C, Shah ZA, Hamilton R, Wang J, Spigel J, Deleon W, et al. The radial scar of the breast diagnosed at core needle biopsy. Proc (Bayl Univ Med Cent) 2012;25(1): 3–5. [11] Patterson JA, Scott M, Anderson N, Kirk SJ. Radial scar, complex sclerosing lesion and risk of breast cancer: analysis of 175 cases in Northern Ireland. Eur J Surg Oncol 2004;30(10):1065–8. [12] Fasih T, Jain M, Shrimankar J, Staunton M, Hubbard J, Griffith CD. All radial scars/ complex sclerosing lesions seen on breast screening mammograms should be excised. Eur J Surg Oncol 2005;31(10):1125–8 [Epub 2005 Jul 15]. [13] Toth D, Sebo E, Sarkadi L, Kovacs I, Kiss C, Damjanovich L. Role of core needle biopsy in the treatment of radial scar. Breast 2012;21(6):761–3 [Epub 2012 Mar 6]. [14] Sohn VY, Causey MW, Steele SR, Keylock JB, Brown TA. The treatment of radial scars in the modern era: surgical excision is not required. Am Surg 2010;76(5):522–5. [15] Rakha EA, Ho BC, Naik V, Sen S, Hamilton LJ, Hodi Z, et al. Outcome of breast lesions diagnosed as lesion of uncertain malignant potential (B3) or suspicious of malignancy (B4) on needle core biopsy, including detailed review of epithelial atypia. Histopathology 2011;58(4):626–32 [Epub 2011 Mar 3].

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