Radiologic-pathologic Correlation at Breast MR Imaging

Radiologic-pathologic C o r re l a t i o n a t Bre a s t M R Imaging What is the Appropriate Management for High-risk Lesions? Samantha L. Heller, PhD, MDa, Ozvaldo Hernandez, MDb, Linda Moy, MDc,* KEYWORDS  Breast  Magnetic resonance imaging  High-risk lesions  Radiologic-pathologic correlation

KEY POINTS  Morphologic features of masses seen on magnetic resonance (MR) imaging, such as spiculated margins and rim enhancement, are highly predictive of malignancy.  High-risk lesions found on MR-guided biopsy may be upgraded to malignancy at surgical excision; however, upgrade rate and management of these lesions should be addressed on a lesion-bylesion basis.  A clearly thought-out MR-guided biopsy technique with checks for appropriate and accurate targeting of lesions, including postbiopsy marker clip placement, is crucial for evaluating radiologicpathologic correlation.  There are no morphologic or kinetic MR imaging characteristics that have been shown to definitively predict high-risk lesion upgrade.  Atypical ductal hyperplasia is the most frequently encountered high-risk lesion encountered on MR-guided biopsy and has the highest likelihood of being upgraded to malignancy of the highrisk lesions.

Breast magnetic resonance (MR) imaging is increasingly being performed for a variety of indications, most commonly with the goal of detecting breast cancer. Percutaneous biopsy (usually under MR guidance or under ultrasound if there is a correlating finding) is commonly used to evaluate suspicious imaging findings detected on

MR imaging with the goal of identifying malignancy. In addition to invasive and in situ breast cancer, there are several other lesions that are generally excised when encountered on percutaneous biopsy; this group includes discordant lesions and high-risk lesions. Discordant lesions are those where pathologic abnormality is not consistent with the expected result based on the radiologic appearance and excision is advised

The authors have no financial disclosures. a Department of Radiology, St. George’s Healthcare NHS Trust, London SW17 0QT, UK; b Department of Pathology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA; c Department of Radiology, NYU Cancer Institute, Breast Imaging Center, NYU School of Medicine, 160 East 34th Street, 3rd Floor, New York, NY 10016, USA * Corresponding author. E-mail address: [email protected] Magn Reson Imaging Clin N Am 21 (2013) 583–599 http://dx.doi.org/10.1016/j.mric.2013.03.001 1064-9689/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

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INTRODUCTION

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Heller et al to exclude the possibility of a missed cancer. High-risk lesions include atypical ductal hyperplasia, lobular carcinoma in situ, atypical lobular hyperplasia, radial scar, papillary lesions, and flat epithelial atypia; excision is often recommended for these lesions because of the possibility of their upgrade to malignancy when more tissue is sampled. In addition to understanding imaging characteristics and management of malignancy detected on MR imaging, it is also important to be familiar with the characteristics and management of high-risk lesions detected or biopsied under MR guidance. In this review, the appearance of a variety of breast lesions detected on MR imaging that require excision with a focus on pathologic correlation is described. In particular, the focus is high-risk lesions detected on MR imaging with a review of the pathologic features of these lesions. The current work on high-risk lesions seen on MR imaging is also reviewed and appropriate management of these lesions is discussed.

IMAGING FINDINGS AND PATHOLOGIC ABNORMALITY Malignancy Invasive carcinoma The MR imaging characteristics of invasive breast cancer presenting as a mass have been well described. In addition to lesion size, certain specific morphologic features, such as smooth or lobulated margins with no or low enhancement, can be predictive of benign disease.1,2 The presence of nonenhancing internal septations in a smooth or lobulated mass is highly specific for the diagnosis of fibroadenoma (specificity 93%– 97%). In contrast, certain morphologic features are very suggestive of malignancy, such as spiculated margins (positive predictive value 5 76%– 88%) and rim enhancement (positive predictive value 5 79%–92%). Schnall and colleagues3 noted that the most important feature was the presence of enhancement of any type; however, the absence of enhancement did not exclude invasive cancer. As Gutierrez and colleagues4 demonstrated, masses of 1 cm or larger with heterogeneous enhancement and irregular margins have a high (68% in their study) probability of malignancy. On the other hand, masses of 1 cm or larger with smooth margins and homogeneous enhancement have a very low probability of malignancy (3% in their cohort). Mahoney and colleagues5 recently analyzed the cancers detected in the ACRIN 6667 trial and noted that masses with irregular shapes and irregular or spiculated margins had the highest likelihood of malignancy.

As has been well demonstrated, kinetic analysis may also aid in cancer detection. Qualitative assessment of kinetic curve parameters is used in most clinical scenarios with initial enhancement defined as slow, medium, or rapid and the shape of the time signal intensity curve defined as type I persistent, type 2 plateau, and type 3 wash-in/wash-out curves. The curves indicating likelihood of benignity or malignancy were shown in the 1999 study by Kuhl and colleagues6 of signal intensity time course data; a type 3 curve should raise suspicion for a malignant lesion. However, there is overlap within these categories and kinetics should not be used independently of morphology. Mahoney and colleagues5 showed that rapid initial enhancement was also associated with carcinomas. Currently, the assessment of the morphologic features is more predictive in the diagnosis of breast cancer than characterization of the kinetic curves.3 In situ carcinoma Recent studies evaluating detection of DCIS on MR imaging have shown that MR imaging is the most sensitive modality currently available for identifying DCIS and is more accurate in evaluating the extent of DCIS than mammography. MR imaging is particularly sensitive for identifying high-grade and intermediate-grade DCIS.7 The imaging appearance of ductal carcinoma in situ (DCIS) on MR imaging has been well described. DCIS may vary in terms of morphology, but nonmass enhancement (NME) morphology is the most common presentation.8 Rosen and colleagues9 reported that the most common pattern of NME for pure DCIS was segmental distribution and clumped enhancement. DCIS may also present as a mass on MR imaging, most likely an irregular mass. Although the kinetics of DCIS are variable, a fast uptake and plateau curve are reported as the most common kinetic pattern.10,11

High-risk Lesions High-risk lesions may demonstrate an upgrade to malignancy after further surgical excision. An initial underestimation at biopsy may occur for a variety of reasons including undersampling at biopsy and difference of opinion among pathologists over the criteria for defining a high-risk lesion versus a cancer. In addition, it is always possible that the targeted concerning finding may have been missed at biopsy. Overall for all types of high-risk lesions, the current literature suggests frequencies of between 3% and 21%.12 Underestimation rates for all high-risk lesions combined on MR imaging range from 13% to 57%.12 Given the

Radiologic-pathologic Correlation at Breast MRI high potential for underestimation of malignancy, radiologic-pathologic correlation after biopsy is extremely crucial. As well, if the pathologic abnormality appears discordant with radiologic imaging, investigation and repeat biopsy or surgical excision is necessary. Review of the MR imaging high-risk lesion literature To the authors’ knowledge, excluding review articles, pictorial essays, technical notes, case reports, non-English articles, and animal studies, there are 27 articles on PubMed reporting frequency of high-risk lesions on MR imaging. Of this group, 20 articles detail frequency and upgrade rates of the lesions and include complete excision data (ie, complete accounting of imaging or surgical follow-up for all lesions) for at least some of the identified types of high-risk lesions. At present, most high-risk data are reported as part of work evaluating outcomes of MR imaging–guided biopsies; only a few studies focus on high-risk lesions outcomes specifically or on outcomes of a specific type of high-risk lesion on MR imaging (for example, one article on atypical ductal hyperplasia [ADH] and one on papillary lesions). There is also a recent review of frequency and underestimation of lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH), although MR imaging detected and MR-guided biopsied lesions comprise only a subset of the cohort.13 Imaging and biopsy techniques Appropriate MR imaging technique is essential with adequate temporal and spatial resolution needed for optimal assessment of detected lesions.14 A few of the MR biopsy and high-risk studies have been performed at 3 T, but most of the available studies have been performed at 1.5 T field strengths. The studies are united in using dynamic contrast-enhanced MR sequences and usually include fat-suppression sequences as well as subtraction images but show variation with respect to plane of acquisition, spatial resolution, and kinetic resolution. Most of the studies evaluate lesions identified and biopsied under MR guidance. However, some studies also include lesions identified on MR but biopsied under other modalities. If a lesion in need of biopsy is detected on MR imaging (BI-RADS 4 or 5), it is the authors’ practice to recommend targeted ultrasound if the lesion is a mass or if is of a large enough size. As several recent articles have discussed, the likelihood of identifying a lesion on targeted ultrasound is greater if it is a mass or of larger size.15 In the metareview of 13 studies, Leung

found that between 23% and 89% of lesions had an ultrasound correlate depending on the study and between 15% and 57% of cancers were identified on second-look ultrasound. Biopsy may then be pursued under ultrasound guidance if there is clear correlation. If there is no mammographic or sonographic correlate, or the lesion is thought unlikely to have a correlate, MR-guided biopsy is recommended. A clearly thought-out biopsy technique with checks for appropriate and accurate targeting of a lesion is crucial for evaluating radiologicpathologic correlation. Studies use different means of verifying accuracy of tissue sampling and establishing radiologic-pathologic correlation once biopsy has been performed (Table 1). Most studies rely on postbiopsy markers and postmarker MR and mammographic imaging after biopsy (see Table 1). There are also multiple studies where radiologic-pathologic correlation is difficult to prove; for example, if final surgical pathologic abnormality is based on mastectomy without localization of the original lesion (see Table 1). Pathology and radiologic-pathologic correlation Overall the literature is consistent in demonstrating no morphologic or kinetic features that can be used to identify high-risk lesions on MR imaging with the exception of papillary lesions discussed later in this article. In addition, there are no imaging characteristics that have been shown to predict upgrade of a lesion to malignancy.12 There are some studies that use MR imaging as a problem-solving mechanism to evaluate high-risk lesions identified through biopsy under other modalities and have suggested that a lack of enhancement on MR imaging may suggest lack of underestimation of an invasive malignancy,16,17 but more studies are needed to verify this possibility. Not all high-risk lesions are the same in terms of likelihood of upgrade to malignancy (Tables 2 and 3): upgrade rate and management of these lesions should be addressed on a lesion-by-lesion basis. In the rest of the article, therefore, the focus is on the pathologic abnormality, radiologic-pathologic correlation, and management of specific high-risk lesions when detected on MR imaging. Atypical ductal hyperplasia Histology ADH consists of a population of monot-

onous, small cells that are similar to those seen in low-grade DCIS (Figs. 1 and 2). The cells grow within ducts in a cribriform, micropapillary, or solid pattern. The extent of duct involvement or the size

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Table 1 Means of establishing radiologic-pathologic correlation for high-risk lesions detected on MR vacuum-assisted biopsy studies

Study

Biopsy Gauge

Verification of Biopsy Site

Liberman et al,30 2003 Chen et al,27 2004

9G

Clip and postbiopsy imaging

14 G

Marker clip in “most patients”; final postbiopsy image

Lehman et al,23 No data 2005

Clip and postbiopsy imaging

Liberman et al,31 2005 Orel et al,33 2006 Perlet et al,34 2006

Clip “may be” placed; assessment of degree of removal of target 75/85 clip, postbiopsy imaging, mammogram in 20/75 Postbiopsy imaging, evaluation of partial or complete removal, radiologic-pathologic review

Liberman et al,24 2007 Han et al,29 2008

9G 9G 11 G

9G

Clip and postbiopsy mammogram

9 G or 10 G

Clip in all except 13; postbiopsy imaging if clip; radiologicpathologic review Clip placed; postbiopsy imaging and mammogram; radiologicpathologic review 35/47 clip Imaging 1 wk post, radiologicpathologic correlation Clip, postbiopsy MR imaging and mammogram; multidisciplinary radiologic-pathologic review Clip, postbiopsy mammogram, radiologic-pathologic review No data

Mahoney,32 2008

10 G

Perretta et al,21 2008

10 G

Malhaire et al,44 2010

10 G

Noroozian et al,45 2010 Strigel et al,20 2010

9G

Tozaki et al,35 2010 Crystal et al,25 2011

Surgical Excision Details and Verification of Surgical All to needle localization and surgery 4/5 ADH 2 surgical excisions 2 mastectomies Biopsy cavity in surgical specimen for one upgraded high-risk lesion “Surgery” “Surgical excision or mastectomy” Surgical excision after ultrasound, mammogram, or MR wire localization of cavity “Surgery” “Surgery performed”

“Surgical excision”

Excisional biopsy

“Surgical”

“Surgical”

14-G core needle OR 9 G vacuumassisted biopsy OR Ultrasound 14-G OR 9-G or 11-G stereotactic 11 G and 10 G Clip placed; postbiopsy imaging

No data

9G

All excisional biopsies guided via clip

Rauch et al,61 2012 Oxner et al,64 2012

9G

Clip at discretion of radiologist; postclip mammogram; multidisciplinary review of rad-path concordance Clip placed; postbiopsy imaging

10 G

Not stated

Dogan et al,65 2012

9G

Clips placed, but not stated if performed for all MR biopsies

“Surgery performed”

Surgical excision Final surgical pathologic abnormality compared with MR-guided biopsy lesion Mastectomy or segmentectomy

Radiologic-pathologic Correlation at Breast MRI

Table 2 Review of studies reporting both frequency and upgrade rate of atypical ductal hyperplasia detected on MR imaging

Author

Total Total No. High-risk Frequency of No. ADH of Lesions Lesions ADH/Total (%) Excised

Final ADH Surgical Upgrade (%) Histology

Liberman et al,30 2003 Chen et al,27 2004 Liberman et al,31 2005 Lehman et al,23 2005 Ghate et al,28 2006 Perlet et al,34 2006 Orel et al,33 2006 Liberman et al,24 2007 Mahoney et al,32 2008 Malhaire et al,44 2010 Perretta et al,21 2008 Noroozian et al,45 2010 Strigel et al,20 2010

27 35 95 38 19 517 85 237 55 72 47 75 482

1 5 10 2 4 17 18a 15 7 10 4a 7 51

1/27 (3.7) 5/35 (14) 4/95 (4) 2/38 (5.3) 2/19 (11) 17/517 (3.3) 8/85 (9.4) 15/237 (6.3) 3/55 (5.5) 1/72 (1) 4/47 (8.5) 2/75 (2.7) 51/482 (10.6)

1 4 4 2 2 17 8 13 3 1 4 2 34

1/1 (100) 2/4 (50) 2/4 (50) 1/2 (50) 1/2 (50) 5/17 (29.4) 2/8 (25) 5/13 (38.5) 2/3 (66.7) 1/1 (100) 1/4 (25) 0/2 (0) 11/34 (32.4)

Tozaki et al,35 2010 Crystal et al,25 2011

102 161

9a 31

4/102 (4) 6/161 (3.7)

2 6

2/2 (100) 3/6 (50)

Rauch et al,61 2012

218

37a

13/218 (6)

NS

4/NS

Oxner et al,64 2012

187

16a

15/187 (8)

Dogan et al,65 2012

199

31

NS

Range (%)

19–572

1–51

1–19

NS (data on 2/NS 3 cases) NS (data on 2/NS 2 cases) 0–100

DCIS 2 IDC 2 DCIS DCIS 1 IDC 5 DCIS 2 DCIS 5 DCIS 2 IDC 1 DCIS 1 DCIS NA 1 ILC 4 IDC 6 DCIS (1 ADH and LCIS) 2 DCIS 2 DCIS 1 IC, NOS 3 DCIS 1 IDC 2 DCIS 1 DCIS 1 IDC

Abbreviations: IC NOS, invasive cancer not otherwise specified; NS, not stated. a Papillomas not counted as high-risk lesions in study.

of the area involved is used to differentiate between ADH and low-grade DCIS. Ducts involved with ADH show partial involvement with the atypical cells, with the remaining uninvolved portions of the ducts showing usual ductal hyperplasia or nonhyperplastic, benign epithelium. If several ducts are entirely involved by a proliferation of atypical ductal cells, a diagnosis of ADH is typically reserved when the involved area measures less that 2 mm.18 Diagnosis is complicated by several factors. Because ADH, DCIS, or even invasive disease may be combined in one lesion, the extent of tissue sampling may affect the specimen seen by the pathologist and lead to underestimation of malignancy. As well, there is interobserver variation between pathologists (for example, the same

sample may be labeled either ADH or low-grade DCIS depending on the individual diagnostic variation).19 ADH on MR imaging ADH is the most commonly encountered high-risk lesion biopsied on MR imaging as demonstrated by multiple studies addressing outcome of MR imaging biopsies (see Fig. 2, see Table 2).20–23 As was the case for the general pool of high-risk lesions, there is no MR imaging appearance predictive of either ADH or ADH upgrade to malignancy. Although Liberman and colleagues24 found ADH in 10% of cases of NME biopsied under MR guidance and in 4% of all masses, this difference was not significant (P 5 .16) nor is size a significant predictor of upgrade to malignancy on MR in the literature.20,25

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Table 3 Studies detailing incidence and upgrade rate of papillary lesion, radial scar, ALH, and LCIS on MRa

Author Liberman et al,31 2005 Orel et al,33 2006 Mahoney,32 2008 Noroozian et al,45 2010 Strigel et al,20 2010 Malhaire et al,44 2010 Crystal et al,25 2011 Brennan et al,62 2012

Niell et al,13 2012

Total Lesions No.

Papillary Lesion No./Upgrade No.

Radial Scar ALH No./ No./Upgrade No. Upgrade No.

LCIS No./ Upgrade No.

95

1/1 (DCIS)b

1/0

1/0

3 (2 excised)/0

85 55 75

0/0 3/1 (DCIS) 0/0

3/0 0/0 0/0

2/0 0/0 2 (1 excised)/0

5/0 1/1 / IDC 3/1 / DCIS

482 72

0/0 2/0

1/0 1/0

6/1 / DCIS 3/1 / DCIS 2/(none excised) 1/0

161 1487

3/0 2/0 LN NOS-8/1 / IC; 3/3 / DCIS 75 (67 excised)/2 DCIS of 23 with atypia 2 DCIS of 44 without atypia LN-12/2 10/2 (excluding either pLCIS or FEA with LCIS)

Abbreviations: IC, invasive cancer; LN NOS, lobular neoplasia not otherwise specified. a Biopsy specimens reported as containing mixed–high-risk pathologic abnormality were excluded. b DCIS found 0.7 cm anterior to the papillary lesion on excision in a patient with known Paget disease.

Fig. 1. A 65-year-old woman with a history of remote lumpectomy for breast carcinoma. (A) Sagittal T1-weighted postcontrast subtraction image demonstrates suspicious linear nonmass enhancement (arrow) with a type 2 (plateau) indeterminate kinetic curve (not shown). (B) Postbiopsy change demonstrating that the lesion has been adequately sampled (double arrows). Lesion proved to be atypical ductal hyperplasia on biopsy and after final excision (see Fig. 2).

Radiologic-pathologic Correlation at Breast MRI

Fig. 2. Atypical ductal hyperplasia. (A) The MR imaging core biopsy shows 2 ducts with a cellular proliferation forming punched-out spaces (arrows). A third duct is only partially involved (arrowhead). The entire area of atypia measures 1 mm. (B) A high power view of one duct shows cribriform architecture and a uniform population of cells with small, round nuclei. (C) At excision, an area of dilated ducts with varying degrees of hyperplasia was identified at low power. (D) High power view of one section shows ADH—some ducts show a proliferation of small, monomorphic cells forming rigid bridges and punched-out spaces (arrowheads).

Newer techniques have not been shown to identify high-risk lesions definitively either: a recent study assessing apparent diffusion coefficients (ADC) of benign and high-risk lesions found that ADH (and also lobular neoplasia) without later upgrade had significantly lower ADCs than benign lesions and were the most common source of false positive findings using an ADC threshold of 1.46  0.39  10 3 mm2/s.26 ADH has the highest risk of underestimation of any of the high-risk lesions detected and biopsied on MR imaging as demonstrated in multiple studies (see Table 2). The reported ADH underestimation for MR imaging detected lesions in recent published studies using a 14-gauge or larger biopsy

device ranging from 11% to 67%.20–25,27–35 Although upgrade is usually to in situ disease in most cases, invasive disease has also been observed (see Table 2). Lobular carcinoma in situ/atypical lobular hyperplasia ALH and LCIS are on a continuum. LCIS is composed of neoplastic lobular cells that distend the acini without stromal invasion (Figs. 3–6).36 Lesions with involvement of less than or equal to half of the acini of a terminal duct-lobular unit are considered ALH.36 Some pathologists group ALH and LCIS together as lobular neoplasia (LN). Another system uses the term “lobular intraepithelial

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Fig. 3. A 64-year-old woman with a family history of breast cancer. (A) Sagittal T1-weighted postcontrast subtraction image demonstrates 1 cm of nonmass enhancement (arrow). (B) Postbiopsy image demonstrates adequate sampling of the lesion (double arrows). Pathology demonstrated atypical lobular hyperplasia at biopsy and after subsequent surgical excision (see Fig. 4).

neoplasia”; this breaks the degree of proliferation of the cells into 3 different grades (LIN 1–3): LN 1 and LN 2 are composed of small, uniform, and loosely cohesive neoplastic cells. In LN 1, the degree of involvement is focal within the terminal ductlobular unit and there is no distention of the acini. LN 2 shows complete to almost complete involvement of the terminal duct-lobular unit and there is diffuse acinar distention. The presence of large, pleomorphic cells, signet-ring morphology or the presence of necrosis defines LN 3.37 At the authors’ institution, the pathologists define LCIS and ALH as distinct entities; in addition, the literature has shown decreased risk for future development of invasive disease in ALH compared with LCIS.

LCIS was originally thought to be malignant.38 It was later thought to be to be an incidental finding or marker of increased breast cancer risk.39 Now LCIS is considered both a risk marker and a nonobligate cancer precursor. Upgrade rates for ALH and LCIS on ultrasound-guided core and stereotactic core needle biopsy have been reported at 6% to 22% and 10% to 25%, respectively.40,41 A separate note is warranted regarding pleomorphic LCIS (pLCIS). Although LCIS is often an incidental finding, pLCIS is frequently associated with amorphous calcifications. When pLCIS is found, excision is warranted and treatment is usually in-line with treatment for DCIS.42,43

Fig. 4. Atypical lobular hyperplasia. (A) A low power view of the core biopsy shows one ductule partially involved by a proliferation of cells (arrows). (B) High power view shows a proliferation of bland, uniform cells within a portion of the ductule. Pathology after surgical excision also demonstrated atypical lobular hyperplasia without evidence of upgrade to malignancy.

Radiologic-pathologic Correlation at Breast MRI

Fig. 5. Axial postcontrast T1-weighted screening MR image demonstrates markedly asymmetric nonmass enhancement (arrows) in the left breast compared with the right with a type 1 (persistent) kinetic curve (not shown) in this 45-year-old woman with a family history of breast cancer. MR-guided biopsy demonstrated lobular carcinoma in situ on biopsy with upgrade to invasive lobular carcinoma on surgical excision (see Fig. 6).

LCIS and ALH on MR imaging Like ADH, LCIS and ALH have no predictive imaging features or imaging features predictive of upgrade. Overall, there are very few cases reported in the MR imaging biopsy literature (see Table 3). The few reported cases have been identified either in studies of MR imaging-guided biopsy outcomes or in the few studies on general high-risk lesion detection on MR imaging. The frequency of ALH and LCIS ranges from 4% (3/72; 4/95) to 26% (8/31)25,31,44 if the entities are accounted for together. If considered as distinct entities, frequency ranges from 0.6% (3/482) to 6% (5/85) for LCIS and 1% (1/95) (6/482) to 3% (2/75) for ALH (see Table 3).20,31,33,45 Interestingly, 2 recent studies have suggested that MR imaging may also be useful in screening women with a history of LCIS. Friedlander and colleagues46 performed a retrospective review of 445 examinations in 198 patients. Cancer was detected in 5 of 307 screening studies and in 5 of 133 patients with a positive predictive value for screening studies for which biopsy was recommended in 18.5%.47 Sung and colleagues47 retrospectively evaluated 670 screening studies in 220 women with a history of LCIS and found 17 cancers in the study period, 12 of which were identified only by MR imaging (9 invasive; 3 DCIS) and 5 of which were identified only by mammography (2 invasive; 3 DCIS). Radial scar/complex sclerosing lesion I Radial scars are stellate lesions with a central fibroelastotic zone and a peripheral zone with

varying degrees of fibrocystic changes (Figs. 7 and 8). Lesions less than 1 cm are designated radial scars, whereas lesions greater than 1 cm are referred to as complex sclerosing lesions. Small, benign ducts are typically entrapped within the central fibroelastic area. The peripheral zone consists of radially oriented ducts showing proliferative or nonproliferative changes, such as usual ductal hyperplasia, adenosis, papillomatosis, cystic change, or apocrine metaplasia. Epithelial atypia may be present in a radial scar, typically in the peripheral zone.48 There is a wide range of upgrade rates in the mammographic and sonographic literature with upgrade rates ranging from 0% to 22%.49 Georgian-Smith and Lawton49 discuss the importance of radiologic-pathologic correlation with regard to radial scar and associated malignancy. One study found that 11 false positive cases of radial scar had actually been missed at original core biopsy (the biopsy tracks were on average 5 mm distant from the actual lesion).50 Radial scar on MR imaging To the authors’ knowledge, recent published studies on consecutive high-risk lesions detected on MR imaging or on results of MR imaging vacuum-assisted biopsy detail very few cases of radial scar with no upgrades reported (see Table 3).12 MR imaging has been used as a problemsolving tool for radial scar found on other modalities. For example, Linda and colleagues16 analyzed 54 radial scar lesions detected on ultrasound and mammography and found that 2 of 54 (3.7%) of these lesions were upgraded, one to invasive lobular carcinoma (ILC) and one to DCIS; the authors looked at MR imaging characteristics of high-risk lesions and found a high negative predictive value for both radial scar (97.6%) and papilloma without atypia (97.4%). Two of the 54 cases of radial scar were upgraded at surgery (3.7%). One case of radial scar was correctly identified on MR imaging as suspicious (BI-RADS 4) and was ILC on surgery. The other case of radial scar did not enhance and was incorrectly assigned a BI-RADS 1; this was upgraded to low-grade DCIS. The authors note that the lack of enhancement on MR imaging may suggest a lack of invasive disease in the context of high-risk lesions found on other modalities, but that more studies need to be performed to confirm this. Flat epithelial atypia Flat epithelial atypia is a lesion of the terminal ductlobular unit in which the normal epithelium is replaced by ductal cells with low-grade cytologic atypia (Figs. 9 and 10). The acini involved with

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Fig. 6. Lobular carcinoma in situ. (A) The core biopsy showed a proliferation of cells within distended acini of numerous terminal duct lobular units (arrows). (B) High power view shows small, uniform cells with bland nuclei similar to those seen in ALH. Nucleoli are not prominent. Occasional intracytoplasmic vacuoles are seen (arrow). (C) Pagetoid involvement of a small duct by LCIS. Cells similar to the ones seen in the distended acini are present beneath attenuated ductal epithelium (arrowhead). (D) The excision showed LCIS (arrows) as well as cells infiltrating the stroma (arrowheads). (E) High power view shows cells with a similar cytologic appearance to those in the LCIS infiltrating the stroma in a linear fashion (arrowheads). The findings are consistent with invasive lobular carcinoma.

Radiologic-pathologic Correlation at Breast MRI

Fig. 7. A 61-year-old woman with newly diagnosed cancer of the left breast (invasive and in situ ductal carcinoma). (A) Sagittal T1-weighted postcontrast image demonstrates an irregular homogeneously enhancing mass measuring 0.9 cm at the 12 o’clock axis (arrow), which proved to be a radial scar on MR-guided biopsy pathology and on final surgical excision pathology (see Fig. 8). (B) Sagittal T1-weighted postcontrast image shows an irregular heterogeneously enhancing mass at the 3 o’clock position compatible with known-biopsy proven malignancy (double arrows).

Fig. 8. Radial scar. (A) The core biopsy shows a central area of fibroelastosis (circle) surrounded by radiating benign ducts, some of which show usual ductal hyperplasia (arrowhead). (B) Another core from the same specimen shows small glands entrapped within fibroelastotic material (arrow). (C) The excision shows a residual radial scar (arrow). Stromal changes from the prior core biopsy site are seen in the lower left portion of the image.

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Fig. 9. A 67-year-old woman newly diagnosed with an 8-mm invasive ductal carcinoma in the left breast. (A) T1-weighted postcontrast subtraction image shows a 6-mm lobulated progressively enhancing mass (arrow). (B) T1-weighted postcontrast image demonstrates postbiopsy changes after MR-guided tissue sampling of the lesion (double arrow). Biopsy pathology showed FEA, but final surgical excision pathology demonstrated an upgrade to DCIS (see Fig. 10).

flat epithelial atypia are usually dilated and are lined by one to several layers of columnar or cuboidal cells with round or oval, monomorphic nuclei with inconspicuous to small nucleoli. Complex architectural growth patterns are not seen in flat epithelial atypia (FEA). FEA has also been described as columnar cell change with atypia, columnar cell hyperplasia with atypia, columnar alteration with prominent apical snouts and secretions with atypia, and atypical cystic lobules. Core biopsies with FEA often show other low-grade lesions, such as ADH, low-grade DCIS, LN, or tubular carcinoma. The rate of finding more advanced lesions after excision of FEA varies from no upgrade to about 30%.51–53 A recent meta-analysis of 24 articles detailing upgrade statistics for columnar cell lesions (CCL) with and without atypia including FEA found that in situ carcinoma underestimation for CCL without atypia was 1.5% (CI 95%, 0.6%–4%). For CCL with atypia, in situ carcinoma upgrade risk was 9% (CI 95%, CI 5%–14%). ADH was associated with CCL in 20% of cases (95%CI, 13%–28%). Analysis of the studies with long-term follow-up data available showed that women with a history of CCL on biopsy had a trend toward limited increased risk of breast cancer.54 FEA on MR imaging There are very few cases of FEA reported on MR imaging with almost no cases of upgrade reported. In the reviewed studies, only 1 case of upgrade was reported (to DCIS).25

Intraductal papilloma Intraductal papillomas are arborizing proliferations within dilated ducts composed of fibrovascular cores lined by myoepithelial cells and an overlying layer of epithelial cells (Figs. 11 and 12). Intraductal papillomas are usually single lesions located in the retroareolar region. Similar papillary proliferations, known as papillomatosis, may occur in small ducts located in the periphery of the breast. Varying degrees of sclerosis may be present within the fibrovascular cores, obscuring the papillary architecture and entrapping benign glands within the fibrotic tissue. The epithelial component may show hyperplasic changes or apocrine metaplasia. In some cases, intraductal papillomas may contain areas of epithelial proliferation showing cytologic and architectural atypia, leading to a diagnosis of atypical ductal hyperplasia or DCIS within the papilloma. Complete surgical excision for intraductal papillomas is often recommended to exclude atypia or neoplasia associated with the papilloma or in the surrounding breast tissue.55,56 Papillary lesions on MR imaging Papillary lesions may have suggestive MR imaging signal characteristics. For example, MR ductography has been used to show ductal dilatation; in at least 2 studies, such dilatation was identified in all cases of papilloma.57,58 Just as on ultrasound and mammography, papillomas appear as masses as opposed to NME. One study showed that papillomas appear most frequently as well-circumscribed masses with

Radiologic-pathologic Correlation at Breast MRI

Fig. 10. Flat epithelial atypia. (A) Low power view shows dilated acini within a lobular unit (arrows). (B) The acini are lined by 1 to 2 layers of columnar or cuboidal cells lacking polarity. The cells have high nuclear-to-cytoplasmic ratios, round or oval nuclei, and small nucleoli (arrow). (C) Excision shows a solid proliferation of cells within ducts (arrows) in an area spanning 4 mm. (D) High power view shows a solid proliferation of cells with large, irregular nuclei and small nucleoli (arrows). The high degree of nuclear atypia and extent of involvement makes this DCIS.

homogenous early enhancement,57 although others have found various categories of mass; for example, small, smooth enhancing masses, irregular enhancing masses, and occult lesions.59 A more recent study found 27 of 44 intraductal papillomas were round or oval in shape; as well, a low early-phase rate of enhancement and early homogeneous or heterogeneous enhancement to delayed rim-like enhancement were significantly suggestive of papilloma versus IDC.60

However, as for other high-risk lesions, there were no definitively unique predictive MR morphologic or kinetic characteristics or specific predictors of upgrade to malignancy. As described elsewhere, some MR imaging studies consider lesions high-risk lesions and others do not, making a coherent analysis of frequency and upgrade rates difficult.12 For several studies, for example, surgical excision of papillary lesions without atypia was not recommended and

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Fig. 11. MR imaging was performed to evaluate for extracapsular implant rupture. (A) A round 1-cm subareolar mass with heterogeneous enhancement (arrow) was identified in the left breast (type 2 kinetics, not shown). (B) MR-guided biopsy was performed (double arrows) with pathology yielding intraductal papilloma. Surgical excision also found intraductal papilloma without evidence of atypia or malignancy (see Fig. 12).

was not considered standard of care, limiting comparative analysis.21,33,35,61 There are very few reported papillary lesion upgrades in the reviewed studies (see Table 3):

Mahoney32 reported one case of a papillary lesion upgrade to DCIS, whereas Liberman and colleagues31 reported a case of questionable upgrade of a papilloma in a patient with known

Fig. 12. Intraductal papilloma. (A) The core biopsy shows a papillary lesion with fibrosis (arrows). (B) High power view reveals papillary fragments (arrowheads) composed of a fibrovascular core and lined by epithelial and myoepithelial cells. (C) Residual portion of an intraductal papilloma on excision (arrow).

Radiologic-pathologic Correlation at Breast MRI Paget disease. Brennan and colleagues62 looked at a relatively large series of papillary lesions on MR imaging and included papillary lesions both with and without atypia. They found that of their 67 excised lesions (of an original biopsied 75), 2 of 23 lesions with atypia and 2 of 44 lesions without atypia were upgraded, all 4 to DCIS. Special cases It is worth distinguishing between lesions identified on MR and incidental microscopic high-risk lesions found at biopsy. A recent article by Lee and colleagues63 looked at 18 microscopic radial scars and 17 microscopic papillary lesions found on biopsy that went on to surgical excision. In this group, there were no cases of upgrade to malignancy at surgery. At present, there are no data on the upgrade rates of incidental microscopic high-risk papillary lesions or radial scars found at MR-guided biopsy, but it would be helpful for future studies to investigate this particular subset of lesions further and distinguish them from nonmicroscopic high-risk lesions in terms of outcome. Management recommendations As discussed, certain lesions have clear management protocols when identified on MR-guided biopsy: malignancy necessitates referral to a surgeon; imaging and pathologic discordance necessitates further excision. However, it is challenging to arrive at a single recommendation for the highrisk lesions that were discussed in this article. Instead, such lesions should be addressed on a type basis. It is generally accepted that excision of ADH is appropriate if detected on MR biopsy given the high likelihood of underestimation. As well, LCIS and ALH have been shown to have a relatively high rate of underestimation and excision is warranted. Radial scar and papillary lesions with atypia should also always be excised; however, excision of radial scar without atypia, papillary lesions without atypia, and FEA detected on MR imaging are more controversial. At present, we also recommend excision of these lesions, given the need for further investigations, but this recommendation may change as more studies are performed and more data become available.

REFERENCES 1. Nunes LW, Schnall MD, Orel SG, et al. Breast MR imaging: interpretation model. Radiology 1997; 202:833–41. 2. Nunes LW, Schnall MD, Siegelman ES, et al. Diagnostic performance characteristics of architectural features revealed by high spatial-resolution MR imaging of the breast. AJR Am J Roentgenol 1997; 169:409–15.

3. Schnall MD, Blume J, Bluemke DA, et al. Diagnostic architectural and dynamic features at breast MR imaging: multicenter study. Radiology 2006; 238:42–53. 4. Gutierrez RL, DeMartini WB, Eby PR, et al. BIRADS lesion characteristics predict likelihood of malignancy in breast MRI for masses but not for nonmasslike enhancement. AJR Am J Roentgenol 2009;193:994–1000. 5. Mahoney MC, Gatsonis C, Hanna L, et al. Positive predictive value of BI-RADS MR imaging. Radiology 2012;264:51–8. 6. Kuhl CK, Mielcareck P, Klaschik S, et al. Dynamic breast MR imaging: are signal intensity time course data useful for differential diagnosis of enhancing lesions? Radiology 1999;211:101–10. 7. Kuhl CK, Schrading S, Bieling HB, et al. MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Lancet 2007;370: 485–92. 8. Jansen SA. Ductal carcinoma in situ: detection, diagnosis, and characterization with magnetic resonance imaging. Semin Ultrasound CT MR 2011;32:306–18. 9. Rosen EL, Smith-Foley SA, DeMartini WB, et al. BI-RADS MRI enhancement characteristics of ductal carcinoma in situ. Breast J 2007;13: 545–50. 10. Jansen SA, Newstead GM, Abe H, et al. Pure ductal carcinoma in situ: kinetic and morphologic MR characteristics compared with mammographic appearance and nuclear grade. Radiology 2007; 245:684–91. 11. Vag T, Baltzer PA, Dietzel M, et al. Kinetic characteristics of ductal carcinoma in situ (DCIS) in dynamic breast MRI using computer-assisted analysis. Acta Radiol 2010;51:955–61. 12. Heller SL, Moy L. Imaging features and management of high-risk lesions on contrast-enhanced dynamic breast MRI. AJR Am J Roentgenol 2012;198: 249–55. 13. Niell B, Specht M, Gerade B, et al. Is excisional biopsy required after a breast core biopsy yields lobular neoplasia? AJR Am J Roentgenol 2012; 199:929–35. 14. Rausch DR, Hendrick RE. How to optimize clinical breast MR imaging practices and techniques on Your 1.5-T system. Radiographics 2006;26: 1469–84. 15. Leung JW. Utility of second-look ultrasound in the evaluation of MRI-detected breast lesions. Semin Roentgenol 2011;46:260–74. 16. Linda A, Zuiani C, Furlan A, et al. Nonsurgical management of high-risk lesions diagnosed at core needle biopsy: can malignancy be ruled out safely with breast MRI? AJR Am J Roentgenol 2012;198: 272–80.

597

598

Heller et al 17. Londero V, Zuiani C, Linda A, et al. High-risk breast lesions at imaging-guided needle biopsy: usefulness of MRI for treatment decision. AJR Am J Roentgenol 2012;199:W240–50. 18. Tavassoli FA, Norris HJ. A comparison of the results of long-term follow-up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast. Cancer 1990;65:518–29. 19. Masood S, Rosa M. Borderline breast lesions: diagnostic challenges and clinical implications. Adv Anat Pathol 2011;18:190–8. 20. Strigel RM, Eby PR, Demartini WB, et al. Frequency, upgrade rates, and characteristics of high-risk lesions initially identified with breast MRI. AJR Am J Roentgenol 2010;195:792–8. 21. Perretta T, Pistolese CA, Bolacchi F, et al. MR imaging-guided 10-gauge vacuum-assisted breast biopsy: histological characterisation. Radiol Med 2008;113:830–40. 22. Carbognin G, Girardi V, Brandalise A, et al. MRguided vacuum-assisted breast biopsy in the management of incidental enhancing lesions detected by breast MR imaging. Radiol Med 2011;116: 876–85. 23. Lehman CD, Deperi ER, Peacock S, et al. Clinical experience with MRI-guided vacuum-assisted breast biopsy. AJR Am J Roentgenol 2005;184: 1782–7. 24. Liberman L, Holland AE, Marjan D, et al. Underestimation of atypical ductal hyperplasia at MRIguided 9-gauge vacuum-assisted breast biopsy. AJR Am J Roentgenol 2007;188:684–90. 25. Crystal P, Sadaf A, Bukhanov K, et al. High-risk lesions diagnosed at MRI-guided vacuum-assisted breast biopsy: can underestimation be predicted? Eur Radiol 2011;21:582–9. 26. Parsian S, Rahbar H, Allison KH, et al. Nonmalignant breast lesions: ADCs of benign and high-risk subtypes assessed as false-positive at dynamic enhanced MR imaging. Radiology 2012;265: 696–706. 27. Chen X, Lehman CD, Dee KE. MRI-guided breast biopsy: clinical experience with 14-gauge stainless steel core biopsy needle. AJR Am J Roentgenol 2004;182:1075–80. 28. Ghate SV, Rosen EL, Soo MS, et al. MRI-guided vacuum-assisted breast biopsy with a handheld portable biopsy system. AJR Am J Roentgenol 2006;186:1733–6. 29. Han BK, Schnall MD, Orel SG, et al. Outcome of MRI-guided breast biopsy. AJR Am J Roentgenol 2008;191:1798–804. 30. Liberman L, Morris EA, Dershaw DD, et al. Fast MRIguided vacuum-assisted breast biopsy: initial experience. AJR Am J Roentgenol 2003;181:1283–93. 31. Liberman L, Bracero N, Morris E, et al. MRI-guided 9-gauge vacuum-assisted breast biopsy: initial

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42. 43.

44.

45.

46.

clinical experience. AJR Am J Roentgenol 2005; 185:183–93. Mahoney MC. Initial clinical experience with a new MRI vacuum-assisted breast biopsy device. J Magn Reson Imaging 2008;28:900–5. Orel SG, Rosen M, Mies C, et al. MR imagingguided 9-gauge vacuum-assisted core-needle breast biopsy: initial experience. Radiology 2006; 238:54–61. Perlet C, Heywang-Kobrunner SH, Heinig A, et al. Magnetic resonance-guided, vacuum-assisted breast biopsy: results from a European multicenter study of 538 lesions. Cancer 2006;106:982–90. Tozaki M, Yamashiro N, Sakamoto M, et al. Magnetic resonance-guided vacuum-assisted breast biopsy: results in 100 Japanese women. Jpn J Radiol 2010;28:527–33. Page DL, Dupont WD, Rogers LW. Ductal involvement by cells of atypical lobular hyperplasia in the breast: a long-term follow-up study of cancer risk. Hum Pathol 1988;19:201–7. Tavassoli FA. Lobular neoplasia: evolution of its significance and morphologic spectrum. Int J Surg Pathol 2010;18:174S–7S. Foote FW, Stewart FW. Lobular carcinoma in situ: a rare form of mammary cancer. Am J Pathol 1941; 17:491–496.3. Haagensen CD, Lane N, Lattes R, et al. Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. Cancer 1978;42:737–69. Brem RF, Lechner MC, Jackman RJ, et al. Lobular neoplasia at percutaneous breast biopsy: variables associated with carcinoma at surgical excision. AJR Am J Roentgenol 2008;190:637–41. Cangiarella J, Guth A, Axelrod D, et al. Is surgical excision necessary for the management of atypical lobular hyperplasia and lobular carcinoma in situ diagnosed on core needle biopsy?: a report of 38 cases and review of the literature. Arch Pathol Lab Med 2008;132:979–83. Brogi E, Murray MP, Corben AD. Lobular carcinoma, not only a classic. Breast J 2010;16(Suppl 1):S10–4. Chivukula M, Haynik DM, Brufsky A, et al. Pleomorphic lobular carcinoma in situ (PLCIS) on breast core needle biopsies: clinical significance and immunoprofile. Am J Surg Pathol 2008;32:1721–6. Malhaire C, El Khoury C, Thibault F, et al. Vacuumassisted biopsies under MR guidance: results of 72 procedures. Eur Radiol 2010;20:1554–62. Noroozian M, Gombos EC, Chikarmane S, et al. Factors that impact the duration of MRI-guided core needle biopsy. AJR Am J Roentgenol 2010; 194:W150–7. Friedlander LC, Roth SO, Gavenonis SC. Results of MR imaging screening for breast cancer in highrisk patients with lobular carcinoma in situ. Radiology 2011;261:421–7.

Radiologic-pathologic Correlation at Breast MRI 47. Sung JS, Malak SF, Bajaj P, et al. Screening breast MR imaging in women with a history of lobular carcinoma in situ. Radiology 2011;261:414–20. 48. Rabban JT, Sgroi DC. Sclerosing lesions of the breast. Semin Diagn Pathol 2004;21:42–7. 49. Georgian-Smith D, Lawton TJ. Controversies on the management of high-risk lesions at core biopsy from a radiology/pathology perspective. Radiol Clin North Am 2010;48:999–1012. 50. Douglas-Jones AG, Denson JL, Cox AC, et al. Radial scar lesions of the breast diagnosed by needle core biopsy: analysis of cases containing occult malignancy. J Clin Pathol 2007;60:295–8. 51. Piubello Q, Parisi A, Eccher A, et al. Flat epithelial atypia on core needle biopsy: which is the right management? Am J Surg Pathol 2009;33:1078–84. 52. Lerwill MF. Flat epithelial atypia of the breast. Arch Pathol Lab Med 2008;132:615–21. 53. Schnitt SJ. The diagnosis and management of pre-invasive breast disease: flat epithelial atypia– classification, pathologic features and clinical significance. Breast Cancer Res 2003;5:263–8. 54. Verschuur-Maes AH, van Deurzen CH, Monninkhof EM, et al. Columnar cell lesions on breast needle biopsies: is surgical excision necessary? A systematic review. Ann Surg 2012;255: 259–65. 55. Ueng SH, Mezzetti T, Tavassoli FA. Papillary neoplasms of the breast: a review. Arch Pathol Lab Med 2009;133:893–907. 56. Mulligan AM, O’Malley FP. Papillary lesions of the breast: a review. Adv Anat Pathol 2007;14:108–19. 57. Bhattarai N, Kanemaki Y, Kurihara Y, et al. Intraductal papilloma: features on MR ductography using a

58.

59.

60.

61.

62.

63.

64.

65.

microscopic coil. AJR Am J Roentgenol 2006;186: 44–7. Tominaga J, Hama H, Kimura N, et al. Magnetic resonance imaging of intraductal papillomas of the breast. J Comput Assist Tomogr 2011;35: 153–7. Daniel BL, Gardner RW, Birdwell RL, et al. Magnetic resonance imaging of intraductal papilloma of the breast. Magn Reson Imaging 2003;21: 887–92. Zhu Y, Zhang S, Liu P, et al. Solitary intraductal papillomas of the breast: MRI features and differentiation from small invasive ductal carcinomas. AJR Am J Roentgenol 2012;199:936–42. Rauch GM, Dogan BE, Smith TB, et al. Outcome analysis of 9-gauge MRI-guided vacuum-assisted core needle breast biopsies. AJR Am J Roentgenol 2012;198:292–9. Brennan SB, Corben A, Liberman L, et al. Papilloma diagnosed at MRI-guided vacuum-assisted breast biopsy: is surgical excision still warranted? AJR Am J Roentgenol 2012;199:W512–9. Lee KA, Zuley ML, Chivukula M, et al. Risk of malignancy when microscopic radial scars and microscopic papillomas are found at percutaneous biopsy. AJR Am J Roentgenol 2012;198:W141–5. Oxner CR, Vora L, Yim J, et al. Magnetic resonance imaging-guided breast biopsy in lesions not visualized by mammogram or ultrasound. Am Surg 2012; 78:1087–90. Dogan BE, Le-Petross CH, Stafford JR, et al. MRIguided vacuum-assisted breast biopsy performed at 3 T with a 9-gauge needle: preliminary experience. AJR Am J Roentgenol 2012;199:W651–3.

599