High-Risk Lesions: Review and Management Update

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Diagnosis and appropriate management of nonmalignant pathology identified at core-needle biopsy (CNB) of the breast often requires complex management strategies and a multidisciplinary approach. Benign breast pathology is complex and several lesions, although not considered malignant at biopsy, are termed high-risk lesions (HRLs). These lesions may be associated with a significant upgrade rate at excision or may portend increased risk of breast cancer. High-risk pathology has been demonstrated in up to 9.2% of breast CNBs.1 After biopsy, pathology results are reviewed and concordance is assessed. Even in the setting where an HRL is considered concordant with imaging characteristics, management recommendations must be made. The recommendations for managing lesions are evolving, as detection has increased with advances in imaging techniques. While excision may be recommended for many HRLs, others may only warrant surveillance. The purpose of this article is to review the common imaging findings, pathology, and current management recommendations of the following breast lesions: mucocele-like lesions (MLLs), lobular neoplasia (LN), atypical ductal hyperplasia (ADH), radial scars (RSs), complex sclerosing lesions (CSLs), flat epithelial atypia (FEA), and papillary lesions.

Mucocele-Like Lesions

MLLs are benign lesions described as similar to mucocele lesions of the minor salivary glands.2 These cysts contain mucin and may rupture, expelling mucin into the surrounding tissue. MLLs, originally described as benign, have now been shown to be associated with a spectrum of atypia and malignancy.3,4 MLLs have been identified concurrently with epithelial variations including benign columnar cell lesions, ADH, ductal carcinoma in situ (DCIS), and mucinous carcinoma.

MLLs may present as indeterminate calcifications on mammography.5 Figure 1 demonstrates a classic imaging presentation of an MLL as calcifications. Less commonly, it may present as a focal asymmetry or asymmetry. Although infrequently identified on ultrasound, MLLs may be seen as a cluster of microcysts or complex cystic/solid masses.6 MLL on MRI examination may be associated with nonmass enhancement as demonstrated in Figure 2.

Management of MLLs is variable. MLLs without atypia at core biopsy demonstrate 0% to 4% upgrade to malignancy.7-9 However, Ha et al found that while MLLs without atypia at core biopsy do not demonstrate significant upgrade to malignancy, they do demonstrate upgrade to atypia at surgical excision.8 On the contrary, MLLs with atypia at core biopsy demonstrate a variable upgrade rate to DCIS of 3% to 31%.7,9 Limitations of the literature include small sample sizes of studies. As with all biopsies, radiologic-pathologic concordance, adequate sampling, and type of biopsy device should be reviewed prior to management decisions. Given the current knowledge of these lesions, if the lesion is concordant and sufficiently sampled, imaging follow-up in lieu of surgical excision may be considered for MLLs without atypia. However, given the high upgrade rate for MLLs with atypia, surgical excision remains the recommendation.

Lobular Neoplasia

LN is a spectrum of disease that originates in the terminal duct lobular unit (TDLU).10 LN has multiple subtypes including atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), and pleomorphic lobular carcinoma in situ (PLCIS). All LN demonstrates reduced or absent expression of E-cadherin, the cell-cell junction protein.11 ALH appears as discohesive small, monotonous, polygonal and round epithelial cells that fill and expand the acini of the lobular unit.11,12 LCIS appears similar to the ALH but is more extensive. It involves the expansion of more than half of the acini in a lobular unit.11,12 PLCIS has the appearance of LCIS with the addition of nuclear membrane irregularity, easily identifiable mitotic forms, significant nuclear pleomorphism, and variable prominent nucleoli.13 Despite these definitions, pathologist interobserver agreement between the WHO classification of ALH, LCIS, and PLCIS is poor.14

LN is often an incidental finding on CNB. Mammographically, it may present as fine pleomorphic calcifications (Figure 3). Less frequently, it may also present as grouped amorphous or grouped coarse heterogeneous calcifications (Figure 4). Unfortunately, calcification appearance on mammography does not assist in differentiating among the pathologic spectrum. LN is histologically associated with calcifications in about 20% to 40% of biopsies. LN may present as foci of enhancement or nonmass enhancement (NME) on MRI. Figure 5 shows an example of LCIS presenting on MRI as focal NME. On MRI examination, there is no evidence that LN forms a mass lesion. If MRI biopsy of a targeted mass demonstrates lobular neoplasia, the biopsy could be considered discordant.10

Management of LN is variable. According to Sen et al, published upgrade rates for ALH range from 0% to 46% with an accepted rate of 2.4%. For LCIS, they found the upgrade rate is 0% to 60% with an accepted rate of 9.3%.15 PLCIS demonstrates a variable upgrade rate of 18% to 100%.16 Pleomorphic LCIS also recurs locally in 4% to 19% of cases.13 Currently the National Comprehensive Cancer Network (NCCN) recommends excision for all LN found at CNB.17 Management of ALH remains controversial, however, as the upgrade rate is relatively low and imaging follow-up is now becoming more of a consideration. LCIS is typically surgically excised. The need for clear margins is controversial but typically not essential.13 PLCIS treatment, on the other hand, is similar to DCIS, often requiring clear margins (optimally > 2mm) with possible radiation.13 Variants such as LCIS with necrosis or florid LCIS may be treated similarly.18 Unfortunately, LCIS may be multifocal and margins may be difficult to clear.13

LN is considered a precursor lesion by the World Health Organization.12 Lobular neoplasia carries with it increased risk for subsequent development of breast cancer. LCIS also carries a 2% per year cancer risk leading to a 26% cumulative risk over 15 years.19 Subsequent cancers arise 3 times more frequently with LCIS than with ALH. Relative risk for the development of invasive breast cancer is 9 times higher after an LCIS diagnosis and 4 to 5 times higher after an ALH diagnosis,20 of which approximately 77% of the subsequent cancers are ductal in origin.11 LCIS is clonally related to synchronous invasive lobular cancer (ILC) and DCIS in 42% of cases.21 Given this risk, excision versus imaging follow-up is not the only treatment consideration. Risk reduction with chemoprevention is often recommended. Classic LCIS is 100% estrogen receptor (ER) and progesterone receptor (PR) positive and pleomorphic LCIS is 72% to 100% ER positive.18

Atypical Ductal Hyperplasia

ADH presents pathologically as a neoplastic epithelial proliferative lesion of the mammary TDLU with micropapillary, tufts, bridges, or solid and cribriform patterns of evenly distributed, monomorphic cells with rounded or ovoid nuclei. ADH resembles low-grade DCIS microscopically and differs only in quantitative measurements. This similarity makes adequate sampling important. One definition of ADH is atypical cells partially or completely filling two or fewer ducts. If more than two duct spaces are involved, then DCIS is the diagnosis. An alternative definition of ADH is when the epithelial cells occupy < 2 mm in maximum dimension. If the cells occupy > 2 mm, the diagnosis would be considered DCIS.

On imaging, ADH frequently presents as microcalcifications but may also present as a mass, asymmetry, or architectural distortion. An example of ADH presenting as calcifications is shown in Figure 6. Although ADH may be occult on ultrasound, it can rarely present as a hypoechoic mass. Often the MRI presentation of ADH is clumped linear nonmass enhancement similar to that of DCIS (Figure 7).

Management of ADH is debated. ADH is common and may be found in 8% to 37% of CNB specimens.22-25 ADH has a variable upgrade rate from 22% to 65%.22,24,25 Attempts to identify clinical, pathological or molecular biomarkers to predict risk factors for upgrade to malignancy have been unsuccessful.23-26 Furthermore, breast cancer risk with ADH is 4 to 5 times that of the general population with a 6 times higher risk in premenopausal women and 10 times higher risk in patients with a family history of breast cancer.22-25 Factors associated with upgrade of ADH include: age > 50, large lesion size, removal of < 95% of calcifications in the absence of an associated mass, smaller needle diameter at core biopsy (12 to 16 gauge), shorter length of biopsy core (< 2 cm), ipsilateral breast symptoms, other mammographic lesions in addition to microcalcifications, concomitant papilloma diagnosis, and severe ADH.

Excisional biopsy is the typical recommendation for ADH.27 Identifying low-risk groups that may be safely observed is the focus of current research efforts.25,26 Increasing evidence suggests that a small volume of ADH, if completely excised on CNB and shown to be concordant on imaging and pathology, may be observed with close follow-up.23,24,28,29 Long-term counseling for women with ADH should include discussion of breast cancer risk, surveillance strategies, and options for prevention therapy.

Radial Scar/Complex Sclerosing Lesions

Radial scars (RS) and complex sclerosing lesions (CSL) may arise from injury, duct ectasia or chronic inflammation. RS has a stellate pattern with a fibroelastic core surrounded by ducts and lobules that merge within the center of the lesion (Figure 8).30 RSs are typically described as < 1 cm, and CSLs are > 1 cm. Sometimes they are difficult to differentiate from malignancy because of the infiltrative appearance. RSs and CSLs are frequently found as incidental lesions identified at biopsy. Patients are usually asymptomatic. The utilization of tomosynthesis has significantly increased the number of biopsies demonstrating these pathologies.

Mammographically, the classic presentation of these lesions is architectural distortion (Figure 9). Additionally, they may present as a focal asymmetry or mass. Infrequently, calcifications may be associated with these lesions (Figure 10).31 RSs and CSLs are often occult on ultrasound but may present as a mass with associated architectural distortion. Although the MRI appearance is variable, architectural distortion is often present. RSs and CSLs may also present as irregular masses, nonmass enhancement, or small foci of enhancement. Figure 11 demonstrates a CSL presenting as NME on MRI. Furthermore, RSs and CSLs may be occult on MRI. This is important to note because a lack of enhancement may be a predictor of benignity.

RSs without atypia demonstrate variable upgrade rates of 0% to 40%. Factors associated with increased risk for upgrade include size > 2 cm, age > 50 years, and the presence of another high-risk lesion. Therefore, excision may be warranted in cases with these associated factors. In addition, factors that appear to be associated with a lower upgrade or no upgrade risk include biopsies performed with vacuum assistance, a larger gauge needle, and increased number of cores taken. Follow-up can be considered for smaller, incidental lesions when large-core, vacuum-assisted sampling is performed.32 The current management of MRI-detected RSs is excision as there is a 15% upgrade rate even without atypia.31 In addition to upgrade risk, RSs have been shown to be an independent risk factor for breast malignancy in some studies, increasing risk to 1.8 times the average breast cancer risk. If atypia is associated with an RS, the risk of malignancy is higher than with atypia alone.32

Flat Epithelial Atypia

Flat epithelial atypia (FEA) presents pathologically as an enlarged TDLU lined by a single or 3 to 5 layers of tightly packed columnar epithelial cells with prominent apical cytoplasmic snouts and intraluminal secretions (Figure 12).33,34 Cells have clear or granular cytoplasm, increased nuclear to cytoplasmic ratio, loss of orientation, and incremental irregularities without complex architectural atypia.

FEA frequently occurs in asymptomatic patients, detected incidentally. The most common characteristic of FEA across all imaging modalities is an occult presentation. On mammography, it can present as grouped amorphous calcifications. Less commonly, FEA is associated with fine pleomorphic and coarse heterogeneous calcifications. On ultrasound, it may present as an irregular mass, and on MRI it may be associated with nonmass enhancement as depicted in Figure 13.

Epithelial atypia is relatively rare, reported in 1% to 17% of breast biopsies.35 Additionally, the upgrade rate is variable ranging 0% to 20%.35 The rate increases with concomitant HRLs. FEA frequently coexists with ADH, lobular neoplasia, and indolent malignancies (tubular carcinoma). Figure 14 demonstrates an example of DCIS with associated FEA presenting as calcifications. Factors associated with increased risk for upgrade rate include older age, African American race, utilization of hormone replacement therapy, and calcifications in the biopsy specimen.35

Management of FEA is typically excisional biopsy.36 Patients with adequate sampling, probable compliance with follow-up, focal pure FEA in the absence of residual calcifications, radiology-pathology concordance, and without personal history of breast cancer may undergo surveillance.37 No single factor can decide if isolated FEA on CNB should forgo excision. A multidisciplinary evaluation tailored to each patient appears to be the most feasible approach to optimize management.36.38

Papillary Lesions

Papillary lesions are described as the proliferation of epithelial cells surrounded by a fibrovascular stalk (Figure 17D). Myoepithelial cells may or may not be present. Papillary lesions may be benign but also may be associated with atypia, noninvasive malignancy, and invasive malignancy. Benign solitary central papillomas typically arise from a large central duct. Peripheral papillomas develop in smaller ducts and may be multiple.

On imaging, central papillomas can present as subareolar masses. They may also be symptomatic, presenting with spontaneous clear or bloody nipple discharge. Furthermore, approximately 25% are associated with calcifications. Papillomas may also present as solitary dilated ducts (Figure 15). Peripheral papillomas, on the contrary, may present as oval masses but are usually further from the nipple and not in the immediate subareolar region. Peripheral papillomas are typically asymptomatic at presentation. On ultrasound, papillary lesions may present as hypoechoic, solid, oval masses or complex cystic and solid masses (Figure 16). An intraductal mass or cyst with a small mural mass is also a classic presentation. Vascularity is sometimes identified in the fibrovascular stalk. Papillary lesions may be identified on MRI examination as oval or round masses that demonstrate homogeneous or heterogeneous enhancement. Galactography is sometimes used to evaluate nipple discharge. Papillomas will appear as intraluminal filling defects on this imaging modality. Figure 17 demonstrates the imaging work-up for a patient presenting with nipple discharge.

Papillary lesions convey a twofold increased risk for breast cancer development. Papillomas without atypia have a relatively low upgrade rate around 2.3%.39 As mentioned previously, papillomas may present with pathologic nipple discharge. If the nipple discharge persists following biopsy, excision is recommended for symptomatic treatment. However, without clinical symptoms, conservative management with follow-up imaging in 6 to 12 months may be considered. Additional factors may be utilized to determine whether conservative management is appropriate. Such factors include the following: radiologic-pathologic concordance, vacuum-assisted biopsy device utilization, small size (< 1 to 1.5 cm), being nonpalpable at presentation, and central location. Fulfillment of such criteria may support conservative management. Papillomas with atypia have a significantly higher upgrade rate of up to 36.9%.40 Surgical excision is recommended for all papillomas with atypia.

Conclusion

Management of benign disease is an important aspect of patient care in breast imaging. Since the literature is constantly evolving, recommendations also change to reflect these updates. From this review of past and recent data, suggestions for management strategies are summarized in Table 1. In addition, an integrated approach is needed to consider patient factors such as past medical history, family history, and clinical presentation. This approach ensures thorough patient evaluation and appropriate multidisciplinary care.

Disclosure

Reprinted/Adapted with permission from ARRS Exhibit—Risky Breast Business. Discussion of High Risk Lesions of the Breast. Amy Newton, Kathryn Zamora, Stefanie Woodard, Leeann Denham, Shi Wei. Annual meeting (virtual) 2020.

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Zamora K, Newton A, Denham SL, Wei S, Woodard SA.  High-Risk Lesions: Review and Management Update.  J Am Osteopath Coll Radiol.  2021;10(1):6-18.

About the Author

Kathryn Zamora, M.D.; Amy Newton, M.D.; S. LeeAnn Denham, M.D.; Shi Wei, M.D., Ph.D.; Stefanie A. Woodard, D.O.

Kathryn Zamora, M.D.; Amy Newton, M.D.; S. LeeAnn Denham, M.D.; Shi Wei, M.D., Ph.D.; Stefanie A. Woodard, D.O.

Drs. Zamora, Denham, and Woodard are with the Department of Radiology, The University of Alabama at Birmingham, Birmingham, AL; Dr. Newton is with the Department of Radiology, Brookwood Baptist Health, Birmingham, AL; and Dr. Wei is with the Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL.



 

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