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Overall, high-risk lesions have a low risk of malignancy. Nevertheless, up to 35% of lesions of uncertain malignant potential (B3) are subsequently upgraded at surgical specimen to DCIS or low-grade carcinoma [5]. These lesions are highly heterogeneous and can be classified according to the presence or absence of assoc... |
The purpose of this work is to provide the reader with an accurate overview focused on the main high-risk lesions of the breast: atypical intraductal epithelial proliferation (AIEDP), lobular neoplasia (including the subcategories lobular carcinoma in situ and atypical lobular hyperplasia), flat epithelial atypia, radi... |
[TABLE] Consensus recommendations for the management of B3 lesions |
High-risk lesion | Management |
Lobular Neoplasia (LN) | Surgical excision or VAEIf after VAB, the lesion has been radiologically removed, imaging follow-up is recommended |
Atypical Intraductal Epithelial Proliferation (AIDEP) | Surgical excision or VAEVAE is suggested in unifocal ADH in small lesionsIf the lesion has been removed completely and only focal ADH with calcifications exists, imaging follow-up recommended |
Flat Epithelial Atypia (FEA) | VAEIf after VAB, the lesion has been radiologically removed, imaging follow-up |
Papillary Lesion (PL) | |
With atypia | Surgical excision and imaging follow-up |
Without atypia | VAE |
Phyllodes Tumor (PT) | Surgical Excision |
Radial Scar (RS) | |
With atypia | VAE and imaging follow-up |
Without atypia | VAE |
## Atypical ductal hyperplasia |
Atypical ductal hyperplasia (ADH) is one of the most common B3 lesions of the breast and the one with the highest risk of malignant transformation. It is therefore considered a non-obligate precursor of invasive cancer as well as an independent risk factor for breast cancer [15, 16]. ADH represents an intraductal proli... |
ADH is diagnosed in 12–17% of percutaneous biopsies [17] in patients from a wide age range, from adolescence to old age [18]. ADH is defined by atypical epithelial proliferation restricted to one terminal ductal-lobular unit (TDLU) of ≤ 2 mm in maximal extension. Of note, the differential diagnosis between ADH and low-... |
Upgrade rates to DCIS or invasive carcinoma from core needle biopsy to excision in the literature range from 0 to 62% for ADH [20]. The reported average upgrade rates for ADH are: 44% for 14-gauge spring-loaded stereotactic core biopsy, 24% for 14-gauge directional VAB, and 19% for 11-gauge VAB needles [21]. In Table 2... |
[TABLE] Upgrade rates for high-risk lesions [5, 15, 22–26] |
High-risk lesion | Upgrade rate to malignancy | Upgrade Rate to Malignancy by Core-Needle Biopsy (CNB) or Vacuum-Assisted Biopsy (VAB) |
Lobular neoplasia (LN) | 17% (95% CI 13–21%) | Overall range 0–40% |
Atypical lobular hyperplasia (ALH) | 12% (95% CI 5–21%) | CNB (14G) 16%VAB (9G): 6–25.4% for ALH and LCIS |
Lobular carcinoma in situ (LCIS) | 22% (95% CI 14–31%) | CNB (14G) 25%VAB: 6–25.4% for ALH and LCIS |
Atypical Intraductal Epithelial Proliferation (AIDEP) | 28% (95% CI 24–31%) | CNB (14G) 31%VAB (14G) 24% & (11G) 19% |
Flat epithelial atypia (FEA) | 11% (95% CI 8–14%) | CNB (14G) 10–21%VAB (11G) 6% |
Papillary lesion (PL) | 12% (95% CI 10–15%) | 13.2% |
No atypia | 7% (95% CI 4–10%) | CNB (14G) mean 3.9% (range 0–20%)VAB (11G) mean 7.7% (range 0–18.3%) |
Atypia | 32% (95% CI 23–41%) | CNB (14G) mean 46.7% (range 6.7–71.4%)VAB (11G) mean 33% (range 0–71%) |
Radial Scar or Complex Sclerosing Lesions (RS/CSL) | 8% (95% CI 6–11%) | |
No atypia | 6% (95% CI 2–13%) | CNB (14G) 9% (1–28%)VAB (11G) 1% (0–10%) |
Atypia | 18% (95% CI 8–32%) | CNB (14G) 33%VAB (11G) 2% (range 0–18%) |
### Histopathology |
Differentiating ADH from low-grade DCIS is challenging on histopathology and is often a diagnosis of exclusion, with cytological atypia and architectural changes similar to low-grade DCIS but with an involvement of no more than two membrane-bound spaces with an extent lower than 2 mm [18]. From the histological point o... |
### Immunoprofile |
Several studies have been performed to determine specific biomarkers for ADH, but currently no biomarker has been clinically validated. The limited data on the molecular biology of ADH demonstrates its close similarity to low-grade DCIS: Cells are positive for ER but negative for high molecular weight cytokeratins [18]... |
### Prognosis |
ADH is associated with a higher risk of invasive breast cancer, four to five times higher compared with the normal population [30]. In their study, Hartman et al. reported that of 698 women with either ADH (n = 330) or atypical lobular hyperplasia (n = 327) who later develop breast cancer, 69% of the women developed mo... |
### Diagnosis |
Imaging findings are not specific, and ADH can be found in the peripheries of a papillary lesion and even inside a fibroadenoma. At mammography, ADH can be seen as microcalcifications, mainly amorphous with grouped, linear, or regional distribution. It can also arise as a mass with or without microcalcifications. Only ... |
[TABLE] Summary of imaging characteristics for the most common high-risk lesions |
High-risk lesion | Imaging findings |
Lobular Neoplasia (LN) | Amorphous microcalcifications and grouped distribution |
Atypical Intraductal Epithelial Proliferation (AIDEP) | Fine pleomorphic microcalcifications and linear or segmental distributionIrregular-shaped small hypoechoic mass with micro-lobulated edges |
Flat Epithelial Atypia (FEA) | Grouped microcalcifications |
Papillary Lesion (PL) | A solid, round mass with well-defined borders; an intra-cystic mass; or a hypo-echoic, well-defined mass in a dilated ductWith internal vascular stalk and with/without microcalcifications |
Phyllodes Tumor (PT) | Ovoid high-density mass lesion with irregular edges and usually lobulatedLarge size |
Radial Scars (RS) | Radiolucent architectural distortion with or without calcifications |
### Management |
ADH has the highest risk of underestimation among all types of high-risk lesions. The diagnosis of ADH at CNB or VAB is challenging, since ADH can be an isolated finding or a small component of DCIS [14]. Kohr et al. reported a high rate of underestimation with both CNB and VAB, although the latter is more accurate [34... |
Initially, the first International Consensus Conference on lesions of uncertain malignant potential (B3 lesions) [14] recommended follow-up without surgical intervention for all ADH lesions determined to have been completely removed through percutaneous biopsies. However, the upgrade rate for this type of lesions was f... |
If clinical surveillance is elected, in women diagnosed with ADH before age 40, there is a lack of consensus between guidelines on how to follow these patients. The majority consider these patients more than average risk for developing breast cancer and close imaging follow-up, even with MRI, should be considered [30, ... |
## Lobular neoplasia |
Lobular neoplasia (LN) is considered both a risk indicator and a non-obligate precursor for breast cancer. LN is found in 0.5–4% of otherwise benign breast biopsies, and it can be seen at any age but is most frequent in premenopausal women [18, 38]. The lesion is multicentric in 85% of cases and bilateral in up to 67% ... |
### Histopathology |
The term lobular neoplasia is used to represent atypical epithelial lesions characterized by the proliferation of poorly linked monomorphic cells due to the lack of E-cadherin expression, with possible pagetoid diffusion into galactophorous ducts. According to World Health Organization (WHO) classification, atypical lo... |
The prognostic significance towards malignancy for ALH and LCIS is not supported by evidence to date. Therefore, on both CNB and VAB samples, they are classified as B3 lesions, whereas pleomorphic or florid LN are classified as B5a (malignant) lesions [41]. LN may also be associated with other lesions including scleros... |
### Immunoprofile |
Immunophenotyping and cytogenetic studies demonstrate similarities between LN and lobular invasive carcinoma as well as low-grade DCIS, namely high expression of estrogen receptor (ER) and progesterone receptor (PR), low Ki-67, and well-differentiated cytokeratin profile (CK5- and CK18+), and these findings lead some t... |
The lack of expression of E-cadherin can be helpful in differentiating LCIS from DCIS or for classifying a lesion as indeterminate. Although rare, LCIS can express E-cadherin, and so in all cases where a histologic sample cannot be surely classified as LCIS or DCIS, the definition “carcinoma in situ with mixed ductal a... |
### Prognosis |
Molecular analysis has demonstrated that LN is a clonal neoplastic proliferation and a precursor to invasive cancer. The relative risk of developing breast cancer is 4–12 times higher for women diagnosed with LCIS compared with women without LN, and 4 to 5 times higher for women with ALH compared with women without LN.... |
A study by Genco et al. which evaluated the upgrade rate after surgical removal of classic LN showed that the upgrade rate was significantly higher for cases with previous or current breast cancer, radiologic asymmetry, and architectural distortion [50]. |
After the diagnosis of LN, the relative risk of developing cancer is 1–2% after one year, 15–17% after 15 years, and 35% after 35 years, with relatively equal rates of ipsi- and contralateral breast cancer (8.7 and 6.7%, respectively) [5, 33, 38]. The risk further doubles when the presence of proliferating high-risk le... |
### Diagnosis |
LN has no typical radiological or clinical manifestations; it is usually discovered fortuitously in breast tissue biopsied for other reasons [14], often as an incidental lesion in association with other radiological abnormalities [52, 53] and without any specific features according to the Breast Imaging Reporting and D... |
On mammography, LN usually goes unnoticed, but when detected, it can be seen as microcalcifications, with amorphous morphology and grouped distribution [31, 38, 55]. In Rendi et al.’s study which included 106 cases of LN (73 ALH and 33 LCIS), imaging findings on mammography led to a biopsy in 74% of the cases [55]. Les... |
### Management |
Management of classic LN diagnosed on CNB remains controversial even though recent studies recommend conservative management based on the low upgrade rate reported [48, 58, 59]. Currently, the second International Consensus Conference on B3 lesions recommends that a lesion containing classical LN which is visible on im... |
Similar considerations for imaging follow-up of ADH have been made for LN. In women diagnosed with LN, close imaging follow-up with beast MRI should be considered, especially if other risk factors are present [30, 37]. |
## Flat atypical epithelia |
Flat atypical epithelia (FEA), also known as columnar cell changes with atypia or cellular hyperplasia with atypia, is a non-malignant, atypical lesion of the breast. The WHO defines FEA as a neoplastic intraductal alteration of the breast characterized by replacement of native epithelial cells by a single layer or thr... |
### Histopathology |
From the histological point of view, FEA appears as a neoplastic alteration in which normal luminal cells are replaced by one layer or three to five layers of columnar cells and the TDLU shows a low grade of atypia [45]. Cellular morphology can vary from the cuboid aspect to the columnar one, but usually bridges and mi... |
Generally, two forms of columnar metaplasia are distinguished: columnar cell changes, in which acini are lined by one or two layers of modified epithelial cells; and columnar cell hyperplasia, in which acini are lined by more than two layers of epithelial cells [65–67]. |
### Immunoprofile |
Immuno-phenotype studies show a correlation between FEA, DCIS, and invasive breast cancer [38]. In fact, FEA cellular types are strongly and widely positive for ER and PR, and negative for low molecular weight cytokeratin, with a low Ki-67 index [18, 45]. In addition, cytogenetic studies of FEA lesions associated with ... |
### Prognosis |
FEA is of great scientific interest as the morphological spectrum of intraductal proliferations from FEA to ADH and low-grade DCIS seems to represent a continuum. FEA seems to be associated with a very slight increased breast cancer risk (1–2 times), which is substantially lower than the risk due to ADH. While the brea... |
Forester et al. in their meta-analysis demonstrated that the upgrade rate to malignancy for FEA lesions is 11% [15]. Malignant findings after FEA diagnosed at CNB or VAB are usually in the form of ADH and low-grade DCIS, while invasive carcinoma (in most instances highly differentiated) can occur but less frequently [5... |
### Diagnosis |
As these lesions produce intraluminal secretions, they commonly present mammographically as fine amorphous or branching microcalcifications with associated marked duct dilatation [9, 74] (Fig. 4). Data about the presentation of FEA on ultrasound are scarce, but FEA can be detected as a non-specific mass with or without... |
### Management |
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