Context.—

Atypical ductal hyperplasia (ADH) is a challenging diagnosis defined by cytologic and architectural features that carries an increased risk of subsequent carcinoma when diagnosed in isolation. In addition, ADH may secondarily involve benign breast lesions, wherein it carries variable clinical significance.

Objectives.—

To review the diagnostic criteria and clinical significance of ADH in isolation and as it involves benign breast lesions, and to review the evolving literature on its molecular signature.

Data Sources.—

Recently published studies that collectively examine ADH were reviewed.

Conclusions.—

Atypical ductal hyperplasia carries an increased risk of subsequent carcinoma in isolation and when it involves most benign breast lesions. Identifying which cases of ADH will be upgraded to carcinoma has been challenging, and new laboratory developments, such as EZH2 overexpression, may have a future role.

Atypical ductal hyperplasia (ADH) includes a group of lesions defined by cytologic and architectural features that resemble, but fall short, either quantitatively or qualitatively, of a diagnosis of low-grade ductal carcinoma in situ.1  Cytologic features include evenly spaced cells with round to ovoid, monotonous nuclei and distinct cell borders. Architectural features include round ductal spaces with smooth luminal borders and nonoverlapping cells, rigid bridging without attenuation (Figure 1, A through C), or micropapillae with a narrow base (Figure 1, D). However, those features are either admixed with usual ductal hyperplasia or show only partial involvement of the terminal duct lobular unit.2,3 

Figure 1

Hematoxylin-eosin–stained sections of atypical ductal hyperplasia showing low-grade, monotonous cytology with rigid bridging (A), partial duct involvement (B and C), and micropapillary architecture (D) (original magnifications ×400 [A], ×600 [B], and ×200 [C and D]).

Figure 1

Hematoxylin-eosin–stained sections of atypical ductal hyperplasia showing low-grade, monotonous cytology with rigid bridging (A), partial duct involvement (B and C), and micropapillary architecture (D) (original magnifications ×400 [A], ×600 [B], and ×200 [C and D]).

Close modal

Although ADH is primarily diagnosed by histologic features, immunohistochemical stains can be useful adjuncts to distinguish ADH from usual ductal hyperplasia. In ADH, there is an absence of staining for high–molecular-weight cytokeratins and the presence of diffuse expression of estrogen receptor, whereas usual ductal hyperplasia shows heterogeneous staining for both markers.47  Notably, those stains do not distinguish between ADH and ductal carcinoma in situ (DCIS) because both entities show an absence of staining for high–molecular-weight cytokeratins. Caution should be taken when using high–molecular-weight cytokeratin and estrogen receptor to evaluate for ADH in a setting of apocrine lesions because they are often negative for both markers, even in the absence of atypia.8  Similarly, columnar cell change in ducts also exhibits loss of high–molecular-weight cytokeratins, as well as diffuse expression of estrogen receptor in the absence of atypia.6,9 

Atypical ductal hyperplasia may secondarily involve benign breast lesions, including intraductal papillomas, fibroepithelial lesions, radial scars, and adenosis. Diagnostic criteria for atypia in such lesions are variably defined and carry differing risks of carcinoma, as highlighted below.

Atypical ductal hyperplasia involving papillomas and apocrine proliferations are examples of lesions with diagnostic criteria that differ from those of isolated conventional ADH. According to the World Health Organization classification, 4th edition,1  a diagnosis of papilloma with ADH (atypical papilloma) is warranted when the atypical epithelial focus is less than 3 mm (Figure 2, A and B). As with ADH in nonlesional parenchyma, papillomas with ADH carry a similar increased risk of carcinoma on subsequent excision.10  Apocrine proliferations include benign lesions, such as apocrine metaplasia, apocrine adenosis, and apocrine-rich papillomas, in addition to atypical and malignant lesions, including atypical apocrine adenosis, atypical apocrine hyperplasia, apocrine DCIS, and invasive carcinoma with apocrine features. Although still a difficult diagnosis, atypia within apocrine proliferations refers to significant cytologic atypia in the form of 3-fold nuclear enlargement, prominent and enlarged nucleoli, hyperchromasia, and cytoplasmic vacuoles.11,12  When apocrine changes are superimposed on architectural patterns characteristic of ADH, those lesions are termed atypical apocrine hyperplasia or ADH with apocrine features (Figure 2, C and D). Although few studies are available in evaluating atypical apocrine lesions, when atypical apocrine adenosis is encountered in isolation, there is a low risk of upgrade to carcinoma on subsequent excision, ranging from 0% to 5.4%.13,14 

Figure 2

Hematoxylin-eosin–stained sections of atypical ductal hyperplasia involving benign breast disease, including intraductal papilloma (A and B), apocrine adenosis (C and D), fibroadenoma (E and F), and radial scar (G and H) (original magnifications ×200 [A, C, F, and H], ×400 [B and D], and ×100 [E and G]).

Figure 2

Hematoxylin-eosin–stained sections of atypical ductal hyperplasia involving benign breast disease, including intraductal papilloma (A and B), apocrine adenosis (C and D), fibroadenoma (E and F), and radial scar (G and H) (original magnifications ×200 [A, C, F, and H], ×400 [B and D], and ×100 [E and G]).

Close modal

The diagnostic criteria of ADH involving fibroepithelial lesions and radial scars (complex sclerosing lesions) are the same as those for otherwise benign breast parenchyma. Atypical hyperplasia (ADH or atypical lobular hyperplasia) involving a fibroadenoma is an uncommon finding that, when confined to a fibroadenoma, does not carry a meaningful risk of carcinoma (Figure 2, E and F).15  Radial scars and complex sclerosing lesions are proliferative and exhibit stellate shapes and central elastoses and scleroses with entrapped ducts that mimic carcinoma. At the periphery, radial scars often show radiating ducts and lobules with a spectrum of proliferative changes, including atypical hyperplasia (Figure 2, G and H). A meta-analysis by Conlon et al16  reported an overall upgrade rate to carcinoma of 26% in excisions following a diagnosis of radial scar with atypia on core needle biopsy.

Since the initial report by Page et al2  in 1985, women with ADH have been recognized as a group at an increased risk for carcinoma.1720  Furthermore, ADH carries an overall increased risk of carcinoma in patients with benign immediate reexcisions.21  After a diagnosis of ADH on core biopsy, wire-localization excisional biopsy is generally indicated because the risk of upgrade to carcinoma on excision ranges to as high as 30.3%.2123 

Hartmann et al24  studied a cohort of 698 women with atypical hyperplasia (ADH and atypical lobular hyperplasia) over a mean follow-up of 12.5 years, of which 143 (20.5%) women developed carcinoma. Of women with ADH who developed carcinoma, 25% were diagnosed with DCIS, whereas 75% developed invasive carcinoma of either ductal or lobular types. The risk for ipsilateral compared with contralateral carcinoma was approximately 2:1 for both ADH and atypical lobular hyperplasia, and the risk for ipsilateral carcinoma was greatest within 5 years after diagnosis of atypia. In women who developed invasive carcinoma with an initial diagnosis of ADH, 31.0% of the invasive carcinomas were grade 1, 42.9% were grade 2, and 26.2% were grade 3. When compared with unselected breast carcinomas, an initial diagnosis of ADH correlated with a slightly lower average grade of invasive carcinoma.24,25 

Moreover, ADH has long been considered a direct precursor of low-grade ductal carcinoma.2628  Genetic profiling of ADH shows a gene expression signature similar to low-grade DCIS and low-grade invasive ductal carcinoma,29  supporting the theory that ADH is a direct precursor of low-grade DCIS and low-grade invasive ductal carcinoma.24,30  Frequent deletion of band 16q is seen in low-grade DCIS and low-grade invasive ductal carcinoma, whereas it is uncommon in high-grade DCIS.30,31 

There are several recent studies evaluating whether the number of foci of ADH can predict an increased risk of subsequent diagnoses of carcinoma, albeit with conflicting findings. Degnim et al32  showed a significantly increased risk of carcinoma with increasing numbers of foci (1, 2, or ≥3) of ADH on excisional or core biopsy in 2 independent cohorts from the Mayo Clinic benign breast disease study (n = 708) and Nashville benign breast disease cohort (n = 466). Although most specimens in the Degnim et al32  study were excisional biopsies, there was no significant difference in the number of foci of ADH identified in excisional biopsies when compared with core biopsies. Collins et al33  evaluated a nested case-control series among women in the Nurses' Health Study and the Nurses' Health Study II who had a previous diagnosis of benign breast disease (n = 488), and found a trend toward greater breast cancer risk with more foci of atypia on biopsy (type of biopsy not specified), although it did not reach statistical significance. Discordance has been attributed to limited statistical power of the smaller Collins et al33  study or differing study design.32  Alternatively, it has been suggested that, with increasing foci of ADH, it is possible that those lesions might be characterized as DCIS and, therefore, be excluded from the Collins et al32  study of benign breast disease.34  Such studies evaluating multiple foci of ADH may offer a new way to predict risk for subsequent carcinoma and warrant further validation.

Recent investigations into breast cancer biomarkers have implicated EZH2 (enhancer of zeste homolog 2) as having an important role in oncogenesis. EZH2 is a Polycomb group protein that regulates gene expression through epigenetic mechanisms. In breast cancer, EZH2 is overexpressed in approximately one half of invasive carcinomas and is significantly associated with poorly differentiated, estrogen receptor–negative tumors and development of metastasis.35,36  In vivo studies have shown that transgenic mice that overexpress EZH2 in mammary epithelial cells develop intraductal epithelial hyperplasia resembling the human counterpart,37  as well as acceleration of breast cancer development in breast cancer models.38 

Furthermore, when compared with benign breast tissue from breast reduction specimens in patients without a family history of breast cancer, we found that EZH2 expression was upregulated in morphologically benign breast epithelium that is adjacent to ADH and DCIS, as well as in morphologically benign breast tissue from patients with BRCA1.39  Based on those data, it has been postulated that increased expression of EZH2 may identify epithelium at an increased risk of carcinoma and may better predict an upgrade of ADH to carcinoma at excision. The role of EZH2 as an independent biomarker for increased risk for carcinoma in benign breast disease is supported by a recent nested case-control study within the Nurses' Health studies.40  Although significant work remains before incorporation into clinical practice, there is potential for cost reduction by improving stratification of upgraded risk.41 

The diagnosis of ADH requires features of both cytologic and architectural atypia and is one of the most challenging diagnoses in breast pathology, particularly when involving benign breast lesions, such as apocrine, papillary, or sclerosing lesions. Atypical ductal hyperplasia carries an increased risk of subsequent carcinoma and is considered a nonobligate and direct precursor of low-grade ductal carcinoma, with which it shares genomic alterations. Identifying which cases of ADH will be upgraded to carcinoma has been difficult; however, new laboratory developments, such as EZH2 overexpression, may have a future role in that identification.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.

This work was presented in part at the New Frontiers in Pathology meeting; University of Michigan; October 19–21, 2017; Ann Arbor, Michigan.