The term UDH refers to a non-neoplastic epithelial proliferation. It can range from mild, consisting of just two to four cell layers, to florid, when it entirely fills and distends the ducts. UDH arising in a radial scar or in a papilloma can show focal necrosis, raising the differential diagnosis of DCIS. The cells comprising UDH are cytologically benign, vary in size, shape and orientation, have poorly defined borders, and are haphazardly arranged (Fig. 21-1B). Fenestrations lined by non-polarized cells are usually present within UDH, and often have circumferential distribution along the periphery of a duct.

Low and heterogenous expression of ER occurs in 30% to 40% of UDH cells, mainly at the periphery of the lesion. The proliferation rate is low (2%-5%). UDH shows a mosaic staining pattern for the basal keratins CK5/6 (see Fig. 21-1C) and 34BE12 (4). The pattern of immunoreactivity helps distinguish UDH from ADH and focal DCIS, as the latter two lesions are usually negative for these antigens with very few exceptions. Although some high-grade DCIS is CK5/6-positive, as discussed later in this chapter, nuclear atypia and pleomorphism distinguish it from UDH. UDH is associated with a 1.5- to 2-folds increase in the risk of breast cancer, which may occur in either breast. The risk is slightly higher in women with UDH who also have a first-degree relative with breast carcinoma (5).

Few and inconsistent genetic alterations have been documented in UDH, but no substantial shared genetic abnormalities with ADH, DCIS, or invasive breast cancer have been
identified (6). Studies have shown that chromosomal loss of heterozygosity (LOH) is lower in UDH (4.5%-13%) than in ADH and low-grade DCIS (7). Comparative genomic hybridization (CGH) has identified few unbalanced chromosomal aberrations in UDH in some studies (8), but not in others (9). Some of the studies reporting chromosomal alterations in UDH used whole genome amplification methods (8) which may be more susceptible to artifacts. Overall, the chromosomal aberrations found in most UDH lesions are not similar to those observed in invasive carcinoma, effectively ruling out the possibility that UDH might represent a morphologic precursor of breast carcinoma (6).

FEA consists of enlarged TDLUs in which the native epithelial cells are replaced by “one to several layers of a single cell type showing low-grade (monomorphic) cytologic atypia” (10) (see Fig. 21-2A). The involved TDLUs have variably dilated acini with rounded contour. The nuclei of FEA cells are monomorphic, round to ovoid, and resemble those of ADH and low-grade DCIS. The proliferation is architecturally “flat” and devoid of any complex pattern (i.e., micropapillae, focal rigid bridges, bars and arcades, or sieve-like fenestrations) seen in ADH and low-grade DCIS. Lesions currently classified as FEA have been previously referred to by a wide range of terms, most notably “clinging carcinoma of the monomorphic type” and “columnar cell change with atypia.” Columnar cell change, columnar cell hyperplasia, and FEA often coexist in adjacent lobules and even within the same TDLU. These diagnoses are not mutually exclusive, but only FEA has cytologic atypia.

The cells of FEA are positive for low-molecular-weight CKs, such as CK8, CK18, and CK19 (9). Even though FEA cells lack expression of high-molecular-weight CKs, such as CK5/6 (9, 11), immunohistochemical stains for CK5/6 do not help to differentiate FEA from monostratified normal ductal epithelium, as the latter is also CK5/6 negative. In FEA strong positivity for ER is present in about 85% of the cells (9, 12) and for PR in about 50% (9, 12). The cells are characterized by strong cytoplasmic expression of bcl-2, and show minimal to no apoptosis (12). The proliferation index of FEA is significantly higher than in morphologically normal TDLUs (6% vs. 2%, respectively) (12).

FEA commonly coexists with ADH (see Fig. 21-2B), lowgrade DCIS and tubular carcinoma, and shares close cytologic and immunophenotypic similarities with these lesions (1, 13, 14). Few investigators have also noted an association between columnar cell lesions/FEA and lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH) (see Fig. 21-2B-C) (13, 15).

Molecular analysis shows that FEA has recurrent chromosomal alterations consistent with a clonal population (9, 16). Recurrent copy number alterations include loss of 16q and gains of 15q, 16p, 17q, and 19q. Allelic imbalances are most frequently seen at 3p, 9q, 10q, 11q, 16q, 17p, and 17q (16).

Based on these findings FEA is part of the spectrum of low-grade mammary epithelial lesions (Fig. 21-3A), which include ADH, low-grade DCIS, tubular and tubulolobular carcinoma, invasive cribriform carcinoma, low-grade invasive ductal carcinoma, ALH, classic LCIS and invasive lobular carcinoma, classic type. It has been proposed that FEA represents the first morphologically recognizable precursor of low-grade mammary neoplasia (9, 14). The risk of subsequent carcinoma associated with FEA has not been fully determined, but it is believed to be lower than for ADH (10). At present, no additional treatment or special screening modalities are recommended for patients with only FEA (10).

ADH is a very focal neoplastic epithelial proliferation confined to the mammary ductal-lobular system. The cells composing ADH are relatively small and monomorphic, with round to avoid nuclei, fine chromatin and inconspicuous nucleoli. They tend to be evenly spaced, show well-defined cell borders and focally form rigid arches and bridges (see Fig. 21-2D), trabecular bars of uniform thickness, or club-shaped micropapillae. They can also display solid foci or focal incomplete cribriform pattern, which results from the orderly arrangement of polarized cells around a neoformed glandular lumen. These cells are morphologically similar to those composing low-grade DCIS, but they are not as homogeneous. Extent of the lesion is an important criterion in differentiating ADH from low-grade DCIS, although there is no universally accepted size cutoff to distinguish between the two. Usually DCIS is diagnosed when the neoplastic proliferation involves at least two separate ducts or spans at least 2 mm, and any smaller lesion is classified as ADH. The diagnosis of ADH applies only to lesions for which the differential diagnosis of low-grade DCIS is considered, but that do not show the full range of diagnostic features. Despite undeniable limitations, the use of size criteria fosters interobserver reproducibility in the interpretation of small borderline ductal lesions.

The cells comprising ADH typically have strong and nearly uniform (90%-100%) positivity for ER and PR, but no cytoplasmic reactivity for CK5/6 (11) and 34BE12 (4). The use of these markers is of no practical value in the differential diagnosis with low-grade DCIS, but can be useful in the differential diagnosis with UDH, that is positive with a checkerboard pattern (see Fig. 21-1C). ADH has a low proliferative rate (4%-5%).

Recurrent chromosomal alterations including losses at 16q and 17p and gains at 1q (9) have been identified in ADH, similar to the changes found in low-grade DCIS as well as in the lesions part of the low-grade mammary epithelial neoplasia family (see Fig. 21-3A).

ADH is associated with a four to five-fold increase in the risk of subsequent breast cancer, with approximately equal frequency in both breasts.

The normal breast often shows apocrine metaplasia. Apocrine metaplastic cells are enlarged, have abundant finely granular, and eosinophilic cytoplasm, large round vesicular nuclei, prominent eosinophilic nucleoli and intracytoplasmic vacuoles (17). The degree of nuclear enlargement and prominence of the nucleoli can be worrisome and misleading, unless the apocrine nature of the process is recognized. Usually apocrine metaplasia is an incidental finding and coexists with benign or malignant lesions.

Apocrine atypical cells are characterized by enlarged nuclei with at least three-fold variation in size (17). The distinction between atypical apocrine adenosis and apocrine DCIS can be challenging, especially when the apocrine proliferation involves sclerosing adenosis or a sclerosing lesion. In equivocal cases a conservative diagnosis of atypical apocrine adenosis is usually preferable. Atypical apocrine adenosis in a core needle biopsy mandates excision.

When atypical apocrine epithelium is present in sclerosing adenosis, the combination of epithelial cells with enlarged nuclei and prominent nucleoli and glandular
distortion produces a pattern that can mimic invasive apocrine carcinoma. Immunostains for MEC markers are useful in the differential diagnosis with invasive carcinoma.

Intraductal apocrine lesions are typically androgen receptor (AR) positive and frequently lack ER and PR expression. HER2 expression has not been reported in benign apocrine lesions, but it has been described in up to 50% of in situ and invasive apocrine carcinomas (18).

Genetic studies of apocrine metaplasia have shown that at least a proportion carries genetic changes, suggesting that some lesions are clonal and may represent non-obligate morphologic precursors of carcinoma (19, 20). Selim et al. (20) assessed LOH in 41 cases of benign apocrine lesions with different degrees of architectural complexity and found that 20% of cases showed allelic alterations in at least one chromosomal locus. Jones et al. (19) used CGH to compare 10 cases of apocrine micropapillary hyperplasia, 10 apocrine DCIS, and 4 invasive apocrine carcinomas, and found that the number of unbalanced genetic aberrations was directly related to the complexity and atypia of the lesion. In particular, the mean number of chromosomal alterations in apocrine hyperplasia was 4.1 compared to 10.2 in apocrine DCIS and 14.8 in invasive apocrine carcinoma. The most common alterations in apocrine hyperplasia included
gains of 2q, 13q, and 1p, and losses of 1p, 17q, 22q, 2p, 10q, and 16q (19). Apocrine in situ and invasive carcinomas most commonly showed gains of 1q, 2q, and 1p, and losses of 1p, 22q, 17q, 12q, and 16q (19).

The breast cancer risk associated with apocrine adenosis and atypical apocrine adenosis has not been well defined. In one study, none of 47 patients with atypical apocrine adenosis developed cancer at a mean follow-up of 35 months (21). A study of 37 patients with mean follow-up of almost 9 years documented a relative risk of 5.5 (17), but the authors acknowledged that some of their index cases may have represented apocrine DCIS involving sclerosing adenosis rather than atypical apocrine adenosis. A recent study (22) of 37 patients with atypical apocrine adenosis and average followup of 14 years identified 3 out of 37 women (8.1%) who developed breast carcinoma. In one patient DCIS was diagnosed in the contralateral breast after a 12 year follow-up. Two patients developed ipsilateral invasive carcinoma after 4 and 18 years. No apocrine atypia was present in the background breast parenchyma and the tumors showed no evidence of apocrine differentiation. Despite the limited number of study patients, the authors concluded that atypical apocrine adenosis does not appear to be an aggressive lesion and it should not be regarded as a direct precursor of breast carcinoma (22).