As UDH is a microscopic finding, there is no specific macroscopic abnormality unless the UDH occurs within an underlying lesion such as a cyst, radial scar, or papilloma.

Mild UDH shows three to four layers of epithelial cells lining the walls of ducts. The epithelial cells project into the duct lumens without anastomosis, bridging, or fusion of the epithelial tufts. The inner lining of the duct has a ruffled appearance due to irregular protrusions of the hyperplastic epithelial cells (Fig. 9.2). In moderate UDH, epithelial cells exceed four layers and efface part of the duct lumen. Epithelial nuclei are crowded and overlapped, with ovoid-to-elongated shapes. Irregular, slit-like spaces may be observed, particularly at the periphery of the epithelial proliferation (Figs. 9.3, 9.4, and 9.5). Florid or marked UDH shows an exaggerated appearance of epithelial proliferation obscuring the duct lumen, sometimes filling the lumen completely. Nuclei are overlapped and have a streaming pattern. Nuclear grooves, pseudoinclusions, occasional mitoses, and even necrosis can be seen (Figs. 9.6, 9.7, and 9.8).

UDH shows a heterogeneous epithelial population with uneven nuclear placement and overlapping. Spaces are irregular, rimmed by swirling epithelial nuclei with their longitudinal axes aligned around the spaces. Atypical ductal hyperplasia (ADH) and low nuclear grade DCIS, on the other hand, show areas of cytoarchitectural atypia, with clonality as evidenced by the uniform cell population within a rigid architectural framework, where well-defined cribriform spaces and rigid micropapillae are present. Immunohistochemistry for CK5/6, CK14, and oestrogen receptor (ER) can help distinguish UDH from ADH and low nuclear grade DCIS, with CK5/6 and CK14 demonstrating a heterogeneous cell population with mosaic-like staining pattern for UDH, compared with diminished to absent reactivity in ADH and low nuclear grade DCIS. Similarly, ER is patchily reactive with variable nuclear immunostaining intensity in UDH, whereas it is diffusely and strongly positive in ADH and low nuclear grade DCIS (Figs. 9.9, 9.10, 9.11, 9.12, 9.13, 9.14, and 9.15).

Sometimes, the heterogeneous appearance of epithelial cells with reactive nuclear atypia in moderate and florid UDH may mimic intermediate nuclear grade DCIS (Figs. 9.16 and 9.17). The presence of mitoses and necrosis which may be encountered in UDH may exacerbate the differential diagnostic challenge. Clues to a benign diagnosis are the epithelial nuclear features of UDH, with vesicularity and smooth nuclear contours without clumpy chromatin or prominent nucleoli. These epithelial cells are often admixed with ovoid, darker myoepithelial cells. The haphazard overlapping placement with slit-like spaces and supportive immunohistochemistry allow a correct diagnosis.

There are no specific gross alterations. Cysts may be observed if there is accompanying cystic change of ducts and ductules. Grittiness related to calcifications can be present when the tissue is sliced.

Histologically, columnar cell change features mild dilatation of terminal ducts and ductules surrounded by a loose stroma, which may appear slightly cellular. Lining epithelial cells disclose columnar shapes with vertical axes exceeding their widths, set perpendicularly to the underlying basement membranes. Nuclei are ovoid or elongated and are also oriented along the vertical plane. Apical snouts, luminal secretions, and calcifications are often present. Columnar cell hyperplasia shows multiple layers of columnar epithelial cells, leading to an irregular, ruffled luminal contour, often with a micropapillary or mound-like appearance.

In flat epithelial atypia, epithelial cells become more cuboidal in shape, with slightly enlarged, rounded, vesicular nuclei that have discernible but usually small nucleoli. Because of cellular uniformity and monotony, the luminal surface appears relatively flat and rigid at low magnification. Additionally, there is a darker appearance that is due to increased nuclear–cytoplasmic ratios. As in columnar cell change, luminal secretions and calcifications are frequently present. By definition, if architectural atypia is observed in such a lesion, it should be classified as ADH. Lobular neoplasia, ADH, and low-grade in situ and invasive carcinomas can be found in proximity because of the similar genetic abnormalities [1] (Figs. 9.24 and 9.25).

In UDH, there is variability of the epithelial cell population without distinct columnarity, contrasting against columnar cell change or hyperplasia, in which the epithelial cells assume columnar shapes, with stratification in columnar cell hyperplasia. On immunohistochemistry, ER shows patchy nuclear reactivity in UDH, whereas columnar cell change or hyperplasia is usually diffusely ER positive (Fig. 9.26). Similarly, columnar cells are nonreactive with basal cytokeratins, whereas heterogeneous basal cytokeratin staining is observed in UDH.

The distinction between columnar cell change or hyperplasia and flat epithelial atypia rests on the presence of nuclear atypia. This distinction may be rather subjective [2, 3], making consistent diagnosis of flat epithelial atypia challenging. It was reported that nuclear size is increased in flat epithelial atypia [4]. Clues to flat epithelial atypia include a relatively rigid luminal contour and darker-appearing cells (because of increased nuclear–cytoplasmic ratios) with more cuboidal shapes, rounded nuclei, and visible nucleoli.

The cells of flat epithelial atypia are similar to those of ADH or low nuclear grade DCIS. The key difference is the presence of architectural atypia in the latter, with patterns of micropapillary, cribriform, solid, and papillary morphology.

High nuclear grade features of a single layer to a few layers of abnormal cells lining duct walls should be diagnosed as DCIS. High nuclear grade cytological atypia is incompatible with flat epithelial atypia (Figs. 9.27, 9.28, 9.29, and 9.30).