and Aysegul A. Sahin2
Division of Pathology, Singapore General Hospital, Singapore, Singapore
The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
KeywordsUsual ductal hyperplasiaColumnar cell lesionsAtypical ductal hyperplasiaDuctal carcinoma in situ
Intraductal proliferative epithelial lesions are a heterogeneous group that have in common an epithelial proliferation within the terminal ductal lobular unit of the breast. They affect women over a broad age range and are associated with varying risks of subsequent breast cancer. Some lesions, such as ductal carcinoma in situ (DCIS), may be direct but non-obligate precursors to invasive carcinoma.
Usual Ductal Hyperplasia
In usual ductal hyperplasia (UDH), epithelial cells proliferate to fill the duct space (Fig. 9.1). UDH is also referred to as usual epithelial hyperplasia, intraductal hyperplasia, epitheliosis, hyperplasia of usual type, and hyperplasia without atypia.
Breast duct cut in a transverse section shows a bilayered epithelial lining, with luminal epithelial cells rimmed by an outer myoepithelial layer. The myoepithelial cells here have a slightly myoid appearance with plump pink cytoplasm
Clinical and Epidemiological Features
UDH associated with cysts and fibrosis may present as breast lumpiness.
UDH does not have a characteristic radiological picture. Clustered amorphous, punctate, or pleomorphic microcalcifications can occur on mammography and can be mixed with or indistinguishable from microcalcifications of low-grade DCIS, atypical ductal hyperplasia, and other benign processes. On sonography, the appearance is diverse, ranging from well-defined lesions to indeterminate, ill-defined masses depending on the associated lesions.
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).
Usual ductal hyperplasia (UDH) of a mild degree, showing three to four layers of epithelial cells lining the duct wall, with a ruffled luminal contour
Moderate UDH. Epithelial cells pile and anastomose, forming secondary luminal spaces that have ruffled borders. Epithelial nuclei are crowded and heterogeneous. A stromal calcification is seen adjacent to the duct
Moderate UDH. The epithelial cells proliferate to form protrusions into the duct lumen, without traversing or effacing the lumen. A differential diagnosis is atypical ductal hyperplasia, but the epithelial tufts are non-rigid, with epithelial nuclei that appear heterogeneous and overlapping. Luminal spaces have gentle contours
Moderate UDH. (a) Proliferating epithelial cells protrude into duct lumens, forming soft arches that feature nuclei oriented in parallel to the direction of the arches. Secondary luminal spaces are variably sized and slit-like. (b) High magnification shows crowded and overlapped epithelial nuclei, with those along the arches being oriented parallel to the direction of the arch (arrow)
Usual ductal hyperplasia. A lobule shows UDH of varying degrees, with a predominance of florid UDH, where crowded epithelial cells efface the ductular lumens
Florid UDH with a heterogeneous population of epithelial cells filling the duct space, containing haphazardly placed nuclei that are overlapping. Irregular spaces are seen towards the periphery of the duct. Intranuclear inclusions (arrows) are present
Usual ductal hyperplasia. Darker, ovoid myoepithelial nuclei are seen at the periphery of the duct and are also occasionally discerned among the proliferative epithelial cells (black arrows indicate some representative myoepithelial nuclei). An intranuclear inclusion (red arrow) is seen
UDH Versus Atypical Ductal Hyperplasia/Low-Grade Ductal Carcinoma In Situ
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).
Florid UDH. (a) The duct space is filled with epithelial cells featuring crowded, overlapping, vesicular, ovoid-to-elongated nuclei with occasional grooves, with interspersed irregular, slit-like spaces. Longitudinal axes of epithelial nuclei tend to align around and parallel to luminal spaces. (b) High magnification shows a heterogeneous epithelial population with crowded and overlapping nuclei. The irregular slit-like spaces are lined by epithelial cells with nuclei that have their longitudinal axes oriented in parallel to the spaces
Usual ductal hyperplasia. Immunohistochemistry for CK14 shows mosaic-like positivity of epithelial cells in UDH. Peripheral myoepithelial cells are also decorated
Florid UDH. A duct is filled with a proliferation of epithelial cells with streaming nuclei, which show overlapping and crowding. A few slit-like spaces are present. The cell population is heterogeneous, with variable nuclear sizes
Florid UDH. CK5/6 immunohistochemistry shows a mosaic pattern of epithelial cell staining in ducts with UDH
Florid UDH. CK14 immunohistochemistry shows a mosaic pattern of epithelial cell staining in ducts with UDH. CK5/6 and CK14 staining patterns are usually similar, although sometimes antibody sensitivities may vary. A panel approach is recommended when immunohistochemistry is applied, using antibodies that the laboratory has validated and is familiar with
Florid UDH. ER immunohistochemistry shows a non-diffuse, patchy pattern of epithelial nuclear staining in ducts with UDH. Note that the staining intensity also varies, with a range of intensities from weak to strong
Florid UDH. Immunohistochemistry for p63 highlights peripheral myoepithelial cells, but it does not demonstrate the mosaic pattern of staining depicted with antibodies to high-molecular-weight keratins (CK5/6 and CK14) observed in UDH. Hence, p63 is less useful in differentiating UDH from atypical ductal hyperplasia (ADH) and low-grade ductal carcinoma in situ (DCIS)
UDH Versus Intermediate Nuclear Grade DCIS
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.
DCIS, intermediate nuclear grade. (a) Complete filling of the duct space by DCIS cells with variability in nuclear size and small intervening spaces among the epithelial cells is reminiscent of florid UDH. Clues to a more sinister nature are the atypical mitosis (arrow), karyorrhexis, and more pronounced cytologic atypia. Additionally, surrounding ducts show features of DCIS. (b) Higher magnification of the malignant epithelial cells shows moderate nuclear pleomorphism. Individual cell necrosis (arrow), karyorrhexis and a mitosis are present
DCIS, intermediate nuclear grade. Immunohistochemistry for CK14 shows a peripheral intact rim of positively staining myoepithelial cells, whereas the neoplastic DCIS population is largely nonreactive
Prognosis and Therapy Considerations
UDH is reported to be associated with a 1.5–2 times increased risk of subsequent breast cancer development, with the risk applicable to both breasts, but this estimate is based on long-term follow-up studies. Whether an individual woman with UDH will develop breast cancer is unknown, and currently UDH is not regarded as a significant risk factor that would alter clinical management.
Columnar Cell Change and Flat Epithelial Atypia
Columnar cell change is an alteration of the terminal ductal lobular unit featuring slightly dilated ducts and ductules lined by columnar cells that often possess apical snouts, accompanied by luminal secretions that not infrequently calcify (Figs. 9.18, 9.19, and 9.20). Columnar cell change is known by several other terms, including blunt duct adenosis, columnar alteration of lobules, columnar metaplasia, hyperplastic unfolded lobules, hyperplastic enlarged lobular units, and enlarged lobular units with columnar alteration.
Columnar cell change. At low magnification, several ductules within the enlarged lobule are slightly dilated
Columnar cell change. Luminal pink secretions are seen
Columnar cell change. In the duct, the lining epithelium is composed of columnar cells with the long axes of the nuclei oriented perpendicularly to the basement membrane. Where there is piling and stratification of nuclei, the term columnar cell hyperplasia is used. The apical portions of the columnar cells disclose apical snouts represented by cytoplasmic blebs
The term columnar cell hyperplasia is used when there is more than one layer of columnar epithelial cells.
Flat epithelial atypia is diagnosed when there is mild nuclear atypia in columnar cell change/hyperplasia, with slightly enlarged, rounded nuclei with visible nucleoli, with cytologic appearances similar to those of low nuclear grade DCIS (Figs. 9.21 and 9.22). Synonymous terms are columnar cell change with atypia or columnar cell hyperplasia with atypia.
Flat epithelial atypia (columnar cell change with nuclear atypia). The ducts are lined by a relatively flat layer of epithelial cells with apical snouts. There is a “dark” appearance of the epithelial cells at low magnification, contributed by the increased nuclear–cytoplasmic ratios. Psammomatous calcifications are observed
Flat epithelial atypia. Short, mound-like protrusions of epithelial cells may be encountered in flat epithelial atypia, but the presence of clear-cut architectural atypia in the form of micropapillae, arches, or bridges warrants the diagnosis of ADH
Clinical and Epidemiological Features
Columnar cell change and flat epithelial atypia are clinically asymptomatic lesions, which can be detected on mammographic screening because of the accompanying calcifications.
Clustered, indistinct amorphous-type, or fine pleomorphic microcalcifications that are deposited within the terminal ductal lobular units can be observed on mammography (Fig. 9.23). Cysts may be encountered on sonography if the columnar cell change or flat epithelial atypia is associated with cystic changes.
Columnar cell change and flat epithelial atypia are often associated with calcifications that are detected on mammography. Here, the calcifications are clustered and resemble crushed stones
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  (Figs. 9.24 and 9.25).
Columnar cell change with atypical lobular hyperplasia. Columnar cell change with nuclear atypia (flat epithelial atypia), ADH, lobular neoplasia, low-grade DCIS, and low-grade invasive carcinoma share similar genetic abnormalities and have been referred to as belonging to the low-grade neoplasia family of breast lesions. Here, a duct with luminal cells demonstrating prominent apical snouts is surrounded by discohesive lobular neoplastic cells that have also involved adjacent ductules
Columnar cell hyperplasia with lobular neoplasia. Several ductules lined by columnar cells with stratified nuclei, associated with calcifications, are present. Lobular neoplasia, with features bordering on lobular carcinoma in situ, is observed in the same lobule where mildly distended acini filled with a population of uniform and slightly discohesive cells are seen
UDH Versus Columnar Cell Change/Hyperplasia
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.
Columnar cell change. Oestrogen receptor (ER) staining shows relatively diffuse nuclear positivity of columnar cells
Columnar Cell Change/Hyperplasia Versus Flat Epithelial Atypia
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 . 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.
Flat Epithelial Atypia Versus Atypical Ductal Hyperplasia or Low Nuclear Grade DCIS
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.
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Flat Epithelial Atypia Versus High Nuclear Grade DCIS
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).
DCIS, clinging subtype, resembling flat epithelial atypia at low magnification. Luminal pink secretions, rectangular crystals, and calcifications are present
DCIS, clinging subtype, at medium magnification, shows mostly single-layered epithelium with apical snouts
DCIS, clinging subtype, with moderate to marked nuclear atypia at high magnification, and luminal debris with rectangular crystals
DCIS, high nuclear grade, which may resemble flat epithelial atypia because of the single-layered lining of abnormal epithelial cells, associated with calcifications. However, the nuclear atypia here is of moderate to marked degree, with accompanying necrotic debris incompatible with flat epithelial atypia
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