Columnar Cell Lesions and Flat Epithelial Atypia

Lesions characterized by the presence of columnar epithelial cells lining the terminal duct lobular units (TDLUs) of the breast have long been recognized by pathologists and have been described under a wide variety of names.1, 2, 3 and 4 These lesions are of current interest because they are being encountered increasingly in breast biopsies performed due to the presence of mammographic microcalcifications.

CLASSIFICATION AND HISTOLOGIC FEATURES

The classification of these lesions has varied among different authors. We currently categorize them as columnar cell change, columnar cell hyperplasia, or flat epithelial atypia (FEA).2

Columnar cell change is characterized by enlarged TDLUs with variably dilated acini that often have an irregular contour (Fig. 4.1, e-Fig. 4.1). The acini are lined by one or two layers of columnar epithelial cells with uniform, ovoid to elongated nuclei oriented in a regular fashion perpendicular to the basement membrane, with evenly dispersed chromatin and without conspicuous nucleoli (Fig. 4.2, e-Figs. 4.2, 4.3, 4.4, 4.5 and 4.6). Mitotic figures are rarely encountered. Apical cytoplasmic blebs or snouts are often present at the luminal surface of the epithelial cells but are not usually prominent or exaggerated. Flocculent secretions may be present in the lumina of the involved acini. In addition, luminal calcifications may be present.

Columnar cell hyperplasia similarly features enlarged TDLUs with variably dilated acini, which are often irregular in contour. These acini are lined by columnar cells that have cytologic features similar to those seen in columnar cell change but that, in addition, show cellular stratification of more than two cell layers. Again, the nuclei are ovoid to elongated and, for the most part, oriented perpendicular to the basement membrane. Crowding or overlapping of the nuclei in these proliferative foci may give the appearance of nuclear hyperchromasia. The proliferating columnar cells may form small mounds, tufts, or abortive micropapillations (Fig. 4.3, e-Figs. 4.7, 4.8, 4.9, 4.10 and 4.11). Exaggerated apical cytoplasmic snouts and abundant flocculent intraluminal secretions are often present, and some of the cells comprising such lesions may have a hobnail appearance (Fig. 4.4). These lesions frequently show intraluminal calcifications, which in some instances may have the configuration of psammoma bodies.

FIGURE 4.1 Columnar cell change. Low-power view illustrating a terminal duct lobular unit with variably dilated acini. The acini have irregular contours and some contain secretions.

FIGURE 4.2 Columnar cell change. High-power view demonstrates the columnar cell nature of the epithelium lining this acinus. Many of the cells have apical cytoplasmic blebs or snouts. The nuclei are slender, ovoid, and oriented in a regular fashion perpendicular to the basement membrane, imparting a “picket-fence”-like appearance.

FIGURE 4.3 Columnar cell hyperplasia. A: Scanning magnification demonstrates an enlarged terminal duct lobular unit with variably dilated acini, many of which have irregular contours. Flocculent luminal secretions and luminal calcifications are evident in many of these spaces. B: Medium-power view demonstrates stratified columnar cells, many with prominent apical snouts. C: At high power, the columnar cells show stratification with foci of cellular tufting. The nuclei generally maintain their ovoid shape as well as their regular orientation perpendicular to the basement membrane. Crowding and overlapping of nuclei impart the appearance of nuclear hyperchromasia.

FIGURE 4.3 (Continued)

Lesions that we now categorize as columnar cell change and columnar cell hyperplasia have been previously described under a variety of other names, including atypical lobules type A, columnar alteration of lobules, columnar metaplasia, blunt duct adenosis, enlarged lobular units with columnar alteration, hyperplastic unfolded lobules, hyperplastic enlarged lobular units, and columnar alteration with prominent apical snouts and secretions without atypia.5

FEA consists of enlarged TDLUs in which the native epithelial cells are replaced by one to several layers of cuboidal to columnar epithelial cells that show cytologic atypia of the low-grade or monomorphic type.6 The acini of the involved TDLUs are variably dilated and often have round contours. The cytologic atypia of FEA is characterized by the presence of relatively monomorphic, round to ovoid nuclei that resemble those seen in the cells comprising low-grade ductal carcinoma in situ (DCIS). These nuclei are not regularly oriented perpendicular to the basement membrane and show an increase in the nuclear/cytoplasmic ratio (Figs. 4.5 and 4.6, e-Figs. 4.12, 4.13, 4.14 and 4.15). As a result of this increased nuclear/cytoplasmic ratio, the involved TDLUs typically have a more basophilic appearance at scanning magnification than normal TDLUs. Cellular and nuclear stratification are seen in some cases. The nuclear chromatin may be evenly dispersed or slightly marginated and nucleoli are variably prominent. Mitotic figures may be seen, but are uncommon. In some cases, apical cytoplasmic snouts or blebs may be prominent or exaggerated, and the cells cytologically may resemble those comprising the tubules of tubular carcinoma. In a minority of cases of FEA, the nuclei retain a more oval shape as well as an orientation perpendicular to the basement membrane (Fig. 4.7). However, in contrast to the relatively slender, bland nuclei of columnar cell change and columnar cell hyperplasia, the chromatin in these nuclei may show clumping and margination, nucleoli are variably prominent, and the nuclear/cytoplasmic ratio of the cells is markedly increased.

FIGURE 4.4 In this example of columnar cell hyperplasia, there is only mild cellular proliferation, but many of the cells have a hobnail appearance.

FIGURE 4.5 Flat epithelial atypia (FEA). A: At scanning magnification, the dilated acini in this enlarged terminal duct lobular unit are evident. Secretions and calcifications are present within the acinar lumina. The acini generally have a more rounded configuration than that of columnar cell change and columnar cell hyperplasia. B: Medium-power view illustrating lining cells with prominent apical cytoplasmic snouts. The nuclei are round to ovoid and relatively uniform in appearance. C: This high-magnification view illustrates the low-grade, monomorphic-type cytologic atypia that characterizes most examples of FEA.

FIGURE 4.5 (Continued)

FIGURE 4.6 Flat epithelial atypia. A: This medium-power illustration demonstrates dilated acini with relatively round contours. Flocculent luminal secretions are evident, as are prominent apical cytoplasmic snouts. B: High-power view illustrating one to several layers of epithelial cells with monomorphic-type cytologic atypia.

FIGURE 4.7 Flat epithelial atypia. A: Low-power view demonstrating basophilia of involved acini, the result of the cells having an increased nuclear/cytoplasmic ratio. B: In this case, the nuclei of the columnar cells maintain an ovoid shape. These cells are distinguished from those of columnar cell change and columnar cell hyperplasia by the presence of marked nuclear stratification, a higher nuclear/cytoplasmic ratio, and irregular nuclear chromatin with variably prominent nucleoli.

The epithelial cells in FEA lesions may form small mounds, tufts, or short, abortive micropapillations. However, complex architectural patterns such as well-developed, club-shaped micropapillations, rigid cellular bridges, bars and arcades, or sieve-like fenestrations are not present nor is there evidence of cellular polarization within the micropapillations and bars or
around the fenestrations. Thus, it should be apparent that flat is a relative term and simply denotes the absence of the complex architectural patterns described previously. These lesions also frequently show intraluminal calcifications, which in some instances may have the configuration of psammoma bodies (Fig. 4.8). However, the mammographic appearance of the calcifications associated with FEA is non-specific.7 A variable lymphocytic infiltrate may be present in the stroma surrounding spaces involved by FEA (Fig. 4.9). Lesions currently included within the category of FEA have previously been described by a wide assortment of other names, most notably “clinging carcinoma” of the monomorphic type (Table 4.1).8, 9 and 10

FIGURE 4.8 Calcifications in flat epithelial atypia are most often irregular and granular (A), but may be psammomatous (B).

FIGURE 4.9 Flat epithelial atypia. A prominent lymphocytic infiltrate is evident in intralobular stroma of the involved terminal duct lobular units.

Columnar cell change, columnar cell hyperplasia, and FEA may coexist in the same breast and even within the same TDLU. Therefore, these diagnoses should not be considered mutually exclusive. The histologic features of these lesions are summarized in Table 4.2. An algorithmic approach to the diagnosis of columnar cell lesions and FEA is presented in Figure 4.10.

TABLE 4.1 Other Names used to Describe Lesions within the Category of Flat Epithelial Atypia^a

Atypical columnar cell lesions (1)

Atypical cystic duct (11)

Atypical cystic lobules (12)

Atypical lobules type A (13)

Clinging carcinoma (monomorphic type) (14, 15)

Columnar alteration with prominent apical snouts and secretions with atypia (16)

Columnar cell change with atypia (5)

Columnar cell hyperplasia with atypia (5)

Ductal intraepithelial neoplasia of the flat monomorphic type (17)

Hypersecretory hyperplasia with atypia (18)

Pretubular hyperplasia (19)

Small ectatic ducts lined by atypical ductal cells with apocrine snouts (20)

^aThe names are listed in alphabetical order.

TABLE 4.2 Histologic Features of Columnar Cell Change, Columnar Cell Hyperplasia, and Flat Epithelial Atypia

	Columnar Cell Change	Columnar Cell Hyperplasia	Flat Epithelial Atypia
Topography	Enlarged TDLUs with variably dilated acini; acini tend to be irregular in contour	Enlarged TDLUs with variably dilated acini; acini tend to be irregular in contour	Enlarged TDLUs with variably dilated acini; acini tend to have round contours; involved TDLUs often more basophilic than normal TDLUs
Architecture	One to two layers of columnar cells	Cellular stratification, with more than two cell layers of columnar cells, sometimes forming tufts or mounds; complex architectural patterns not present	One to several layers of cuboidal to columnar epithelial cells; complex architectural patterns not present
Cytology	Columnar cells with uniform ovoid to elongated nuclei; nucleoli absent or inconspicuous	Columnar cells with uniform ovoid to elongated nuclei; nucleoli absent or inconspicuous; hobnail cells may be present	Cuboidal to columnar cells with monomorphictype cytologic atypia; cells may resemble those of tubular carcinoma
Apical snouts	Often present; usually not prominent or exaggerated	Often present; may be exaggerated	Often present; may be exaggerated
Intraluminal secretions	May be present; usually not prominent	May be present and prominent	May be present and prominent
Calcifications	May be present	Often present; may be psammomatous	Often present; may be psammomatous
TDLU, terminal duct lobular unit.
Modified from Schnitt SJ, Vincent-Salomon A. Columnar cell lesions of the breast. Adv Anat Pathol. 2003;10(3):113-124.

FIGURE 4.10 Algorithmic approach to the diagnosis of columnar cell lesions and flat epithelial atypia. DCIS=ductal carcinoma in situ.

IMMUNOPHENOTYPE AND GENETICS

The cells comprising columnar cell change, columnar cell hyperplasia, and FEA exhibit expression of low-molecular-weight cytokeratins (CKs), such as CK8, 18, and 19 (Fig. 4.11).9,10,21,22 In contrast, most if not all of these cells lack expression of high-molecular-weight cytokeratins (HMW-CKs) as defined by antibody 34βE12 and antibodies to CK5 or CK5/6 (Fig. 4.12, e-Fig. 4.16).10,21, 22 and 23 The practical implication of the latter observation is that absence of HMW-CK expression cannot be used as an objective marker of atypia in columnar cell lesions.23

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