DOI: 10.1148/rg.27si075515
RadioGraphics 2007;27:S79-S89
© RSNA, 2007
Columnar Cell Lesions of the Breast: Mammographic Findings with Histopathologic Correlation1
Shilpa Pandey, MD,
Michael J. Kornstein, MD,
Whitney Shank, and
Ellen Shaw de Paredes, MD
1 From the School of Medicine, Virginia Commonwealth University, Richmond, Va (S.P.); Commonwealth Laboratory Consultants, Henrico Doctors’ Hospital-Forest Campus, Richmond, Va (M.J.K.); and Ellen Shaw de Paredes Institute for Women’s Imaging, 4480 Cox Rd, Suite 100, Glen Allen, VA 23060 (W.S., E.S.d.P.). Recipient of a Certificate of Merit award for an education exhibit at the 2006 RSNA Annual Meeting. Received April 2, 2007; revision requested April 24 and received May 28; accepted June 5. Supported in part by a grant from the Ellen Shaw de Paredes Research Foundation.
Address correspondence to E.S.d.P. (e-mail: esdp{at}paredesinstitute.com).
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Abstract
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Because of advances in mammography and a concomitant rise in the number of breast biopsies being performed for mammographically detected abnormalities, increasing numbers of columnar cell lesions (CCLs) are being described by pathologists. However, these lesions can be challenging to manage, since their classification has changed over time and only limited research has been conducted regarding their clinical significance. CCLs may be characterized by a single layer of columnar cells (columnar cell change [CCC]), multiple layers with stratification and apical tufting (columnar cell hyperplasia [CCH]), or monomorphic cells with cytologic atypia (flat epithelial atypia [FEA]). The differentiation between CCC, CCH, and FEA is clinically significant: CCC and CCH are considered benign lesions, whereas FEA can be associated with, and even a precursor to, low-grade ductal carcinoma in situ and atypical ductal hyperplasia. Therefore, the identification of FEA at core biopsy should prompt excision of the remaining portion of the lesion.
© RSNA, 2007
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LEARNING OBJECTIVES FOR TEST 3
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After reading this article and taking the test, the reader will be able to:
- List the three types of columnar cell lesions.
- Describe the mammographic and histopathologic features of these lesions.
- Discuss the clinical significance of flat epithelial atypia.
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Introduction
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With advances in the detection of microcalcifications with improved mammographic techniques, increasing numbers of columnar cell lesions (CCLs) are being identified at breast biopsy. Consequently, it is important that radiologists understand how to define and manage these lesions. Breast lesions that are characterized by columnar epithelium–lined enlarged terminal duct lobular units (TDLUs) are frequently found at biopsy performed for mammographic microcalcifications (1,2). CCLs are epithelial changes in the breast consisting of variably dilated TDLUs with cells that are characterized by prominent apical "snouts" (3). CCLs differ with respect to the degree of architectural atypia, which ranges from no atypia to atypia bordering on ductal carcinoma in situ (DCIS) (3). CCLs can be composed of a single layer of columnar cells (columnar cell change [CCC]), multiple layers with stratification and apical tufting (columnar cell hyperplasia [CCH]), or monomorphic cells with cytologic atypia (flat epithelial atypia [FEA]). The lesion now known as FEA was originally described by Azzopardi (4) as "clinging carcinoma," and this lesion may coexist with atypical ductal hyperplasia (ADH), DCIS, and tubular carcinoma.
Over the years, CCC and CCH have been described using a variety of terms, including columnar alterations of lobules (5), columnar metaplasia (6), blunt duct adenosis (4,7), columnar alteration with prominent apical snouts and secretions (CAPPS) (2), enlarged lobular units with columnar alteration (8,9), hyperplastic unfolded lobules (10,11), and hyperplastic enlarged lobular units (12). Furthermore, classification of these lesions has changed over the years, and the World Health Organization Working Group on the Pathology and Genetics of Tumors of the Breast recently introduced a new category, namely, FEA (13). FEA includes lesions that were once characterized as either atypical CCLs, atypical cystic ducts, atypical cystic lobules, clinging carcinoma (monomorphic type), CAPPS with atypia, CCC with atypia (14), and CCH with atypia (14).
In this article, we discuss and illustrate the histologic and mammographic features of CCLs. We also discuss the clinical significance of these lesions and the suggested management of CCLs that are encountered at breast biopsy.
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Histologic Features of CCLs
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Columnar Cell Change
CCC is the simplest form of CCL and is characterized by enlarged TDLUs with variably dilated acini that may have an irregular contour (3). CCC consists of one to two layers of columnar epithelial cells that have uniform ovoid nuclei oriented perpendicular to the basement membrane (3) and that have no conspicuous nucleoli. Apical cytoplasmic blebs, or snouts, are often present at the luminal surface of the cells, and flocculent secretions may be present in the lumina of the acini (Figs 1–3). CCC and apocrine metaplasia are both characterized by apical snouts; however, in apocrine metaplasia the cytoplasm is more abundant and eosinophilic (3).
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Figure 1a. CCC. (a, b) Left craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are clustered amorphous microcalcifications at the 12-o’clock position (circled) that are suggestive of malignancy. Biopsy was performed. (c) Specimen radiograph of the core biopsy samples shows numerous fine microcalcifications (arrows) in the tissue. (d) High-power photomicrograph (hematoxylin-eosin [H-E] stain) demonstrates one to two layers of columnar cells with uniform nuclei, absent nucleoli, and apical snouts (arrow). (e) Photomicrograph (H-E stain) demonstrates prominent apical snouts (arrow) and intraluminal calcifications.
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Figure 1b. CCC. (a, b) Left craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are clustered amorphous microcalcifications at the 12-o’clock position (circled) that are suggestive of malignancy. Biopsy was performed. (c) Specimen radiograph of the core biopsy samples shows numerous fine microcalcifications (arrows) in the tissue. (d) High-power photomicrograph (hematoxylin-eosin [H-E] stain) demonstrates one to two layers of columnar cells with uniform nuclei, absent nucleoli, and apical snouts (arrow). (e) Photomicrograph (H-E stain) demonstrates prominent apical snouts (arrow) and intraluminal calcifications.
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Figure 1c. CCC. (a, b) Left craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are clustered amorphous microcalcifications at the 12-o’clock position (circled) that are suggestive of malignancy. Biopsy was performed. (c) Specimen radiograph of the core biopsy samples shows numerous fine microcalcifications (arrows) in the tissue. (d) High-power photomicrograph (hematoxylin-eosin [H-E] stain) demonstrates one to two layers of columnar cells with uniform nuclei, absent nucleoli, and apical snouts (arrow). (e) Photomicrograph (H-E stain) demonstrates prominent apical snouts (arrow) and intraluminal calcifications.
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Figure 1d. CCC. (a, b) Left craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are clustered amorphous microcalcifications at the 12-o’clock position (circled) that are suggestive of malignancy. Biopsy was performed. (c) Specimen radiograph of the core biopsy samples shows numerous fine microcalcifications (arrows) in the tissue. (d) High-power photomicrograph (hematoxylin-eosin [H-E] stain) demonstrates one to two layers of columnar cells with uniform nuclei, absent nucleoli, and apical snouts (arrow). (e) Photomicrograph (H-E stain) demonstrates prominent apical snouts (arrow) and intraluminal calcifications.
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Figure 1e. CCC. (a, b) Left craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are clustered amorphous microcalcifications at the 12-o’clock position (circled) that are suggestive of malignancy. Biopsy was performed. (c) Specimen radiograph of the core biopsy samples shows numerous fine microcalcifications (arrows) in the tissue. (d) High-power photomicrograph (hematoxylin-eosin [H-E] stain) demonstrates one to two layers of columnar cells with uniform nuclei, absent nucleoli, and apical snouts (arrow). (e) Photomicrograph (H-E stain) demonstrates prominent apical snouts (arrow) and intraluminal calcifications.
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Figure 2a. CCC. (a, b) Left mediolateral oblique (a) and magnified craniocaudal (b) mammograms show clustered fine pleomorphic microcalcifications at the 9-o’clock position (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates normal TDLUs (black arrow) and expanded TDLUs (white arrow), the latter representing an area of CCC. (d) High-power photomicrograph (H-E stain) demonstrates a single layer of epithelial cells with apical snouts (arrow) and flocculent secretions.
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Figure 2b. CCC. (a, b) Left mediolateral oblique (a) and magnified craniocaudal (b) mammograms show clustered fine pleomorphic microcalcifications at the 9-o’clock position (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates normal TDLUs (black arrow) and expanded TDLUs (white arrow), the latter representing an area of CCC. (d) High-power photomicrograph (H-E stain) demonstrates a single layer of epithelial cells with apical snouts (arrow) and flocculent secretions.
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Figure 2c. CCC. (a, b) Left mediolateral oblique (a) and magnified craniocaudal (b) mammograms show clustered fine pleomorphic microcalcifications at the 9-o’clock position (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates normal TDLUs (black arrow) and expanded TDLUs (white arrow), the latter representing an area of CCC. (d) High-power photomicrograph (H-E stain) demonstrates a single layer of epithelial cells with apical snouts (arrow) and flocculent secretions.
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Figure 2d. CCC. (a, b) Left mediolateral oblique (a) and magnified craniocaudal (b) mammograms show clustered fine pleomorphic microcalcifications at the 9-o’clock position (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates normal TDLUs (black arrow) and expanded TDLUs (white arrow), the latter representing an area of CCC. (d) High-power photomicrograph (H-E stain) demonstrates a single layer of epithelial cells with apical snouts (arrow) and flocculent secretions.
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Figure 3a. CCC. (a, b) Standard (a) and magnified (b) right craniocaudal mammograms show heterogeneously dense tissue with architectural distortion (arrow in a) surrounding amorphous microcalcifications at the 9-o’clock position (circled in b). (c) Intermediate-power photomicrograph (H-E stain) shows dilated ducts and uniform nuclei oriented perpendicular to the basement membrane. (d) High-power photomicrograph (H-E stain) shows dilated ducts with an irregular contour lined by a single layer of epithelial cells (white arrow) with apical snouts (black arrows).
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Figure 3b. CCC. (a, b) Standard (a) and magnified (b) right craniocaudal mammograms show heterogeneously dense tissue with architectural distortion (arrow in a) surrounding amorphous microcalcifications at the 9-o’clock position (circled in b). (c) Intermediate-power photomicrograph (H-E stain) shows dilated ducts and uniform nuclei oriented perpendicular to the basement membrane. (d) High-power photomicrograph (H-E stain) shows dilated ducts with an irregular contour lined by a single layer of epithelial cells (white arrow) with apical snouts (black arrows).
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Figure 3c. CCC. (a, b) Standard (a) and magnified (b) right craniocaudal mammograms show heterogeneously dense tissue with architectural distortion (arrow in a) surrounding amorphous microcalcifications at the 9-o’clock position (circled in b). (c) Intermediate-power photomicrograph (H-E stain) shows dilated ducts and uniform nuclei oriented perpendicular to the basement membrane. (d) High-power photomicrograph (H-E stain) shows dilated ducts with an irregular contour lined by a single layer of epithelial cells (white arrow) with apical snouts (black arrows).
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Figure 3d. CCC. (a, b) Standard (a) and magnified (b) right craniocaudal mammograms show heterogeneously dense tissue with architectural distortion (arrow in a) surrounding amorphous microcalcifications at the 9-o’clock position (circled in b). (c) Intermediate-power photomicrograph (H-E stain) shows dilated ducts and uniform nuclei oriented perpendicular to the basement membrane. (d) High-power photomicrograph (H-E stain) shows dilated ducts with an irregular contour lined by a single layer of epithelial cells (white arrow) with apical snouts (black arrows).
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Columnar Cell Hyperplasia
Like CCC, CCH is characterized by enlarged TDLUs with variably dilated acini that may have an irregular contour and are lined by columnar epithelium. However, CCH is characterized by stratification of more than two layers of columnar cells, which sometimes form tufts or mounds with exaggerated apical snouts. Abundant luminal secretions are present, as are microcalcifications. Cytologic analysis reveals columnar cells with ovoid to elongated nuclei (Figs 4, 5). The nuclei are oriented perpendicular to the basement membrane, but there is crowding and overlapping of nuclei (3).
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Figure 4a. CCH. (a, b) Left mediolateral (a) and magnified craniocaudal (b) mammograms show dense parenchyma. There are clustered fine pleomorphic microcalcifications located centrally (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates enlarged TDLUs containing calcifications. (d, e) High-power photomicrographs (H-E stain) demonstrate psammomatous calcifications (arrow in d) and ossifying calcifications (arrow in e). (f) High-power photomicrograph (H-E stain) demonstrates columnar cell stratification (arrow) with calcifications.
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Figure 4b. CCH. (a, b) Left mediolateral (a) and magnified craniocaudal (b) mammograms show dense parenchyma. There are clustered fine pleomorphic microcalcifications located centrally (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates enlarged TDLUs containing calcifications. (d, e) High-power photomicrographs (H-E stain) demonstrate psammomatous calcifications (arrow in d) and ossifying calcifications (arrow in e). (f) High-power photomicrograph (H-E stain) demonstrates columnar cell stratification (arrow) with calcifications.
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Figure 4c. CCH. (a, b) Left mediolateral (a) and magnified craniocaudal (b) mammograms show dense parenchyma. There are clustered fine pleomorphic microcalcifications located centrally (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates enlarged TDLUs containing calcifications. (d, e) High-power photomicrographs (H-E stain) demonstrate psammomatous calcifications (arrow in d) and ossifying calcifications (arrow in e). (f) High-power photomicrograph (H-E stain) demonstrates columnar cell stratification (arrow) with calcifications.
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Figure 4d. CCH. (a, b) Left mediolateral (a) and magnified craniocaudal (b) mammograms show dense parenchyma. There are clustered fine pleomorphic microcalcifications located centrally (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates enlarged TDLUs containing calcifications. (d, e) High-power photomicrographs (H-E stain) demonstrate psammomatous calcifications (arrow in d) and ossifying calcifications (arrow in e). (f) High-power photomicrograph (H-E stain) demonstrates columnar cell stratification (arrow) with calcifications.
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Figure 4e. CCH. (a, b) Left mediolateral (a) and magnified craniocaudal (b) mammograms show dense parenchyma. There are clustered fine pleomorphic microcalcifications located centrally (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates enlarged TDLUs containing calcifications. (d, e) High-power photomicrographs (H-E stain) demonstrate psammomatous calcifications (arrow in d) and ossifying calcifications (arrow in e). (f) High-power photomicrograph (H-E stain) demonstrates columnar cell stratification (arrow) with calcifications.
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Figure 4f. CCH. (a, b) Left mediolateral (a) and magnified craniocaudal (b) mammograms show dense parenchyma. There are clustered fine pleomorphic microcalcifications located centrally (arrow) that are suggestive of malignancy. (c) Low-power photomicrograph (H-E stain) demonstrates enlarged TDLUs containing calcifications. (d, e) High-power photomicrographs (H-E stain) demonstrate psammomatous calcifications (arrow in d) and ossifying calcifications (arrow in e). (f) High-power photomicrograph (H-E stain) demonstrates columnar cell stratification (arrow) with calcifications.
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Figure 5a. CCH. (a, b) Magnified right craniocaudal mammogram (a) and specimen radiograph (b) show scattered fibroglandular breast tissue with amorphous microcalcifications at the 10-o’clock position (arrow in a). (c) Low-power photomicrograph (H-E stain) demonstrates dilated TDLUs with variably dilated acini and fibrosis. (d) High-power photomicrograph (H-E stain) demonstrates thickened columnar epithelium with crowded columnar cells (arrow) having slender nuclei, most of which are oriented perpendicular to the basement membrane.
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Figure 5b. CCH. (a, b) Magnified right craniocaudal mammogram (a) and specimen radiograph (b) show scattered fibroglandular breast tissue with amorphous microcalcifications at the 10-o’clock position (arrow in a). (c) Low-power photomicrograph (H-E stain) demonstrates dilated TDLUs with variably dilated acini and fibrosis. (d) High-power photomicrograph (H-E stain) demonstrates thickened columnar epithelium with crowded columnar cells (arrow) having slender nuclei, most of which are oriented perpendicular to the basement membrane.
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Figure 5c. CCH. (a, b) Magnified right craniocaudal mammogram (a) and specimen radiograph (b) show scattered fibroglandular breast tissue with amorphous microcalcifications at the 10-o’clock position (arrow in a). (c) Low-power photomicrograph (H-E stain) demonstrates dilated TDLUs with variably dilated acini and fibrosis. (d) High-power photomicrograph (H-E stain) demonstrates thickened columnar epithelium with crowded columnar cells (arrow) having slender nuclei, most of which are oriented perpendicular to the basement membrane.
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Figure 5d. CCH. (a, b) Magnified right craniocaudal mammogram (a) and specimen radiograph (b) show scattered fibroglandular breast tissue with amorphous microcalcifications at the 10-o’clock position (arrow in a). (c) Low-power photomicrograph (H-E stain) demonstrates dilated TDLUs with variably dilated acini and fibrosis. (d) High-power photomicrograph (H-E stain) demonstrates thickened columnar epithelium with crowded columnar cells (arrow) having slender nuclei, most of which are oriented perpendicular to the basement membrane.
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Flat Epithelial Atypia
FEA is characterized by enlarged TDLUs with variably dilated acini that are rounded and basophilic. It consists of one or more layers of cuboidal to columnar epithelial cells with cytologic atypia and with apical snouts that may be exaggerated. Cytologic analysis reveals cuboidal to columnar cells with low-grade cytologic atypia that are characterized by the presence of relatively monomorphic round to oval nuclei. The nuclei are not oriented perpendicular to the basement membrane (3). The chromatin in the nuclei shows clumping and margination, variably prominent nucleoli, and a markedly increased nucleus-cytoplasm ratio (3). Consequently, the TDLUs have a more basophilic appearance than do those in nonatypical CCLs.
The columnar epithelium in FEA may form small mounds, tufts, or short micropapillations; however, complex architectural patterns with rigid cellular bridges are absent.
Mammographic Features of CCLs
At mammography, CCLs typically demonstrate clustered, amorphous, or fine pleomorphic microcalcifications that are deposited within the duct lumina of the TDLUs (15). Amorphous calcifications are very fine and have an indistinct contour because they are secreted as either calcium phosphate or calcium oxalate salts by the epithelial cell lining. Amorphous calcifications are seen in the lobule or the terminal ducts and can be found in DCIS, ADH, ordinary epithelial hyperplasia, papillomatosis, and sclerosing adenosis as well as CCLs. Fine pleomorphic calcifications are located in the terminal ducts of the TDLUs and can represent either DCIS, typical ductal hyperplasia, ADH, or CCLs. Pleomorphic calcifications are produced by the secretion of calcium salts from the epithelial cells as well as by the formation of dystrophic calcifications of debris in comedocarcinoma.
In a study of 100 breast biopsies performed for microcalcifications, Fraser et al (2) found that CAPPS lesions occurred in 42% of cases. The term CAPPS was formerly used for lesions that are now classified as CCLs. In 74% of cases, the microcalcifications were present in the CAPPS lesions, frequently having a round or pleomorphic appearance at mammography. Branching microcalcifications were present in only 11% of cases.
Amorphous and fine pleomorphic microcalcifications are the usual mammographic features of FEA (Figs 6, 7). Intraluminal calcifications that may have the appearance of psammoma bodies are frequently found in this lesion.
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Figure 6a. FEA. (a, b) Right craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are regional amorphous microcalcifications (arrowheads in a) as well as more clustered microcalcifications (arrow in b) that are suspect. (c) Specimen radiograph shows the calcifications (arrows) included in multiple core biopsy specimens. (d) High-power photomicrograph (H-E stain) demonstrates stratified layers of columnar epithelial cells (arrow). (e) High-power photomicrograph (H-E stain) demonstrates stratified atypical epithelial cells with distinct nucleoli (arrow).
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Figure 6b. FEA. (a, b) Right craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are regional amorphous microcalcifications (arrowheads in a) as well as more clustered microcalcifications (arrow in b) that are suspect. (c) Specimen radiograph shows the calcifications (arrows) included in multiple core biopsy specimens. (d) High-power photomicrograph (H-E stain) demonstrates stratified layers of columnar epithelial cells (arrow). (e) High-power photomicrograph (H-E stain) demonstrates stratified atypical epithelial cells with distinct nucleoli (arrow).
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Figure 6c. FEA. (a, b) Right craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are regional amorphous microcalcifications (arrowheads in a) as well as more clustered microcalcifications (arrow in b) that are suspect. (c) Specimen radiograph shows the calcifications (arrows) included in multiple core biopsy specimens. (d) High-power photomicrograph (H-E stain) demonstrates stratified layers of columnar epithelial cells (arrow). (e) High-power photomicrograph (H-E stain) demonstrates stratified atypical epithelial cells with distinct nucleoli (arrow).
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Figure 6d. FEA. (a, b) Right craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are regional amorphous microcalcifications (arrowheads in a) as well as more clustered microcalcifications (arrow in b) that are suspect. (c) Specimen radiograph shows the calcifications (arrows) included in multiple core biopsy specimens. (d) High-power photomicrograph (H-E stain) demonstrates stratified layers of columnar epithelial cells (arrow). (e) High-power photomicrograph (H-E stain) demonstrates stratified atypical epithelial cells with distinct nucleoli (arrow).
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Figure 6e. FEA. (a, b) Right craniocaudal (a) and magnified mediolateral (b) mammograms show heterogeneously dense tissue. There are regional amorphous microcalcifications (arrowheads in a) as well as more clustered microcalcifications (arrow in b) that are suspect. (c) Specimen radiograph shows the calcifications (arrows) included in multiple core biopsy specimens. (d) High-power photomicrograph (H-E stain) demonstrates stratified layers of columnar epithelial cells (arrow). (e) High-power photomicrograph (H-E stain) demonstrates stratified atypical epithelial cells with distinct nucleoli (arrow).
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Figure 7a. FEA. (a, b) Standard (a) and magnified (b) left craniocaudal mammograms show heterogeneously dense parenchyma. There are clustered amorphous microcalcifications (arrow) located laterally that are somewhat pleomorphic on the magnified image. (c) Low-power photomicrograph (H-E stain) demonstrates dilated basophilic TDLUs (arrow) containing prominent secretions within the duct lumina. (d) High-power photomicrograph (H-E stain) demonstrates multiple layers of epithelial cells with cytologic atypia lining the duct.
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Figure 7b. FEA. (a, b) Standard (a) and magnified (b) left craniocaudal mammograms show heterogeneously dense parenchyma. There are clustered amorphous microcalcifications (arrow) located laterally that are somewhat pleomorphic on the magnified image. (c) Low-power photomicrograph (H-E stain) demonstrates dilated basophilic TDLUs (arrow) containing prominent secretions within the duct lumina. (d) High-power photomicrograph (H-E stain) demonstrates multiple layers of epithelial cells with cytologic atypia lining the duct.
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Figure 7c. FEA. (a, b) Standard (a) and magnified (b) left craniocaudal mammograms show heterogeneously dense parenchyma. There are clustered amorphous microcalcifications (arrow) located laterally that are somewhat pleomorphic on the magnified image. (c) Low-power photomicrograph (H-E stain) demonstrates dilated basophilic TDLUs (arrow) containing prominent secretions within the duct lumina. (d) High-power photomicrograph (H-E stain) demonstrates multiple layers of epithelial cells with cytologic atypia lining the duct.
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Figure 7d. FEA. (a, b) Standard (a) and magnified (b) left craniocaudal mammograms show heterogeneously dense parenchyma. There are clustered amorphous microcalcifications (arrow) located laterally that are somewhat pleomorphic on the magnified image. (c) Low-power photomicrograph (H-E stain) demonstrates dilated basophilic TDLUs (arrow) containing prominent secretions within the duct lumina. (d) High-power photomicrograph (H-E stain) demonstrates multiple layers of epithelial cells with cytologic atypia lining the duct.
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Clinical Significance of CCLs
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Several studies have shown that FEA commonly coexists with other more significant lesions, including ADH, DCIS, and tubular carcinoma (1,2,16–19). In addition, FEA and these other lesions have similar atypical cytologic and immunophenotypic features. Therefore, FEA may be considered a "neoplastic proliferation that may represent either a precursor to or the earliest morphologic manifestation of low-grade DCIS, as well as a precursor to invasive carcinoma, particularly tubular carcinoma" (3). The carcinoma associated with FEA tends to be of low nuclear grade.
In a study of 100 cases in which microcalcifications led to breast biopsy, Fraser et al (2) found that low-grade DCIS coexisted with CCLs in 56% of cases, whereas high-grade DCIS was associated with CCLs in only 19% of cases.
In a study of 3303 women with benign findings at breast biopsy, Page et al (8,19) found an increased prevalence of breast cancer in women with CCC. For these patients, the relative risk of breast cancer increases to 1.3 after biopsy has shown CCC. When CCC or CCH is identified at percutaneous breast biopsy, clinical follow-up rather than excision is performed. With FEA, the association with more significant lesions is stronger, so the entire lesion is excised. In a study of excisional biopsies performed in 25 women with clinging carcinoma (low-grade FEA), Eusebi et al (20) found that an identical lesion recurred in only one patient (4%). In another study of five patients with clinging carcinoma conducted by the European Organization for Research and Treatment of Cancer, no recurrence was found after treatment with excision alone (21). De Mascarel et al (22) studied 115 patients with FEA, 70 of whom were treated with surgical excision alone and 45 of whom underwent surgical excision with radiation therapy. The authors found recurrent FEA in the ipsilateral breast in three patients, ipsilateral invasive breast cancer following surgical excision alone in two, and invasive cancer after surgical excision and radiation therapy in one. These results seem to indicate that the risk of FEA progressing to invasive cancer is extremely low. However, Schnitt and Collins (3) suggest that the presence of FEA in an excisional biopsy specimen should prompt releveling of the block and a careful search for areas of ADH and DCIS. The Table summarizes these authors’ recommendations for the work-up and management of CCLs and FEA when found at core needle biopsy versus excisional biopsy.
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Discussion
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When percutaneous breast biopsy is performed with core needles or vacuum assistance, underestimation of disease involvement can occur. This phenomenon has been described in cases of DCIS in which core needle biopsy revealed only ADH (23–30). The lesion may be complex, composed of areas of both ADH and DCIS, with the core sample including only the region of ADH, leading to the underestimation of DCIS. This result may also occur when a few abnormal ducts are included in the core sample, leading to a diagnosis of ADH alone. However, when a larger volume of tissue is excised, the number of abnormal ducts raises the diagnosis to the level of DCIS.
Other lesions that are considered to pose a higher risk or that may be associated with underestimation of a more significant lesion are atypical lobular hyperplasia (31), lobular carcinoma in situ (31), radial scar (32), and some papillary lesions (33,34).
There has not been extensive research on the management of CCLs found at core needle biopsy. However, existing data suggest that a finding of CCC or CCH at core needle biopsy requires no additional work-up (35,36). Because FEA is a more advanced lesion at core needle biopsy, excision is recommended (35–38).
The diagnostic reproducibility of FEA compared with that of nonatypical CCLs is a concern. In one study in which the pathologists used their own criteria to classify CCLs, there was only 40% agreement as to the presence of cytologic atypia (39). However, in another study in which experienced breast pathologists were given specific training in classifying CCLs, a much higher level of agreement was observed (91.8%) (40).
In about one-third to one-quarter of cases of FEA seen at core biopsy, a more advanced lesion is found at excision (35–38). The identification of FEA at excisional biopsy should prompt the pathologist to search carefully for DCIS elsewhere in the specimen.
Studies correlating the outcome of patients in whom excisional biopsy reveals FEA have shown a rate for local recurrence of FEA of 2.6% and an identical rate for invasive breast cancer in the ipsilateral breast (22). As mentioned earlier, the risk of FEA progressing to invasive cancer appears to be very low, despite the histologic and genetic similarities between FEA and DCIS (3). Studies conducted by Moinfar et al (41) and Dabbs et al (42) showed that the genetic alterations found in CCLs were similar to those found in DCIS and invasive carcinoma.
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Conclusions
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Mammographic microcalcifications that are classified as suspicious for malignancy, leading to core biopsy, are increasingly indicating the presence of entities classified as CCLs. The differentiation between CCC, CCH, and FEA is clinically significant. The identification of FEA at core biopsy should prompt excision of the remaining portion of the lesion because of the strong association between FEA and DCIS. Additional research is needed to determine optimal clinical management of FEA alone discovered at excisional biopsy.
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Footnotes
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Abbreviations: ADH = atypical ductal hyperplasia, CAPPS = columnar alteration with prominent apical snouts and secretions, CCC = columnar cell change, CCH = columnar cell hyperplasia, CCL = columnar cell lesion, DCIS = ductal carcinoma in situ, FEA = flat epithelial atypia, H-E = hematoxylin-eosin, TDLU = terminal duct lobular unit
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References
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Abstract
LEARNING OBJECTIVES FOR TEST...
