General
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• Replacement of epithelium by up to 5 layers of mildly atypical cells, presumably neoplastic
• Introduced by WHO Working Group on Pathology and Genetics of Tumours of the Breast to encompass columnar cell lesions with low grade / monomorphic cytologic atypia that lacked architectural features of ADH or low grade DCIS

Terminology
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• Also called atypical columnar change (columnar cell change with atypia or columnar cell hyperplasia with atypia), flat ductal intraepithelial neoplasia grade 1A (DIN1A), low grade clinging carcinoma monomorphous type, atypical columnar alternation with prominent apical spouts and secretions, columnar cell change with atypia

Epidemiology
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• Seen in 3.8-10% of core needle biopsy samples (Am J Clin Pathol 2009;131:802)
• Radiologically classified as B3 - uncertain malignant potential (Hum Pathol 2010;41:522)

Etiology
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• Biology still being investigated - may be an early neoplastic breast lesion (Semin Diagn Pathol 2010;27:37)
• Mitochondrial DNA sequencing and phylogenetic tree clustering revealed direct transitions between FEA and LG-DCIS in 10 of 10 cases, supporting the interpretation of FEA as part of the low grade pathway in the development of breast cancer (Am J Surg Pathol 2012;36:1247)

Clinical features / prognostic factors
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• Diagnosis is reproducible with available histologic diagnostic criteria (Mod Pathol 2006;19:172)
• Underdiagnosed; often coexists with lobular neoplasia (Histopathology 2007;50:859)
• Associated with tubular carcinoma (Am J Surg Pathol 2007;31:417)
• Subsequent excision after core biopsy shows ADH, ALH, DCIS or invasive carcinoma in 5-15%
• Risk for DCIS / invasive carcinoma after core biopsy varies from slightly increased warranting follow up (Virchows Arch 2007;451:883, Breast 2014;23:352), to similar to traditional ADH warranting excision (Hum Pathol 2007;38:35, J Clin Pathol 2011;64:1001, Virchows Arch 2012;461:419), to warranting excision if > 1 cm (J Radiol 2006;87:1671)
• See also Treatment (below)

Treatment
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• No consensus on whether to excise after biopsy diagnosis of pure FEA:
• Recommended: see Breast J 2010;16:55, Am J Clin Pathol 2009;131:802, Breast Cancer Res Treat 2011;125:121, Ann Surg Oncol 2013;20:133; or consider since upgrade risk is not negligible (Ann Clin Lab Sci 2009;39:270)
• Recommended: if residual microcalcification / lesion present due to possibility of ADH/ALH (17.2%) or DCIS (5.4%) (Breast J 2014;20:606) or if size > 1 cm (Breast Cancer 2014 Apr 24 [Epub ahead of print], J Radiol 2006;87:1671)
• Not recommended: (a) if pure flat epithelial atypia and 9 or 11 gauge biopsy has removed most of small radiologic target (Am J Surg Pathol 2009;33:1078) (Clin Breast Cancer 2013;13:450); (b) if only low radiologic risk calcifications are present (Mod Pathol 2009;22:762); (c) if concordant pathology and imaging results, and patient has breast examinations every 6-12 months and mammograms yearly (Mayo Clin Proc 2014;89:536); (d) in general, according to some authors, due to insufficient data for evidence based guidelines (Cancer 2015 January 13 [Epub ahead of print])

Micro description
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• Atypia that does not fulfill criteria of ADH or low grade DCIS
• Distention of terminal duct lobular unit (TDLU); usually more blue than normal TDLU at low power
• Replacement of epithelial cells by single or stratified layer of cells with low grade cytologic atypia resembling low grade DCIS
• Flat growth pattern usually resembles blunt duct adenosis; cells are not regularly oriented perpendicular to basement membrane
• Also cystically dilated ducts with secretions or apocrine features (apical snouts)
• Nuclei are usually round with variably prominent nucleoli
• Often calcifications
• Usually no/rare micropapillary formations

Micro images
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Low grade cytologic atypia

Dilated terminal duct lobular unit

Dilated acinus lined by 1ñ2 cell layers

Cells have prominent snouts

Monomorphic appearance of atypical nuclei

 

Columnar cell change

Variably dilated acini

   

Various images

 

Courtesy of Dr. Mark R. Wick

Compare to
blunt duct adenosis

Virtual slides
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With atypical lobular hyperplasia

With ADH

Positive stains
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• CK19, ER, PR

Negative stains
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• CK5, CK6, 34betaE12

Molecular / cytogenetics description
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• Phosphatidylinositol 3 kinase catalytic subunit (P13KCA) mutations frequently observed similar to other breast epithelial proliferations (Mod Pathol 2014;27:740)
• Does not share similar molecular profiles of p16(INK4a) epigenetic modification with atypical ductal hyperplasia and low-grade ductal carcinoma in situ (Hum Pathol 2008;39:1637)
• Clonally related to invasive tubular carcinoma (Am J Surg Pathol 2009;33:1646)

Differential diagnosis
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• Atypical ductal hyperplasia: architectural features of ADH are present
• Blunt duct adenosis / columnar cell-change: lacks atypia
• DCIS, low grade

Additional references
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• Breast Cancer Res 2003;5:263, Arch Pathol Lab Med 2008;132:615, Stanford University - Flat Epithelial Atypia of the Breast

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