General
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• Neoplastic intraductal lesion with architectural and cytological features suggestive but not diagnostic of low grade DCIS

Terminology
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• Also called DIN 1B, atypical intraductal hyperplasia (AIDH), mammary intraepithelial Neoplasia (MIN)

Epidemiology
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• May be present in women as young as 18-26 years (Am J Surg Pathol 1992;16:246)
• Rates have decreased over past decade, possibly due to significant reduction in use of postmenopausal hormonal therapy (Cancer Epidemiol Biomarkers Prev 2009;18:2822)

Etiology
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• ADH and coexisting cancers may arise independently in field of increased cancer risk, as genetic changes (at 1q and 16q) are not identical (J Pathol 2006;209:307)

Clinical features
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• There are no clinical features associated with ADH

Radiology
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• No definite diagnostic features
• On mammography, lesions may be identified as masses, asymmetric densities, microcalcifications and architectural distortions
• On ultrasound, lesions appear as hypoechoic masses with irregular shape, microlobulated margins, abrupt interface
• Underestimation rate of ADH is high (56% by mammograph/USG and 32% by MRI) (AJR Am J Roentgenol 2014;202:1389, AJR Am J Roentgenol 2014;203:682)

Prognostic features (for carcinoma)
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• Relative risk of carcinoma is 4-5x; lower risk if 0-2 foci at core biopsy (see below)
• Early studies suggested a 10x relative risk if positive family history of breast cancer, but newer studies find no such increase (Cancer Prev Res (Phila) 2014;7:211)
• Estimated 10 year cancer risk is 17-26% (Breast Cancer Res Treat 2012;136:627)
• There is a 2:1 ratio of ipsilateral to contralateral breast cancer, with higher ipsilateral risk within the first five years (Cancer Prev Res (Phila) 2014;7:211)
• Risk for breast cancer is higher for younger women and those with multiple foci of ADH
• Mean time from atypia to carcinoma diagnosis is 10.3 years
• 25% develop DCIS, 75% develop invasive carcinoma
• 76% of carcinomas are ductal, 8.5% are lobular; 75% are node negative
• 2/3 are moderate or high grade

Treatment
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• ADH at core biopsy: excision recommended since associated with DCIS and invasive carcinoma, particularly if target lesion is not completely excised (Am J Surg Pathol 2002;26:1095)
  • DCIS found in 12-36% of excision specimens
  • Invasive carcinoma found up to 14% of excision specimens
  • Additional foci of ADH found in 25% of excision specimens
• Same recommendations pertain to 11 gauge (Ann Surg Oncol 2007;14:2497) or 9 gauge needles (AJR Am J Roentgenol 2007;188:684)
• Page found no worse lesion at excision if ADH limited to 0-2 foci at core biopsy (Am J Surg Pathol 2001;25:1017) but other studies have found malignancy in 12% of these cases (Radiology 2010;255:723)
• ADH at margin: reexcision is controversial, recommended by some since 25% may have DCIS or invasive carcinoma at reexcision (Ann Surg Oncol 2008;15:843)
• In the NSABP trial, women with atypia receiving tamoxifen had a 75% reduction of risk in breast cancer at 7 years (Breast Cancer (Dove Med Press) 2014;6:29)

Micro description
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• Usually less than 2-3 mm, may be multicentric
• Must rule out DCIS (Breast Cancer Res 2003;5:254)
• Micropapillae, tufts, bridges, solid and cribriform patterns of evenly distributed, monomorphic cells with rounded or ovoid nuclei
• Either closely mixed with epithelial ductal hyperplasia (without atypia) or only partially involving the terminal duct lobular unit
• Perineural invasion is rare and usually associated with sclerosing adenosis or radial scar (Hum Pathol 2001;32:785)
• Variable microcalcifications
• Recommended to include size of lesion in surgical pathology report
• Either (1), (2) or (3) AND no high grade cytology (Stanford University - Atypical Ductal Hyperplasia):
  1. Ducts are completely filled and exhibit sharp punched out spaces or micropapillae but lack uniform cytologic features due to partial population of columnar cells or focal streaming of cells
  2. Ducts filled by uniform population of cells with cytologic features of low grade DCIS but lack architectural features due to only partial filling of ducts or no uniformly sharp punched out spaces, microacini or characteristic micropapillae AND have excluded solid low grade DCIS
  3. Cytologic and architectural features of DCIS but lesion is too small (fewer than two duct spaces involved or less than 2-3 mm in aggregate dimension)*
• * Differentiation of ADH and low grade DCIS based on size cutoffs is controversial due to lack of expert agreement

Micro images
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Cells don't stream and are haphazardly arranged in cellular bridges with mitotic activity (arrows), but secondary lumina are irregular

Cells have uniform size and shape, small foci of necrosis and calficiation, but secondary lumina are irregular and more numerous at periphery

Uniform cells but irregular secondary lumina

Rounded secondary lumens and heterogenous cell population

Ducts are lined by crowded, hyperplastic, tall columnar cells forming small papillae

 

Papillary proliferation of multilayered epithelium involving only part of duct

Irregular glandular spaces

Enlarged, irregular, hyperchromatic nuclei

Solid filling of a duct

Atypical cells quite homogeneous

Atypical ductal hyperplasia is present (arrows)

Boxed area have less active-appearing nuclei

Micropapillary and cribriform pattern

Nuclei are crowded and hyperchromatic

Similar architecture seen in DCIS

Nuclei are crowded and overlapping

Proliferating epithelium are rigid and "punched out"

Nuclei are haphazardly arranged

Cribriform type

Micropapillary type

Cribriform type, high power

Cells are irregularly arranged

Cell margins are indistinct

Various images of ADH at core biopsy

 

Courtesy of Dr. Mark R. Wick

Usual ductal hyperplasia (CK903+) versus ADH (CK903-)

ADH and subsequent invasive carcinoma

     

Contributed by Dr. Marilin Rosa, University of Florida - ADH involving areas of sclerosing adenosis in complex sclerosing lesion

Virtual slides
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ALH and ADH involving a fibroadenoma

ADH, papillary lesions

Cytology description
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• Three-dimensional cells with uniform nuclei and occasional mild atypia

Cytology images
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ADH

Ductal lavage

Positive stains
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• CK8/18

Negtaive stains
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• Only 10% of ADH express high molecular weight keratins (CK34βE12, CK903) - useful in differentiation from UDH (100% positive)
• Usually negative for CK 5/6
• Usually negative for HER 2 (10% positive Mod Pathol 1990;3:449)

Differential diagnosis
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• Low grade DCIS: larger lesion involving entire terminal duct lobular unit, uniform cells, no secondary lumina
• Columnar cell lesion: prominent apical cytoplasmic snouts and intraluminal secretions
• Flat epithelial atypia: replacement of epithelial cells by single or stratified layer of cells with low grade cytologic atypia resembling low grade DCIS, but does not fulfill criteria of ADH or low grade DCIS
• Usual ductal hyperplasia: Mix of cell types (luminal, basal, myoepithelial) that express different cytokeratins (note that because ADH is clonal, CK expression is restricted to one type, usually luminal)

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