The diagnosis and management of pre-invasive breast disease: Ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia (ADH) – current definitions and classification
© BioMed Central Ltd 2003
Published: 1 October 2003
Intraductal epithelial proliferations of the breast are at present classified into three groups; distinction is made histologically and clinically between usual epithelial hyperplasia and atypical ductal hyperplasia (ADH) and between ADH and ductal carcinoma in situ (DCIS). Although evidence indicates that these boundaries are not ideal on a morphological, immunohistochemical, or genetic basis, this three-tier system is accepted and used at present. The current definitions, histological features, and system of classification of ADH and DCIS are described in this manuscript.
Keywordsatypical ductal hyperplasia ductal carcinoma in situ epithelial proliferation
There is a need for an improved classification system for epithelial proliferative lesions and in situ malignancy of the breast, as reproducibility of diagnosis and categorisation is problematic. Clearly, classification of any disease process should have biological and clinical relevance as well as high reproducibility. As with diseases elsewhere in the body, distinguishing hyperplasia from neoplasia in the breast is based on identification of a clonal cell process. Clonality is recognised by uniformity of morphology and phenotype, and markers such as cytokeratin expression or hormone receptor expression can be used. While usual epithelial hyperplasia is morphologically and phenotypically heterogeneous, atypical ductal hyperplasia (ADH) and established ductal carcinoma in situ (DCIS) are homogeneous in cell type and marker expression. In addition, studies of loss of heterozygosity in low-grade DCIS and ADH have revealed similar genetic changes in the two conditions ; this finding is interpreted as confirmatory evidence that these are clonal processes and both therefore fulfil the basic concept of neoplasia. The frequency of loss of heterozygosity in cases of usual hyperplasia is much lower.
The conceptual distinction between benign neoplasia and in situ malignancy in the intraductal epithelial proliferations of the breast has been arbitrarily drawn at the boundary between ADH and low-grade DCIS. This may not be the appropriate place. Indeed morphological, immunohistochemical, and genetic studies indicate that it is more appropriate to draw the boundary between usual epithelial hyperplasia and ADH . Nevertheless, this three-tier system is the system accepted and used clinically at present and is outlined below.
Atypical ductal hyperplasia
The distinction between DCIS and ADH is based on evidence derived from many series, including studies by David Page and co-workers . These have been supported by other studies, such as the Nurses' Health Study [4, 5]. Clearly, ADH is a rare condition , being seen in 4% of symptomatic benign biopsies , although it is more common in association with screen-detected benign microcalcifications (31%) and is seen most commonly as an incidental finding .
The significance of the diagnosis of ADH lies in the increased risk of invasive breast carcinoma, which is about four to five times that of the general population [8–12] and may be even greater for premenopausal women (approaching a sixfold risk) . This risk is further increased if the patient has a first-degree relative with breast cancer (10-fold risk) [8, 13, 14].
The diagnostic criteria used to define ADH are imperfect. ADH was described initially based on exclusion rather than positive criteria, i.e. the recognition of some but not all of the features of DCIS (as well as the lack of the characteristics of usual-type epithelial hyperplasia) . This definition of ADH has been updated and, while the diagnosis stills rests on an absence of all the features of DCIS, additional supporting features have been described [15, 16]. The view of Page and colleagues that the cellular changes of DCIS are present but occupy fewer than two separate duct spaces is widely accepted. Others use a 2-mm cutoff; a lesion less than 2 mm in maximum dimension being classified as ADH and a larger one as DCIS . These criteria recognise essentially the same lesions. In essence, ADH is usually small and focal, measuring less than 2 to 3 mm. Larger foci are accepted if associated with a radial scar/complex sclerosing lesion or a papilloma.
There are three components to the diagnosis of ADH, namely the architectural pattern, cytology, and disease extent. ADH is formed from a uniform population of small or medium-sized, round, cuboidal or polygonal hyperchromatic cells, which are regularly arranged. The nuclei are evenly distributed and may form a rosette-like pattern. Single small nucleoli only are present. Mitoses, particularly abnormal forms, are infrequently seen. Geometric spaces are present and, in the cribriform type, the cells are arranged at right angles to the bridges formed. Micropapillary ADH is also recognised and a solid pattern may very rarely be seen. Small foci of necrosis may rarely be identified in ADH and do not indicate that the process should be classified as DCIS.
At present, it is recommended that the diagnosis of ADH should be restricted to lesions that show the features described by Page and colleagues [8, 15], to which the quantified risk of developing breast carcinoma is linked. Even then, the diagnosis of ADH should be made with caution and only if low-grade DCIS has been seriously considered in the differential diagnosis. Lesser changes for which the possible classification lies between florid usual epithelial hyperplasia and ADH are less relevant with regard to a risk of developing breast carcinoma and should not be classified as ADH. However, it should also always be borne in mind that a proliferation at the edge of a biopsy may represent the periphery of a more established lesion of DCIS and further excision of the adjacent tissue may be warranted.
The major problem of ADH is the difficulty in achieving acceptable levels of concordance or consistency in diagnosis. Various strategies have been used to try to improve its recognition, including revision of the criteria, providing a more positive basis for recognition, and education and emphasis on the use of one system by all for diagnosis . Despite the adoption of such principles, the reliable classification around the boundaries of ADH and the 'borderline' epithelial intraductal proliferations in the breast remained elusive in several [18, 19], although not all , studies.
Ductal carcinoma in situ
DCIS is defined as a proliferation of malignant epithelial cells within the breast parenchymal structures with no evidence of invasion across the basement membrane. This lack of invasive foci may be confirmed with immunohistochemical assessment for the presence of myoepithelial cells (e.g. smooth muscle actin, smooth muscle myosin) or basement membrane (collagen type IV, laminin). Pure DCIS accounts for 15 to 20% of breast cancers compared with only 5% of cases before the advent of breast cancer screening [21–23].
DCIS is a unicentric disease process, as shown by elegant three-dimensional studies showing that only one region of the breast is involved in the vast majority of cases and two-thirds of tumours involve only one quadrant . However, the natural history of DCIS is not well understood, as it has largely been extrapolated from historical series and reassessment of previously misdiagnosed lesions, most of which were low grade. The numbers in these series are low; in the series of Page and colleagues [25, 26], 28 patients were found to have DCIS from the 11,760 biopsies reviewed, and none of these lesions was of the comedo type. Studies suggest that up to 50% of patients with microscopic foci of DCIS develop invasive carcinoma. The invasive lesion occurs in the same area as the original lesion [27, 25], indicating a precursor process. Series of cases in which DCIS was not completely excised have also been reviewed , and these indicate that progression to invasion is related to the subtype of DCIS: comedo disease progresses into invasive carcinoma both more often and more rapidly than low-grade DCIS.
Several systems for subdividing DCIS have been described. The traditional classification based on a combination of architectural growth pattern and cytological features provides poor reproducibility, with up to 30% of cases in multicentre trials requiring reclassification . The National Coordinating Group for Breast Screening Pathology in the United Kingdom  recommend a system derived from the work of Holland and colleagues , classifying DCIS as high, low, or intermediate grade based on cytonuclear features.
High-nuclear-grade DCIS is composed of pleomorphic large cells with abundant, including abnormal, mitoses. Architecture is variable, although often solid. Central necrotic debris may undergo calcification. Low-nuclear-grade DCIS is composed of uniform cells, which are small. The nuclei are also small, although larger than in adjacent normal epithelium. Low-nuclear-grade DCIS frequently has a cribriform or micropapillary configuration; often both patterns are seen in the same lesion. Individual apoptotic cells or small foci of necrosis may be seen and associated calcification may be present, usually within inspissated secretions. Intermediate-grade disease is diagnosed if the neoplastic nuclei show pleomorphism of a degree between high- and low-grade DCIS. The nuclear-to-cytoplasmic ratio is often high in intermediate disease. The growth pattern may be micropapillary or cribriform but is often solid. Some degree of polarisation around architectural features may be seen.
This system of classification has clinical relevance and shows reasonable reproducibility . Several other systems for typing of DCIS have been proposed, including categorisation based on nuclear grade and necrosis [32, 33]. Silverstein and colleagues  have grouped DCIS into high-grade, non-high-grade with necrosis, and non-high-grade without necrosis and found an association between the subtypes and local recurrence and disease-free survival .
The existing system for the classification of intraductal epithelial proliferations assumes a spectrum from usual epithelial hyperplasia through ADH and low-grade DCIS to high-grade disease. Recently published work using comparative genomic hybridisation to investigate DCIS of the breast has prompted the proposal of a hypothetical model for the pathogenesis of DCIS, which recognises genetic lesions associated with particular morphological subtypes. These data also indicate that ADH/low-grade DCIS is more closely related to lobular in situ neoplasia than to high-grade DCIS. Thus new molecular genetic techniques are demonstrating that current dogma is untrue: (a) the fundamental separation of LCIS from DCIS may not be appropriate; (b) distinguishing ADH from low-grade DCIS is illogical; (c) the assumption that DCIS is a spectrum of the same disease is flawed. It is likely that some of these new methods will form the basis of a revised system of classification in the future with an underlying molecular genetic basis while maintaining clinical relevance.
This article is the second in a review series on The diagnosis and management of pre-invasive breast disease – current challenges, future hopes, edited by Sunil R Lakhani.
Other articles in the series can be found at http://breast-cancer-research.com/articles/series.asp?series=bcr_thediagnosis
atypical ductal hyperplasia
ductal carcinoma in situ.
- Lakhani SR, Collins N, Stratton MR, Sloane JP: Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p. J Clin Pathol. 1995, 48: 611-615.View ArticlePubMedPubMed CentralGoogle Scholar
- Ellis IO, Pinder SE, Elston CW: A critical appraisal of existing classification systems of epithelial hyperplasia and in situ neoplasia of the breast with proposals for future methods of categorization: where are we going?. Semin Diagn Pathol. 1999, 16: 202-208.PubMedGoogle Scholar
- Page DL, Dupont WD: Anatomic indicators (histologic and cytologic) of increased breast cancer risk. Breast Cancer Res Treat. 1993, 28: 157-166.View ArticlePubMedGoogle Scholar
- Connolly JL, Schnitt SJ: Clinical and histologic aspects of proliferative and non-proliferative benign breast disease. J Cell Biochem – Supplement. 1993, 17G: 45-48.View ArticleGoogle Scholar
- Marshall LM, Hunter DJ, Connolly JL, Schnitt SJ, Byrne C, London SJ, Colditz GA: Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types. Cancer Epidemiol Biomarkers Prev. 1997, 6: 297-301.PubMedGoogle Scholar
- Bartow SA, Pathak DR, Black WC, Key CR, Teaf SR: Prevalence of benign, atypical, and malignant breast lesions in populations at different risk for breast cancer. A forensic autopsy study. Cancer. 1987, 60: 2751-2760.View ArticlePubMedGoogle Scholar
- Stomper PC, Cholewinski SP, Penetrante RB, Harlos JP, Tsangaris TN: Atypical hyperplasia: frequency and mammographic and pathologic relationships in excisional biopsies guided with mammography and clinical examination. Radiology. 1993, 189: 667-671.View ArticlePubMedGoogle Scholar
- Page DL, Dupont WD, Rogers LW, Rados MS: Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer. 1985, 55: 2698-2708.View ArticlePubMedGoogle Scholar
- Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield AC, Worrell JA, Schuyler PA, Plummer WD: Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer. 1993, 71: 1258-1265.View ArticlePubMedGoogle Scholar
- Ma L, Boyd NF: Atypical hyperplasia and breast cancer risk: a critique. Cancer Causes Control. 1992, 3: 517-525.View ArticlePubMedGoogle Scholar
- Page DL, Jensen RA: Evaluation and management of high risk and premalignant lesions of the breast. World J Surg. 1994, 18: 32-38.View ArticlePubMedGoogle Scholar
- London SJ, Connolly JL, Schnitt SJ, Colditz GA: A prospective study of benign breast disease and the risk of breast cancer. JAMA. 1992, 267: 941-944. 10.1001/jama.267.7.941.View ArticlePubMedGoogle Scholar
- Tavassoli FA, Norris HJ: A comparison of the results of long-term follow-up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast. Cancer. 1990, 65: 518-529.View ArticlePubMedGoogle Scholar
- Page DL, Dupont WD: Indicators of increased breast cancer risk in humans. J Cell Biochem. 1992, 50 (suppl G): 175-182.View ArticleGoogle Scholar
- Page DL, Rogers LW: Combined histologic and cytologic criteria for the diagnosis of mammary atypical hyperplasia. Hum Pathol. 1992, 23: 1095-1097.View ArticlePubMedGoogle Scholar
- National Coordinating Group for Breast Screening Pathology: Pathology Reporting in Breast Cancer Screening. Sheffield: NHSBSP Publications. 1995, 2Google Scholar
- Tavassoli FA: Intraduct hyperplasias, ordinary and atypical. In Pathology of the Breast Connecticut: Appleton and Lange. 1992, 155-191.Google Scholar
- Sloane JP, Amendoeira I, Apostolikas N, Bellocq JP, Bianchi S, Boecker W, Bussolati G, Coleman D, Connolly CE, Eusebi V, DeMiguel C, Dervan P, Drijkoningen R, Elston CW, Faverly D, Gad A, Jacquemier J, Lacerda M, MartinezPenuela J, Munt C, Peterse JL, Rank F, Sylvan M, Tsakraklides V, Zafrani B: Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and reporting prognostic features of carcinomas. Virchows Archiv. 1999, 434: 3-10. 10.1007/s004280050297.View ArticlePubMedGoogle Scholar
- Rosai J: Borderline epithelial lesions of the breast. Am J Surg Pathol. 1991, 15: 209-221.View ArticlePubMedGoogle Scholar
- Schnitt SJ, Connolly JL, Tavassoli FA, Fechner RE, Kempson RL, Gelman R, Page DL: Interobserver reproducibility in the diagnosis of ductal proliferative breast lesions using standardised criteria. Am J Surg Pathol. 1992, 16: 1133-1143.View ArticlePubMedGoogle Scholar
- Van Dongen JA, Fentiman IS, Harris JR, Holland R, Peterse JL, Salvadori B, Stewart HJ: In situ breast cancer: the EORTC consensus meeting. Lancet. 1989, ii: 25-27. 10.1016/S0140-6736(89)90263-8.View ArticleGoogle Scholar
- Faverly DR, Burgers L, Bult P, Holland R: Three dimensional imaging of mammary ductal carcinoma in situ: clinical implications. Semin Diagn Pathol. 1994, 11: 193-198.PubMedGoogle Scholar
- Lagios MD: Duct carcinoma in situ. Pathology and treatment. Surg Clin North Am. 1990, 70: 853-871.View ArticlePubMedGoogle Scholar
- Holland R, Hendriks JHCL, Verbeek ALM, Mrauvunac M, Schuur-mans Stekhoven JH: Extent, distribution, and mammographic/histological correlations of breast ductal carcinoma in situ. Lancet. 1990, 335: 519-522. 10.1016/0140-6736(90)90747-S.View ArticlePubMedGoogle Scholar
- Page DL, Dupont WD, Rogers LW, Landenberger M: Intraductal carcinoma of the breast: Follow up after biopsy alone. Cancer. 1982, 49: 751-758.View ArticlePubMedGoogle Scholar
- Page DL, Dupont WD, Rogers LW, Jensen RA, Schuyler PA: Continued local recurrence of carcinoma 15–25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer. 1995, 76: 1197-1200.View ArticlePubMedGoogle Scholar
- Betsill WLJ, Rosen PP, Lieberman PH, Robbins GF: Intraductal carcinoma. Long-term follow-up after treatment by biopsy alone. JAMA. 1978, 239: 1863-1867. 10.1001/jama.239.18.1863.View ArticlePubMedGoogle Scholar
- Ketcham A, Moffat F: Vexed surgeons, perplexed patients, and breast cancer which may not be be cancer. Cancer. 1990, 65: 387-393.View ArticlePubMedGoogle Scholar
- Van Dongen JA, Holland R, Peterse JL, Fentiman IS, Lagios MD, Millis RR, Recht A: Ductal carcinoma in-situ of the breast; second EORTC consensus meeting. Eur J Cancer. 1992, 28: 626-629.View ArticlePubMedGoogle Scholar
- Holland R, Peterse JL, Millis RR, Eusebi V, Faverly D, Vandevijver MJ, Zafrani B: Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol. 1994, 11: 167-180.PubMedGoogle Scholar
- Badve S, A'Hern RP, Ward AM, Millis RR, Pinder SE, Ellis IO, Gusterson BA, Ellis IO: Prediction of local recurrence of ductal carcinoma in situ of the breast using five histological classifications: A comparative study with long follow-up. Hum Pathol. 1998, 29: 915-923.View ArticlePubMedGoogle Scholar
- Silverstein MJ, Poller DN, Waisman JR, Colburn WJ, Barth A, Gierson ED, Lewinsky B, Gamagami P, Slamon DJ: Prognostic classification of breast ductal carcinoma-in-situ. Lancet. 1995, 345: 1154-1157. 10.1016/S0140-6736(95)90982-6.View ArticlePubMedGoogle Scholar
- Poller DN, Silverstein MJ, Galea M, Locker AP, Elston CW, Blamey RW, Ellis IO: Ductal carcinoma in situ of the breast. A proposal for a new simplified histological classification. Association between cellular proliferation and c-erbB-2 protein expression. Mod Pathol. 1994, 7: 257-262.PubMedGoogle Scholar
- Silverstein MJ, Lagios MD, Craig PH, Waisman JR, Lewinsky BS, Colburn WJ, Poller DN: A prognostic index for ductal carcinoma in situ of the breast. Cancer. 1996, 77: 2267-2274. 10.1002/(SICI)1097-0142(19960601)77:11<2267::AID-CNCR13>3.0.CO;2-V.View ArticlePubMedGoogle Scholar