Abstract
Background
Ductal carcinoma in situ represents about 20% of all tumours diagnosed within mammographic screening programs. The natural history of DCIS is poorly understood, as it cannot be observed directly. Estimates of the proportion of DCIS that progress to invasive cancer, as well as factors that may influence progression, are important for clinical management. Here we review various sources of evidence regarding the natural history of DCIS.
Methods
We identified relevant publications of studies on: follow-up studies of DCIS initially misdiagnosed as benign, studies of recurrence of DCIS as invasive cancer, autopsy studies, studies of risk factors for DCIS, animal studies and studies that used mathematical models to study growth of DCIS and invasive cancer. Data sources included the MEDLINE data base, searches of articles cited in key reviews and editorials.
Results
The most direct evidence regarding the progression of DCIS to invasive cancer comes from studies where DCIS was initially misdiagnosed as benign and treated by biopsy alone. These studies suggest that between 14–53% of DCIS may progress to invasive cancer over a period of 10 or more years. The reported prevalence of undiagnosed DCIS in autopsy studies, of approximately 9%, has been used to suggest a larger reservoir of DCIS may exist in the population. All types of study designs reviewed had limitations that may bias the estimate of progression in either direction.
Conclusion
The available evidence suggests not all DCIS will progress to invasive cancer in the medium term but precise estimates of progression are not possible given the limitations of the data. Mathematical modelling of various scenarios of progression and studies of genetic factors involved in progression may shed further light on the natural history of DCIS.
Similar content being viewed by others
References
Rosner D, Bedwani RN, Vana J, Baker HW, Murphy GP, 1980 Noninvasive breast carcinoma: results of a national survey by the American College of Surgeons Ann Surg 192: 139–147
Ernster VL, Barclay J, Kerlikowske K, Grady D, Henderson C, 1996 Incidence of and treatment for ductal carcinoma in situ of the breast Jama 275: 913–918
Leonard GD, Swain SM, 2004 Ductal carcinoma in situ, complexities and challenges J Natl Cancer Inst 96: 906–920
Burstein HJ, Polyak K, Wong JS, Lester SC, Kaelin CM, 2004 Ductal carcinoma in situ of the breast N Engl J Med 350: 1430–1441
Tavassoli FA, 1998 Ductal carcinoma in situ: introduction of the concept of ductal intraepithelial neoplasia Mod Pathol 11: 140–154
Frykberg ER, Bland KI, 1994 Overview of the biology and management of ductal carcinoma in situ of the breast Cancer 74: 350–361
Boyages J, Delaney G, Taylor R, 1999 Predictors of local recurrence after treatment of ductal carcinoma in situ: a meta-analysis Cancer 85: 616–628
Buerger H, Otterbach F, Simon R, Schafer KL, Poremba C, Diallo R, Brinkschmidt C, Dockhorn-Dworniczak B, Boecker W, 1999 Different genetic pathways in the evolution of invasive breast cancer are associated with distinct morphological subtypes J Pathol 189: 521–526
Buerger H, Otterbach F, Simon R, Poremba C, Diallo R, Decker T, Riethdorf L, Brinkschmidt C, Dockhorn-Dworniczak B, Boecker W, 1999 Comparative genomic hybridization of ductal carcinoma in situ of the breast-evidence of multiple genetic pathways J Pathol 187: 396–402
James LA, Mitchell EL, Menasce L, Varley JM, 1997 Comparative genomic hybridisation of ductal carcinoma in situ of the breast: identification of regions of DNA amplification and deletion in common with invasive breast carcinoma Oncogene 14: 1059–1065
Aubele M, Mattis A, Zitzelsberger H, Walch A, Kremer M, Welzl G, Hofler H, Werner M, 2000 Extensive ductal carcinoma In situ with small foci of invasive ductal carcinoma: evidence of genetic resemblance by CGH Int J Cancer 85: 82–86
Aubele M, Cummings M, Walsch A, Zitzelsberger H, Nahrig J, Hofler H, Werner M, 2000 Heterogeneous chromosomal aberrations in intraductal breast lesions adjacent to invasive carcinoma [In Process Citation] Anal Cell Pathol 20: 17–24
Provenzano E, Hopper JL, Giles GG, Marr G, Venter DJ, Armes JE, 2003 Biological markers that predict clinical recurrence in ductal carcinoma in situ of the breast Eur J Cancer 39: 622–630
Poller DN, Roberts EC, Bell JA, Elston CW, Blamey RW, Ellis IO, 1993 p53 protein expression in mammary ductal carcinoma in situ: relationship to immunohistochemical expression of estrogen receptor and c-erbB-2 protein Hum Pathol 24: 463–468
Bobrow LG, Happerfield LC, Gregory WM, Springall RD, Millis RR, 1994 The classification of ductal carcinoma in situ and its association with biological markers Semin Diagn Pathol 11: 199–207
Rudas M, Neumayer R, Gnant MF, Mittelbock M, Jakesz R, Reiner, 1997 A p53 protein expression, cell proliferation and steroid hormone receptors in ductal and lobular in situ carcinomas of the breast [see comments] Eur J Cancer 33: 39–44
Albonico G, Querzoli P, Ferretti S, Rinaldi R, Nenci I, 1998 Biological profile of in situ breast cancer investigated by immunohistochemical technique Cancer Detect Prev 22: 313–318
Kuukasjarvi T, Tanner M, Pennanen S, Karhu R, Visakorpi T, Isola J, 1997 Optimizing DOP-PCR for universal amplification of small DNA samples in comparative genomic hybridization Genes Chromosomes Cancer 18: 94–101
Kuukasjarvi T, Tanner M, Pennanen S, Karhu R, Kallioniemi OP, Isola J, 1997 Genetic changes in intraductal breast cancer detected by comparative genomic hybridization Am J Pathol 150: 1465–1471
Tsuda H, Fukutomi T, Hirohashi S, 1995 Pattern of gene alterations in intraductal breast neoplasms associated with histological type and grade Clin Cancer Res 1: 261–267
Buerger H, Mommers EC, Littmann R, Diallo R, Brinkschmidt C, Poremba C, Dockhorn-Dworniczak B, van Diest PJ, Bocker W, 2000 Correlation of morphologic and cytogenetic parameters of genetic instability with chromosomal alterations in in situ carcinomas of the breast Am J Clin Pathol 114: 854–859
Fiche M, Avet-Loiseau H, Maugard CM, Sagan C, Heymann MF, Leblanc M, Classe JM, Fumoleau P, Dravet F, Mahe M, Dutrillaux B, 2000 Gene amplifications detected by fluorescence in situ hybridization in pure intraductal breast carcinomas: relation to morphology, cell proliferation and expression of breast cancer-related genes [In Process Citation] Int J Cancer 89: 403–410
Glockner S, Lehmann U, Wilke N, Kleeberger W, Langer F, Kreipe H, 2001 Amplification of growth regulatory genes in intraductal breast cancer is associated with higher nuclear grade but not with the progression to invasiveness Lab Invest 81: 565–571
Hwang ES, DeVries S, Chew KL, Moore DH, II Kerlikowske K, Thor A, Ljung BM, Waldman FM, 2004 Patterns of chromosomal alterations in breast ductal carcinoma in situ Clin Cancer Res 10: 5160–5167
Poller DN, Silverstein MJ, Galea M, Locker AP, Elston CW, Blamey RW, Ellis IO, 1994 Ideas in pathology. 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 7: 257–262
Vos CB, ter Haar NT, Rosenberg C, Peterse JL, Cleton-Jansen AM, Cornelisse CJ, van de Vijver MJ, 1999 Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type Br J Cancer 81: 1410–1418
Kanthan R, Xiang J, Magliocco AM, 2000 p53, ErbB2, and TAG-72 expression in the spectrum of ductal carcinoma in situ of the breast classified by the Van Nuys system Arch Pathol Lab Med 124: 234–239
Provenzano E, Hopper JL, Giles GG, Marr G, Venter DJ, Armes JE, 2003 Biological markers that predict clinical recurrence in ductal carcinoma in situ of the breast Eur J Cancer 39: 622–630
Buerger H, Mommers EC, Littmann R, Simon R, Diallo R, Poremba C, Dockhorn-Dworniczak B, van Diest PJ, Boecker W, 2001 Ductal invasive G2 and G3 carcinomas of the breast are the end stages of at least two different lines of genetic evolution J Pathol 194: 165–170
Lakhani SR, 1999 The transition from hyperplasia to invasive carcinoma of the breast J Pathol 187: 272–278
Shoker BS, Sloane JP, 1999 DCIS grading schemes and clinical implications Histopathology 35: 393–400
Boecker W, Moll R, Dervan P, Buerger H, Poremba C, Diallo RI, Herbst H, Schmitt A, Lerch MM, Buchwalow IB, 2002 Usual ductal hyperplasia of the breast is a committed stem (progenitor) cell lesion distinct from atypical ductal hyperplasia and ductal carcinoma in situ J Pathol 198: 458–467
Barnes DM, Bartkova J, Camplejohn RS, Gullick WJ, Smith PJ, Millis RR, 1992 Overexpression of the c-erbB-2 oncoprotein: why does this occur more frequently in ductal carcinoma in situ than in invasive mammary carcinoma and is this of prognostic significance? Eur J Cancer 28: 644–648
Jacquemler J, Eisinger F, Guinebretiere JM, Stoppa-Lyonnet D, Sobol H, 1996 Intraductal component and BRCA1-associated breast cancer Lancet 348: 1098
Marcus JN, Page DL, Watson P, Narod SA, Lenoir GM, Lynch HT, 1997 BRCA1 and BRCA2 hereditary breast cancer phenotypes Cancer 80: 543–546
Armes JE, Egan AJ, Southey MC, Dite GS, McCredie MR, Giles GG, Hopper JL, Venter DJ, 1998 The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study Cancer 83: 2335–2345
Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations, sporadic cases. Breast Cancer Linkage Consortium. Lancet 349: 1505–1510,1997
Hoogerbrugge N, Bult P, de Widt-Levert LM, Beex LV, Kiemeney LA, Ligtenberg MJ, Massuger LF, Boetes C, Manders P, Brunner HG, 2003 High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer J Clin Oncol 21: 41–45
Kauff ND, Brogi E, Scheuer L, Pathak DR, Borgen PI, Hudis CA, Offit K, Robson ME, 2003 Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations Cancer 97: 1601–1608
Fisher ER, Dignam J, Tan-Chiu E, Costantino J, Fisher B, Paik S, Wolmark N, 1999 Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma [see comments] Cancer 86: 429–438
Ringberg A, Idvall I, Ferno M, Anderson H, Anagnostaki L, Boiesen P, Bondesson L, Holm E, Johansson S, Lindholm K, Ljungberg O, Ostberg G, 2000 Ipsilateral local recurrence in relation to therapy and morphological characteristics in patients with ductal carcinoma in situ of the breast Eur J Surg Oncol 26: 444–451
Bijker N, Peterse JL, Duchateau L, Julien JP, Fentiman IS, Duval C, Di Palma S, Simony-Lafontaine J, de Mascarel I, van de Vijver MJ, 2001 Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853 J Clin Oncol 19: 2263–2271
Stallard S, Hole DA, Purushotham AD, Hiew LY, Mehanna H, Cordiner C, Dobson H, Mallon EA, George WD, 2001 Ductal carcinoma in situ of the breast – among factors predicting for recurrence, distance from the nipple is important Eur J Surg Oncol 27: 373–377
Sanders ME, Schuyler PA, Dupont WD, Page DL, 2005 The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up Cancer 103: 2481–2484
Vicini FA, Kestin LL, Goldstein NS, Chen PY, Pettinga J, Frazier RC, Martinez AA, 2000 Impact of young age on outcome in patients with ductal carcinoma-in- situ treated with breast-conserving therapy J Clin Oncol 18: 296–306
Kestin LL, Goldstein NS, Lacerna MD, Balasubramaniam M, Martinez AA, Rebner M, Pettinga J, Frazier RC, Vicini FA, 2000 Factors associated with local recurrence of mammographically detected ductal carcinoma in situ in patients given breast-conserving therapy Cancer 88: 596–607
Goldstein NS, Vicini FA, Kestin LL, Thomas M, 2000 Differences in the pathologic features of ductal carcinoma in situ of the breast based on patient age Cancer 88: 2553–2560
Page DL, Dupont WD, Rogers LW, Landenberger M, 1982 Intraductal carcinoma of the breast: follow-up after biopsy only Cancer 49: 751–758
Eusebi V, Feudale E, Foschini MP, Micheli A, Conti A, Riva C, Di Palma S, Rilke F, 1994 Long-term follow-up of in situ carcinoma of the breast Semin Diagn Pathol 11: 223–235
Collins L, Tamimi R, Baer H, Connolly J, Colditz G, Schnitt S, 2004 Risk of invasive breast cancer in patients with ductal carcinoma in situ [DCIS] treated by diagnostic biopsy alone: results from the Nurses’ Health StudyBreast Cancer Res Treat Treat 88(sup1):1083
Betsill WL Jr., Rosen PP, Lieberman PH, Robbins GF, 1978 Intraductal carcinoma. Long-term follow-up after treatment by biopsy alone Jama 239: 1863–1867
Rosen P, Snyder RE, Foote FW, Wallace T, 1970 Detection of occult carcinoma in the apparently benign breast biopsy through specimen radiography Cancer 26: 944–952
Lewis D, Geschickter CF, 1938 Comedo carcinoma of the breast Arch Surg 36: 225–234
Haagensen CD, Lane N, Lattes R, 1972 Neoplastic proliferation of the epithelium of the mammary lobules: adenosis, lobular neoplasia, and small cell carcinoma Surg Clin North Am 52: 497–524
Kraus FT, Neubecker RD, 1962 The differential diagnosis of papillary tumors of the breast Cancer 15: 444–455
Millis RR, Thynne GS, 1975 In situ intraduct carcinoma of the breast: a long term follow-up study Br J Surg 62: 957–962
Farrow JH, 1970 Current concepts in the detection and treatment of the earliest of the early breast cancers Cancer 25: 468–477
Page DL, Dupont WD, Rogers LW, Jensen RA, Schuyler PA, 1995 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 76: 1197–1200
Harris EE, Schultz DJ, Peters CA, Solin LJ, 2000 Relationship of family history and outcome after breast conservation therapy in women with ductal carcinoma in situ of the breast [In Process Citation] Int J Radiat Oncol Biol Phys 48: 933–941
Silverstein MJ, Lagios MD, Craig PH, Waisman JR, Lewinsky BS, Colburn WJ, Poller DN, 1996 A prognostic index for ductal carcinoma in situ of the breast Cancer 77: 2267–2274
Silverstein MJ, Lagios MD, Groshen S, Waisman JR, Lewinsky BS, Martino S, Gamagami P, Colburn WJ, 1999 The influence of margin width on local control of ductal carcinoma in situ of the breast [see comments] N Engl J Med 340: 1455–1461
Cutuli B, Cohen-Solal-le Nir C, de Lafontan B, Mignotte H, Fichet V, Fay R, Servent V, Giard S, Charra-Brunaud C, Lemanski C, Auvray H, Jacquot S, Charpentier JC, 2002 Breast-conserving therapy for ductal carcinoma in situ of the breast: the French Cancer Centers’ experience Int J Radiat Oncol Biol Phys 53: 868–879
Gertig DM, Stillman IE, Byrne C, Spiegelman D, Schnitt SJ, Connolly JL, Colditz GA, Hunter DJ, 1999 Association of age and reproductive factors with benign breast tissue composition Cancer Epidemiol Biomarkers Prev 8: 873–879
Stomper PC, Geradts J, Edge SB, Levine EG, 2003 Mammographic predictors of the presence and size of invasive carcinomas associated with malignant microcalcification lesions without a mass AJR Am J Roentgenol 181: 1679–1684
Ernster VL, Barclay J, Kerlikowske K, Wilkie H, Ballard-Barbash R, 2000 Mortality among women with ductal carcinoma in situ of the breast in the population-based surveillance, epidemiology and end results program Arch Intern Med 160: 953–958
Erbas B, Amos A, Kavanagh A, Fletcher A, Gertig DM: Incidence of invasive breast cancer and ductal carcinoma in situ in a screening program by age: should older women continue screening? Cancer Epidemiol Biomarkers Prev Oct; 13(10): 1569–1573, 2004
Brinton LA, Hoover R, Fraumeni JF Jr. 1983 Epidemiology of minimal breast cancer Jama 249: 483–487
Schairer C, Byrne C, Keyl PM, Brinton LA, Sturgeon SR, Hoover RN, 1994 Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States) Cancer Causes Control 5: 491–500
Longnecker MP, Bernstein L, Paganini-Hill A, Enger SM, Ross RK, 1996 Risk factors for in situ breast cancer Cancer Epidemiol Biomarkers Prev 5: 961–965
Weiss HA, Brinton LA, Brogan D, Coates RJ, Gammon MD, Malone KE, Schoenberg JB, Swanson CA, 1996 Epidemiology of in situ and invasive breast cancer in women aged under 45 Br J Cancer 73: 1298–1305
Kerlikowske K, Barclay J, Grady D, Sickles EA, Ernster V, 1997 Comparison of risk factors for ductal carcinoma in situ and invasive breast cancer J Natl Cancer Inst 89: 76–82
Henrich JB, Kornguth PJ, Viscoli CM, Horwitz RI, 1998 Postmenopausal estrogen use and invasive versus in situ breast cancer risk J Clin Epidemiol 51: 1277–1283
Gapstur SM, Morrow M, Sellers TA, 1999 Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women’s Health Study Jama 281: 2091–2097
Trentham-Dietz A, Newcomb PA, Storer BE, Remington PL, 2000 Risk factors for carcinoma in situ of the breast Cancer Epidemiol Biomarkers Prev 9: 697–703
Claus EB, Stowe M, Carter D, 2001 Breast carcinoma in situ: risk factors and screening patterns J Natl Cancer Inst 93: 1811–1817
Lambe M, Hsieh CC, Tsaih SW, Ekbom A, Trichopoulos D, Adami HO, 1998 Parity, age at first birth and the risk of carcinoma in situ of the breast Int J Cancer 77: 330–332
Dubin N, Hutter RV, Strax P, Fazzini EP, Schinella RA, Batang ES, Pasternack BS, 1984 Epidemiology of minimal breast cancer among women screened in New York City J Natl Cancer Inst 73: 1273–1279
Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE, 1995 The use of estrogens and progestins and the risk of breast cancer in postmenopausal women N Engl J Med 332: 1589–1593
Nielsen M, Jensen J, Andersen J, 1984 Precancerous and cancerous breast lesions during lifetime and at autopsy. A study of 83 women Cancer 54: 612–615
Alpers CE, Wellings SR, 1985 The prevalence of carcinoma in situ in normal and cancer-associated breasts Hum Pathol 16: 796–807
Bhathal PS, Brown RW, Lesueur GC, Russell IS, 1985 Frequency of benign and malignant breast lesions in 207 consecutive autopsies in Australian women Br J Cancer 51: 271–278
Bartow SA, Pathak DR, Black WC, Key CR, Teaf SR, 1987 Prevalence of benign, atypical, and malignant breast lesions in populations at different risk for breast cancer. A forensic autopsy study Cancer 60: 2751–2760
Nielsen M, Thomsen JL, Primdahl S, Dyreborg U, Andersen JA, 1987 Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies Br J Cancer 56: 814–819
Azzopardi JG, Ahmed A, Millis RR: Problems in breast pathology. Major Probl Pathol 11: i–xvi, 1–466, 1979
Page DL, Dupont WD, Rogers LW, Rados MS, 1985 Atypical hyperplastic lesions of the female breast. A long-term follow-up study Cancer 55: 2698–2708
Welch HG, Black WC, 1997 Using autopsy series to estimate the disease “reservoir” for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med 127: 1023–1028
Schulze-Garg C, Lohler J, Gocht A, Deppert WA, 2000 transgenic mouse model for the ductal carcinoma in situ (DCIS) of the mammary gland Oncogene 19: 1028–1037
Miller FR, Santner SJ, Tait L, Dawson PJ, 2000 MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ J Natl Cancer Inst 92: 1185–1186
Hart D, Shochat E, Agur Z, 1998 The growth law of primary breast cancer as inferred from mammography screening trials data Br J Cancer 78: 382–387
Franks SJ, Byrne HM, King JR, Underwood JC, Lewis CE, 2003 Modelling the early growth of ductal carcinoma in situ of the breast J Math Biol 47: 424–452
Kopans DB, Rafferty E, Georgian-Smith D, Yeh E, D’Alessandro H, Moore R, Hughes K, Halpern E, 2003 A simple model of breast carcinoma growth may provide explanations for observations of apparently complex phenomena Cancer 97: 2951–2959
Brown BW, Atkinson EN, Bartoszynski R, Thompson JR, Montague ED, 1984 Estimation of human tumor growth rate from distribution of tumor size at detection J Natl Cancer Inst 72: 31–38
Atkinson E, Bartoszynski R, Brown BW, Thompson JR, 1983 On Estimating the growth function of tumors Mathematical Biosci 67: 145–166
Acknowledgements
Bircan Erbas is funded by NHMRC Public Health (Australia) Post-doctoral Research Fellowship. This research is supported by a DOD Concept Award No. DAMD 17-03-1-0687.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Erbas, B., Provenzano, E., Armes, J. et al. The natural history of ductal carcinoma in situ of the breast: a review. Breast Cancer Res Treat 97, 135–144 (2006). https://doi.org/10.1007/s10549-005-9101-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-005-9101-z