Utilizing routine histopathologic parameters obtained from appropriately handled lumpectomy and mastectomy specimens, a rational therapeutic plan based on epidemiologic and outcome-based data can be devised for any patient diagnosed with ductal carcinoma in situ (DCIS). In order to make a sound decision when weighing the current treatment options for DCIS—which include excision alone, excision plus radiation, and mastectomy—the following are mandatory: 1) assurance of an accurate diagnosis, 2) assessment of DCIS size and grade, and 3) careful margin evaluation. Accurate grading of DCIS is critical, since high nuclear grade and the presence of necrosis are highly predictive of the inability to achieve adequate margins, of local recurrence, and of the probability of missed areas of invasion. Margin status is the single most important determinant of local control following breast conservation for DCIS; numerous studies have shown that as the margin width increases, the risk of local failure decreases. The pros and cons of irradiating conservatively treated patients with DCIS should be carefully weighed on a case-by-case basis. Despite the 20-year-old dogma that all patients treated with breast conservation should receive postoperative radiation, a subset of patients who can be successfully treated by excision alone has been identified.
It is ironic that while huge strides have been made in the treatment of invasive breast carcinoma, resulting in breast conservation for many women, the most appropriate treatment of noninvasive breast carcinoma remains a topic of hot debate. This article explores some of the issues related to this controversy, with an emphasis on critical therapy-guiding information that can be derived from appropriately handled specimens using routine histopathologic parameters.
The diagnosis of ductal carcinoma in situ (DCIS) was rare before the 1980s; however, DCIS now represents a significant proportion of breast cancers, with an estimated 54,010 new cases diagnosed in 2010. This markedly increased incidence is a reflection of the widespread use of high-quality mammography as well as the histologic recognition of a wide spectrum of disease. Before a definitive treatment plan can be devised for any patient diagnosed with DCIS, three things are mandatory: 1) assurance of an accurate diagnosis, 2) assessment of DCIS size and grade, and 3) careful margin evaluation. The information these provide should be considered when weighing the current therapeutic options for DCIS, which include excision alone, excision plus radiation, and mastectomy.
What is the most important entity in the differential diagnosis for DCIS?
Atypical ductal hyperplasia (ADH) is the most important entity included in the differential diagnosis for low-grade DCIS. ADH has histologic and molecular features that are similar to those of DCIS, but its natural history and therapeutic implications are quite different. ADH is associated with a bilateral increased risk of later cancer development (verified by several large epidemiologic studies) that is four to five times higher than that in age-matched controls.[1-4] This contrasts sharply with DCIS, a nonobligate local precursor for which subsequent risk is localized to the same breast and same site as the index DCIS.[5-7] Although establishing the diagnosis of DCIS is usually straightforward, distinguishing small, low-grade DCIS lesions from ADH can occasionally be difficult; however, this difficulty has recently been exaggerated. In general practice, when strict epidemiologically validated criteria are followed, pathologists are able to accurately diagnose DCIS and can easily make this important distinction (Figure 1). For the uncommon but clearly acknowledged borderline cases, a conservative diagnostic stance is favored to assure that the patient is not overtreated.
What is the natural history of DCIS?
Natural history studies from the premammographic era that retrospectively identified small, incidental, low-grade examples of DCIS clearly demonstrated that untreated DCIS carries a 25% to 30% absolute risk of recurrence localized to the same breast and same site as the index DCIS.[7,10] For low- and intermediate-grade DCIS, this risk may extend more than 20 years (although the greatest risk is in the first 10 years following biopsy). The interval of increased recurrence risk following a diagnosis of high-grade DCIS is significantly shorter. Because under normal circumstances no woman today would go untreated when DCIS is diagnosed, these data do not apply directly. However, they can be used to make informed decisions regarding close or involved margins. Women with large DCIS lesions (greater than 5 cm) may not be candidates for breast conservation, since 10-year follow-up studies show that radiation cannot adequately compensate for close or involved margins and may delay recurrence detection, resulting in a greater proportion of invasive recurrences than are seen with excision only.[13,14] In contrast, for small, completely excised DCIS, especially cases that are low grade and in older women, the recurrence interval may well extend beyond the life expectancy of the patient. Such lesions carry a low potential for subsequent invasive cancer development—approximately 1% per year. This risk is only slightly greater than that associated with lobular carcinoma in situ, a lesion typically treated with close clinical follow-up. This wide spectrum of behavior underscores the important contributions made by studies that seek to identify a subset of low-risk patients who can be successfully treated by excision alone (see below). Indeed, Ozanne et al have suggested, using statistical models, that the potential for DCIS to progress to invasive cancer is currently overestimated, often resulting in overtreatment.
1. Dupont W, Page D. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985;312:146-51.
2. London S, Connolly J, Schnitt S, Colditz G. A prospective study of benign breast disease and the risk of breast cancer. JAMA. 1992;267:941-4.
3. Dupont W, Parl F, Hartmann W, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer. 1993;71:1258-65.
4. Hartmann L, Sellers T, Frost M, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005;353:229-37.
5. Sanders M, Schuyler P, Dupont W, Page D. 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. 2005;103:2481-4.
6. Collins L, Tamimi R, Baer H, et al. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy: results from the Nurses' Health Study. Cancer. 2005;103:1778-84.
7. Betsill W, Jr, Rosen P, Lieberman P, Robbins G. Intraductal carcinoma. Long-term follow-up after treatment by biopsy alone. JAMA. 1978;239:1863-7.
8. Saul S. Prone to error: earliest steps to find cancer. The New York Times. July 20, 2010.
9. Simpson J, Sanders M, Page D, editors. Diagnostic accuracy of ductal carcinoma in situ: results of Eastern Cooperative Oncology Trial 5194. USCAP; March 2011; San Antonio, TX.
10. Page DL, Dupont WD, Rogers LW, et al. 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.
11. Collins LC, Tamimi RM, Baer HJ, et al. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy: results from the Nurses' Health Study. Cancer. 2005;103:1778-84.
12. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med. 1999;340:1455-61.
13. Guerra LE, Smith RM, Kaminski A, et al. Invasive local recurrence increased after radiation therapy for ductal carcinoma in situ. Am J Surg. 2008;196:552-5.
14. Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol. 2006;24:1031-6.
15. Silverstein MJ, Lagios MD. Should all patients undergoing breast conserving therapy for DCIS receive radiation therapy? No. One size does not fit all: an argument against the routine use of radiation therapy for all patients with ductal carcinoma in situ of the breast who elect breast conservation. J Surg Oncol. 2007;95:605-9.
16. Ozanne EM, Shieh Y, Barnes J, et al. Characterizing the impact of 25 years of DCIS treatment. Breast Cancer Res Treat. 2011;129:165-73.
17. Grin A, Horne G, Ennis M, O'Malley FP. Measuring extent of ductal carcinoma in situ in breast excision specimens: a comaprison of four methods. Arch Pathol Lab Med. 2009;133:31-7.
18. Dadmanesh F, Fan X, Dastane A, et al. Comparative analysis of size estimation by mapping and counting number of blocks with ductal carcinoma in situ in breast excision specimens. Arch Pathol Lab Med. 2009;133:26-30.
19. O'Sullivan M, Li T, Freedman G, Morrow M. The effect of multiple reexcisions on the risk of local recurrence after breast conserving surgery. Ann Surg Oncol. 2007;14:3133-40.
20. Silverstein M Lagios M, Recht A, et al. Image-detected breast cancer: state of the art diagnosis and treatment. J Am Coll Surg. 2005;201:586-97.
21. Cheng L, Al-Kaisi NK, Gordon NH, et al. Relationship between the size and margin status of ductal carcinoma in situ of the breast and residual disease. J Natl Cancer Inst. 1997;89:1356-60.
22. Di Saverio S, Catena F, Santini D, et al. 259 patients with DCIS of the breast applying USC/Van Nuys prognostic index: a retrospective review with long term follow up. Breast Cancer Res Treat. 2008;109:405-16.
23. MacDonald HR, Silverstein MJ, Mabry H, et al. Local control in ductal carcinoma in situ treated by excision alone: incremental benefit of larger margins. Am J Surg. 2005;190:521-5.
24. Sigal-Zafrani B, Lewis JS, Clough KB, et al. Histological margin assessment for breast ductal carcinoma in situ: precision and implications. Mod Pathol. 2004;17:81-8.
25. Dillon MF, Mc Dermott EW, O'Doherty A, et al. Factors affecting successful breast conservation for ductal carcinoma in situ. Ann Surg Oncol. 2007;14:1618-28.
26. Neuschatz A, DiPetrillo T, Steinhoff M, et al. The value of breast lumpectomy margin assessment as a predictor of residual tumor burden in ductal carcinoma in situ of the breast. Cancer. 2002;94:1917-24.
27. Asjoe FT, Altintas S, Huizing MT, et al. The value of the Van Nuys Prognostic Index in ductal carcinoma in situ of the breast: a retrospective analysis. Breast J. 2007;13:359-67.
28. Muffuz A, Barroso-Bravo S, Najera I, et al. Tumor size as predictor of microinvasion, invasion, and axillary metastasis in ductal carcinoma in situ. J Exp Clin Cancer Res. 2006;25:223-7.
29. Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with invasive carcinoma of the breast. Arch Pathol Lab Med. 2009;133:1515-38.
30. Patchefsky AS, Schwartz GF, Finkelstein SD, et al. Heterogeneity of intraductal carcinoma of the breast. Cancer. 1989;63:731-41.
31. Bellamy CO, McDonald C, Salter DM, et al. Noninvasive ductal carcinoma of the breast: the relevance of histologic categorization. Hum Pathol. 1993;24:16-23.
32. Boland GP, Chan KC, Knox WF, et al. Value of the Van Nuys Prognostic Index in prediction of recurrence of ductal carcinoma in situ after breast-conserving surgery. Br J Surg. 2003;90:426-32.
33. Neuschatz AC, DiPetrillo T, Steinhoff M, et al. The value of breast lumpectomy margin assessment as a predictor of residual tumor burden in ductal carcinoma in situ of the breast. Cancer. 2002;94:1917-24.
34. Macdonald HR, Silverstein MJ, Lee LA, et al. Margin width as the sole determinant of local recurrence after breast conservation in patients with ductal carcinoma in situ of the breast. Am J Surg. 2006;192:420-2.
35. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001;28:400-18.
36. Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853—a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol. 2006;24:3381-7.
37. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;362:95-102.
38. Fisher ER, Dignam J, Tan-Chiu E, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer. 1999;86:429-38.
39. Bijker N, Peerse JL, Duchateau L, et al. 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. 2001;19:2263-71.
40. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087-2106.
41. Hughes LL, Wang M, Page DL, et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:5319-24.
42. Silverstein MJ. The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast. Am J Surg. 2003;186:337-43.
43. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet. 2000;355:528-33.
44. Moore KH, Sweeney KJ, Wilson ME, et al. Outcomes for women with ductal carcinoma-in-situ and a positive sentinel node: a multi-institutional audit. Ann Surg Oncol. 2007;14:2911-7.
45. Mabry H, Giuliano AE, Silverstein MJ. What is the value of axillary dissection or sentinel node biopsy in patients with ductal carcinoma in situ? Am J Surg. 2006;192:455-7.
46. Lari SA, Kuerer HM. Biological markers in DCIS and risk of breast recurrence: a systematic review. J Cancer. 2011;2:232-61.
47. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287-5312.