"Her agony came from the fact that mastectomy would be curative
and it was hard to turn that down. A lesser procedure, while preserving
her breast and her femininity, offered her somewhat less chance for a complete
cure--but exactly how much less was unknown. Perhaps only a small amount
less. It didn't seem worth losing her breast for a few percentage points.
Yet, maybe it was. It was the most difficult decision of her life. But
medicine had failed her. The data upon which to base her judgment was weak,
and we had shifted the burden of that judgment to her."
That paragraph was written in 1991 about a woman with ductal carcinoma
in situ (DCIS) of the breast and her arduous journey through the medical
system as she searched for the "correct" treatment. There were
a number of "correct" treatments then for her particular form
of DCIS, but each was flawed in one way or another, confounding her thoughts
and making her decision more difficult. But that was 1991. Today, we know
much more about DCIS. But is the decision-making process any easier?
The results of the National Surgical Adjuvant Breast Project (NSABP)
Protocol B-17 were published in 1993 and updated in 1995 and 1997[3a].
This prospective, randomized clinical trial was designed to resolve the
controversy over the treatment of DCIS. More than 800 patients with DCIS
excised with clear surgical margins were randomized to one of two treatments:
excision only or excision plus radiation therapy. At 5 years, there was
a statistically significant decrease in local recurrence of both DCIS and
invasive breast cancer in patients treated with radiation therapy. These
data led the NSABP to recommend postexcision radiation therapy for all
patients with DCIS who chose to save their breasts--a recommendation that
some consider too broad.[4,5]
The NSABP B-17 study was criticized for a number of reasons, including
its definition of clear margins (which the NSABP defined as a tumor that
is not transected), determination of size by central review of the pathology
report, the absence of size measurements for more than 40% of cases, and,
perhaps most important, the lack of pathologic subset analysis in the initial
report.[4,5] In defense of the NSABP, the trial did exactly what it was
designed to do; namely, it proved that radiation therapy was effective
for patients with DCIS. It was not designed to answer the questions about
patient subgroups that we ask today.
Consider the following two patients, both of whom merit radiation therapy
based on the results of NSABP B-17. The first patient is a woman with a
12-mm low-grade lesion that has been widely excised with a minimum of 15-mm
margins in all directions. Compare her with the second patient, a woman
with a 35-mm high-grade lesion with DCIS approaching to within 0.2 mm of
the inked margin but not involving it. According to the NSABP, both of
these patients should be treated with radiation therapy.
At our facilities, based on data that will be presented below, the first
patient would receive no additional therapy. Rather, she would be carefully
followed with physical examination every 6 months and mammography every
6 to 12 months. The second patient would undergo a wide reexcision prior
to making a final treatment decision. Significant residual disease approaching
the new margins would earn a recommendation for mastectomy and immediate
reconstruction; widely clear new margins with little or no residual DCIS
would warrant consideration for radiation therapy.
Thus, despite the results of NSABP B-17, there continues to be debate
regarding the DCIS decision-making process, which is not much clearer now
than it was in 1991.
Numerous clinical, pathologic, and laboratory factors can aid clinicians
and patients wrestling with the difficult treatment decision-making process.
Our research has shown that nuclear grade, the presence of comedo-type
necrosis (coagulative necrosis), tumor size, and margin width are all key
factors in predicting local recurrence in patients with DCIS.[6-8] By using
a combination of these factors, it may be possible to identify subgroups
of patients who do not require irradiation, if breast conservation is elected;
it also may be possible to identify patients whose recurrence rate is potentially
so high, even with breast irradiation, that mastectomy is preferable.
Ductal carcinoma in situ is a biologically and histologically heterogeneous
group of lesions.[9,10] With the appreciation and acceptance of this heterogeneity,
DCIS has become confusing for both patients and physicians. Currently,
it is not uncommon for DCIS patients to seek second, third, and even fourth
opinions and to receive a diverse spectrum of advice ranging from biopsy
only to wide excision, segmental resection, quadrant resection, mastectomy,
or even bilateral mastectomy. As an adjunct to all these treatments except
mastectomy, radiation therapy may be advised.
Patients seeking treatment advice will find physicians willing to support
most of these options. The second opinion-givers are usually oncologists
specializing in medicine, surgery, or radiation therapy. Some patients,
however, seek advice from their gynecologists, internists, or family practitioners.
Many women also turn for counsel to family, friends, and other women who
have had breast cancer, most of whom have had invasive disease.
Table 1 shows the changing nature
of DCIS during the last decade. Before the widespread use of mammography,
DCIS was diagnosed infrequently, representing less than 1% of all breast
cancer cases.[11,12] Today, DCIS is common, accounting for approximately
12% to 15% of all newly diagnosed cases and as many as 20% to 40% of
cases at institutions that effectively utilize mammography.[14,15] In 1997,
more than 36,000 new cases of DCIS are expected to be diagnosed in the
Previously, most patients with DCIS presented with clinical symptoms,
such as a breast mass, bloody or serous nipple discharge, or Paget's disease
and frequently had extensive disease.[11,17-19] Today, most lesions are
smaller, nonpalpable, subclinical, and detected by mammography alone.
Until recently, the treatment for most patients with DCIS was mastectomy.
Currently, many patients are being treated with breast preservation. Fifteen
years ago, when mastectomy was common, reconstruction was infrequent and,
if performed, was generally done as a delayed procedure with implants.
Today, reconstruction for patients with DCIS treated by mastectomy is common
and is usually done immediately, at the time of mastectomy, and often with
In the past, when a mastectomy was performed, large amounts of skin
were discarded. Now, it is considered safe to perform a skin-sparing mastectomy
for DCIS.[20-23] We must keep in mind, however, that in patients with extensive
disease, recurrences may develop after mastectomy (with or without reconstruction)
in the scant residual breast tissue. The thicker the skin flaps, the more
residual breast tissue is left behind and the more likely there is to be
In the past, there was no confusion. All breast cancers were considered
the same and mastectomy was the only treatment. Today, we know that all
breast cancers are different. There are many treatments and a great deal
Factors Responsible for the Changes
These changes were brought about by numerous factors. The most important
of these are increased utilization of mammography, improvements in mammographic
technique, and the acceptance of breast-conservation therapy for invasive
Mammography--The acceptance of mammography not only changed the
way we detect DCIS, it also altered the nature of the disease that we detected
by allowing us to enter the neoplastic continuum at an earlier time. Every
institution employing mammography has witnessed a relatively large increase
in the number of small, mammographically detected cases of DCIS. This can
be appreciated by charting the impact that mammography has had on the number
and type of DCIS cases at one of our facilities, the Breast Center in Van
From 1979 to 1981, the Van Nuys group treated a total of only 15 patients
with DCIS, an average of 5 per year. Only two lesions (13%) were nonpalpable.
Two new mammography units and a full-time, experienced mammographer were
added in 1982, and immediately the number of new DCIS cases increased to
more than 30 per year, most of them nonpalpable. With the addition of a
third mammography machine in 1987, almost 40 new cases per year were diagnosed.
In 1994, a fourth mammography machine and a stereotactic biopsy unit were
added. Analysis of the Van Nuys series through June 1996 (more than 500
patients) revealed that 81% of lesions were nonpalpable. If we consider
only those lesions that were diagnosed after 1991, 92% were nonpalpable.
Breast Conservation--The second factor that affected how we think
about DCIS was the acceptance of breast-conservation therapy (lumpectomy,
axillary node dissection, and radiation therapy) for patients with invasive
breast cancer. Until 1980, the treatment for most patients with any form
of breast cancer was mastectomy. Since then, numerous prospective randomized
trials have revealed that survival in patients with invasive breast cancer
treated with lumpectomy and radiation therapy is equivalent to that in
women who undergo mastectomy.[25-32] Based on these results, it was difficult
to continue treating noninvasive disease with mastectomy while treating
more aggressive invasive breast cancer with breast preservation.
Patients often ask the question, "You mean if I waited until my
cancer was invasive, I could have saved my breast?" The answer is
not that simple. Although there is clearly a relationship between DCIS
and invasive breast cancer, the two entities are different heterogeneous
groups of diseases with some overlap. It is extremely common to see both
DCIS and invasive breast cancer within a single specimen. Authorities agree
that DCIS is an obligate precursor to invasive breast cancer, but there
is speculation that DCIS may be less amenable to control with irradiation.
Thus, while patients with invasive breast cancers that are 4 cm or smaller
and have little or no intraductal component can readily be treated by lumpectomy
and radiation therapy, the same may not be true for patients with pure
DCIS or for those with invasive breast cancer with an extensive intraductal
Nevertheless, current data suggest that many patients with DCIS can
be successfully treated with breast preservation (with or without radiation
therapy). In the sections that follow, we will show how easily available
data can be used to predict which patients are more likely to suffer a
recurrence after breast conservation. Knowing the probability of local
recurrence can help simplify the complex treatment selection process.
1. Silverstein MJ: Intraductal breast carcinoma: Two decades of progress?
Am J Clin Oncol 14(6):534-537, 1991.
2. Fisher B, Costantino J, Redmond C, et al: Lumpectomy compared with
lumpectomy and radiation therapy for the treatment of intraductal breast
cancer. N Engl J Med 328:1581-1586, 1993.
3. Fisher ER, Constantino J, Fisher B, et al: Pathologic findings from
the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Cancer
3a. Mamounas E, Fisher B, Dignam J, et al: Effect of breast irradiation
following lumpectomy in intraductal breast cancer (DCIS): Update results
from NSABP B-17. Proc Soc Surg Oncol 50:7, 1997.
4. Lagios MD, Page DL: Radiation therapy for in situ or localized breast
cancer (letter). N Engl J Med 21:1577-1578, 1993.
5. Page DL, Lagios MD: Pathologic analysis of the NSABP-B17 trial: Unanswered
questions remaining unanswered considering current concepts of ductal carcinoma
in situ. Cancer 75:1219-1222, 1995.
6. Silverstein MJ, Barth A, Waisman JR, et al: Predicting local recurrence
in patients with intraductal breast carcinoma (DCIS). Proc Am Soc Clin
Oncol 14:117, 1995.
7. Silverstein MJ, Barth A, Poller DN, et al: Ten-year results comparing
mastectomy to excision and radiation therapy for ductal carcinoma in situ
of the breast. Eur J Cancer 31:1425-1427, 1995.
8. Lagios NM, Margolin FR, Westdahl PR, et al: Mammographically detected
duct carcinoma in situ: Frequency of local recurrence following tylectomy
and prognostic effect of nuclear grade on local recurrence. Cancer 63:619-624,
9. Lennington WJ, Jensen RA, Dalton LW, et al: Ductal carcinoma in situ
of the breast: Heterogeneity of individual lesions. Cancer 73:118-124,
10. Patchefsky AS, Schwartz GF, Finkelstein SD, et al: Heterogeneity
of intraductal carcinoma of the breast. Cancer 63:731-741, 1989.
11. Morrow M, Schnitt SJ, Harris JR: Ductal carcinoma in situ, in Harris
JR, Lippman MC, Morrow M, et al (eds): Diseases of the Breast, pp 355-368.
Philadelphia-New York, Lippincott-Raven, 1995.
12. Nemoto T, Vana J, Bedwani RN, et al: Management and survival of
female breast cancer: Results of a national survey by The American College
of Surgeons. Cancer 45:2917-2924, 1980.
13. SEER Cancer Statistics Review: 1973-1990. National Cancer Institute.
NIH Pub No. 93-2789, 1993.
14. Lagios MD: Duct carcinoma in situ: Pathology and treatment. Surg
Clin North Am 70:853-871, 1990.
15. Silverstein MJ, Cohlan B, Gierson ED, et al: Duct carcinoma in situ:
227 cases without microinvasion. Eur J Cancer 28(2/3):630-634, 1992.
16. Parker SL, Tong T, Bolden S, et al: Cancer statistics, 1997. CA
Cancer J Clin 47(1):5-27, 1997.
17. Ashikari R, Hadju SI, Robbins GF: Intraductal carcinoma of the breast.
Cancer 28:1182-1187, 1971.
18. Barth A, Brenner J, Giuliano AE: Current management of ductal carcinoma
in situ. Western J Med 163:360-366, 1995.
19. Stockdale AD, Brierley JD, Whire WF, et al: Radiotherapy for Paget's
disease of the nipple: A conservative alternative. Lancet 2 (8664):664-666,
20. Jensen JA, Handel N, Silverstein MJ: Glandular replacement therapy
(GRT) for intraductal breast carcinoma (DCIS). Proc Am Soc Clin Oncol 14:138,
21. Jensen JA, Handel N, Silverstein MJ: Glandular Replacement Therapy:
An argument for a combined surgical approach in the treatment of noninvasive
breast cancer. The Breast Journal 2:121-123, 1996.
22. Kroll SS, Ames F, Singletary SE, et al: The oncologic risks of skin
preservation at mastectomy when combined with immediate reconstruction
of the breast. Surg Gynecol Obstet 172:17-20, 1991.
23. Singletary ES: Skin-sparing mastectomy with immediate breast reconstruction:
Is it safe? Breast Diseases: A Yearbook Quarterly 6:259-260, 1995.
24. Silverstein MJ, Handel N, Hoffman RS, et al: The breast center--a
multidisciplinary model, in Paterson AHG, Lees AW (eds): Fundamental Problems
in Breast Cancer, pp 47-58. Boston, Martinus Nijhoff, 1987.
25. Blichert-Toft M, Brincker H, Andersen J, et al: A Danish randomized
trial comparing breast preserving therapy with mastectomy in mammary carcinoma.
Acta Oncol 27:671, 1988.
26. Blichert-Toft M, Rose C, Andersen J, et al: Danish randomized trial
comparing breast conservative treatment with mastectomy: Six years of life
table analysis. J Natl Cancer Inst Monogr11:19, 1992.
27. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized
clinical trial comparing total mastectomy and lumpectomy with or without
irradiation in the treatment of breast cancer. N Engl J Med 320:822-828,
28. Fisher B, Anderson S, Redmond CK, et al: Reanalysis and results
after 12 years of follow-up in a randomized clinical trial comparing total
mastectomy with lumpectomy with or without irradiation in the treatment
of breast cancer. N Engl J Med 333:1456-1461, 1995.
29. Lichter A, Lippman M, Danforth D, et al: Mastectomy versus breast
conserving therapy in the treatment of stage I and II carcinoma of the
breast: a randomized trial at The National Cancer Institute. J Clin Oncol
30. Van Dongen JA, Bartelink H, Fentiman IS, et al: Randomized clinical
trial to assess the value of breast-conserving therapy in stage I and II
breast cancer, EORTC 10801 trial. Monogr Natl Cancer Inst 11:15-18, 1992.
31. Veronesi U, Saccozzi R, Del Vecchio M, et al: Comparing radical
mastectomy with quadrantectomy, axillary dissection and radiotherapy in
patients with small cancers of the breast. N Engl J Med 305:6, 1981.
32. Veronesi U, Banfi A, Salvadori B, et al: Breast conservation is
the treatment of choice in small breast cancer: Long-term results of a
randomized trial. Eur J Cancer 26:668-670, 1990.
33. Page DL, Anderson TJ: Intraductal Barcinoma, in Page DL, Anderson
TJ. (eds): Diagnostic Histopathology of the Breast, pp 157-174. New York,
Churchill Livingstone, 1987.
34. Tavassoli FA: Intraductal carcinoma, in Tavassoli FA (ed): Pathology
of the Breast, pp 229-261. Norwalk, Appleton & Lange, 1992.
35. Rosen PP, Oberman HA: Intraepithelial (Preinvasive or in situ) carcinoma,
in Rosen PP, Oberman HA (eds): Atlas of Tumor Pathology--Tumors of the
Mammary Gland, pp 119-156. Washington, DC, Armed Forces Institute of Pathology,
36. Aasmundstad TA, Haugen OA: DNA Ploidy in intraductal breast carcinomas.
Eur J Cancer 26:956-959, 1992.
37. Meyer J: Cell kinetics of histologic variants of in situ breast
carcinoma. Breast Cancer Res Treat 7:171-180, 1986.
38. Allred DC, Clark GM, Molin R, et al: Overexpression of progression
of in situ to invasive breast cancer. Hum Pathol 23:974-979, 1992.
39. Barnes DM, Meyer JS, Gonzalez JG, et al: Relationship between c-erbB-2
immunoreactivity and thymidine labelling index in breast carcinoma in situ.
Breast Cancer Res Treat 18:11-17, 1991.
40. Bartkova J, Barnes DM, Millis RR, et al: Immunohistochemical demonstration
of c-erbB-2 protein in mammary ductal carcinoma in situ. Hum Pathol 21:1164-1167,
41. Bobrow LG, Happerfield LC, Gregory WM, et al: The classification
of ductal carcinoma in situ and its association with biological markers.
Semin Diagn Pathol 11:199-207, 1994.
42. Liu E, Thor A, He M, et al: The HER2 (c-erbB-2) oncogene is frequently
amplified in in situ carcinomas of the breast. Oncogene 7:1027-1032, 1992.
43. Van de Vijver MJ, Peterse JL, Mooi WJ, et al: Neu-protein overexpression
in breast cancer: association with comedo-type ductal carcinoma in situ
and limited prognostic value in stage II breast cancer. N Engl J Med 319:1239-1245,
44. Schwartz GF: The role of excision and surveillance alone in subclinical
DCIS of the breast. Oncology 8(2):21-26, 1994.
45. Silverstein MJ, Waisman JR, Gierson ED, et al: Radiation therapy
for intraductal carcinoma: Is it an equal alternative? Arch Surg 126:424-428,
46. Solin LJ, Yet IT, Kurtz J, et al: Ductal carcinoma in situ (intraductal
carcinoma) of the breast treated with breast-conserving surgery and definitive
irradiation. Correlation of pathologic parameters with outcome of treatment.
Cancer 71:2532-2542, 1993.
47. Holland R, Peterse JL, Millis R et al: Ductal carcinoma in situ:
A proposal for a new classification. Semin Diag Pathol 11(3):167-180, 1994.
48. Kuske RR, Bean JM, Garcia DM, et al: Breast conservation therapy
for intraductal carcinoma of the breast. Int J Radiat Oncol Biol Phys 26:391-396,
49. Silverstein MJ, Poller DN, Waisman JR: Prognostic classification
of breast ductal carcinoma in situ. Lancet 345:1154-1557, 1995.
50. Silverstein MJ, Poller DN, Craig PH, et al: A prognostic index for
breast ductal carcinoma in situ (abstract). Breast Cancer Res Treat 37(suppl):34,
51. Lagios MD, Westdahl PR, Margolin FR, et al: Duct Carcinoma in situ:
Relationship of extent of noninvasive disease to the frequency of occult
invasion, multicentricity, lymph node metastases, and short-term treatment
failures. Cancer 50:1309-1314, 1982.
52. Poller DN, Silverstein MJ, Galea M, et al: 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, 1994.
53. Bellamy COC, McDonald C, Salter DM, et al: Noninvasive ductal carcinoma
of the breast: The relevance of histologic categorization. Hum Pathol 24:16-23,
54. Sloane JP, Ellman R, Anderson TJ, et al: Consistency of histopathological
reporting of breast lesions detected by breast screening: Findings of the
UK national external quality assessment (EQA) scheme. Eur J Cancer 30:1414-1419,
55. Douglas-Jones AG, Gupta SK, Attanoos RL, et al: A critical appraisal
of six modern classificaitons of ductal carcinoma in situ of the breast
(DCIS): Correlation with grade of associated invasive disease. Histopathology
56. Dickson RB, Lippman ME: Growth factors in breast cancer. Endocrine
Reviews 16(5):559-589, 1995.
57. Lippman ME: The rational development of biological therapies for
breast cancer. Science 259:631-632, 1993.
58. Archer SG, Kemp BL, Gadd M, et al: Ductal carcinoma in situ of the
breast: Comedo versus noncomedo subtype nonpredictive of recurrence of
contralateral new breast primary. Breast Dis 7:353-360, 1994.
59. Arnesson LG, Smeed S, Fagerberg G, et al: Follow-up of two treatment
modalities for ductal carcinoma in situ of the breast. Br J Surg 76:672-675,
60. Carter D, Smith RRL: Carcinoma in situ of the breast. Cancer 40:1189-1193,
61. Ciatto S, Bonardi R, Cataliotti L, et al: Intraductal breast carcinoma.
Review of a multicenter series of 350 cases. Tumori 76:552-554, 1990.
62. Farrow JH: Current concepts in the detection and treatment of the
earliest of the breast cancers. Cancer 25:468-477, 1970.
63. Fentiman IS, Fagg N, Millis RR, et al: In situ ductal carcinoma
of the breast: Implications of disease pattern and treatment. Eur J Surg
Oncol 12:261-266, 1986.
64. Haffty BG, Peschel RE, Papadopoulos D, et al: Radiation therapy
for ductal carcinoma in situ of the breast. Connecticut Medicine 54:482-484,
65. Solin LJ, Kurtz J, Fourquet A, et al: Fifteen-year results of breast-conserving
surgery and definitive irradiation for the treatment of ductal carcinoma
in situ of the breast. J Clin Oncol 14:754-763, 1996.
66. Lagios MD: Ductal carcinoma in situ: Controversies in diagnosis,
biology, and treatment. The Breast Journal 1:68-78, 1995.
67. Ottesen GL, Graversen HP, Blichert-Toft M, et al: Ductal carcinoma
in situ of the female breast: Short-term results of a prospective nationwide
study. Am J Surg Pathol 16:1183-1196, 1992.
68. Zafrani B, Leroyer A, Fourquet A, et al: Mammographically-detected
ductal carcinoma in situ of the breast analysed with a new classification:
A study of 127 cases: Correlation with estrogen and progesterone receptors,
p53 and c-erbB-2 proteins and proliferative activity. Semin Diag Pathol
69. Silverstein MJ, Lagios MD, Craig PH, et al: The Van Nuys Prognostic
Index for ductal carcinoma in situ. The Breast Journal 2:38-40, 1996.
70. Silverstein MJ, Lagios MD, Craig PH, et al: A prognostic index for
ductal carcinoma in situ of the breast. Cancer 77:2267-2274, 1996.
71. Galea MH, Blamey RW, Elston CE, et al: The Nottingham Prognostic
Index in primary breast cancer. Breast Cancer Res Treat 22:207-219, 1992.
72. Bradley SJ, Weaver DW, Bouwman DL: Alternatives in the surgical
management of in situ breast cancer. Am Surg 56:428-432, 1990.
73. Fisher ER, Leiming ER, Anderson S, et al: Conservative management
of intraductal carcinoma (DCIS) of the breast. J Surg Oncol 47:139-147,
74. Kinne DW, Petrek JA, Osborne MP, et al: Breast carcinoma in situ.
Arch Surg 124:33-36, 1989.