Background: Ductal
carcinoma in situ (DCIS) is detected more often since the advent of mammography.
A standardized pathologic staging and grading system does not exist, but nuclear
grade is assuming greater importance. The history of DCIS is long, and its treatment
is a controversial issue in breast cancer today.
Methods: Data
have been reviewed regarding the role of HER-2 expression as a prognostic variable,
as a predictive factor for response to chemotherapy and hormonal therapies,
and as a directed therapeutic target for breast cancer.
Results: The
NSABP protocol B06 revealed a recurrence rate of 43% in patients treated with
local excision alone. Half of recurrences are still DCIS, but 50% are invasive.
Local control is markedly improved by the addition of radiation. Recurrence
is also minimized by careful cytologic review of margins. Sentinel lymph node
biopsy has resulted in more accurate nodal staging.
Conclusions:
As a heterogeneous lesion, DCIS may not lend itself to a uniform treatment approach.
Careful analysis of resection margins is required. As our understanding of the
diagnosis and treatment of this disease develops, a coordinated team approach
is optimal.
Introduction
Major advances in the detection of
carcinoma of the breast have occurred in the past several decades. The increased
use of mammography for screening and early detection has resulted in a significant
increase in the diagnosis of early breast cancer and specifically ductal carcinoma
in situ (DCIS). The number of patients found to have this lesion has
grown 10-fold (from 2% to 20%) in the last two decades.1
DCIS includes a heterogeneous group
of lesions with diverse clinical presentations, histologic features, and biologic
potential. Histologically, DCIS is defined as proliferating malignant ductal
cells limited to existing ductal and lobular units without invasion through
the basement membrane. Conventionally, DCIS has been classified into comedocarcinoma
and noncomedocarcinoma subtypes. Comedocarcinoma DCIS is characterized
by the presence of necrosis and cells with marked cytologic atypia and frequent
mitotic figures. Noncomedocarcinoma DCIS is further divided into cribriform,
micropapillary, and solid subtypes and is characterized by proliferation of
a uniform population of cells with mild to moderate cytologic atypia. DCIS is
often heterogeneous, usually occurring with several subtypes noted within the
same lesion.
This morphologic categorization is
less reproducible in terms of prognosis and biologic behavior compared with
lesions that are defined by nuclear grade and the presence of necrosis, as recognized
in the classification system of Holland et al2 and Lagios et al.3
This classification system groups DCIS by nuclear grade from low to high. This
method is particularly useful when variations in growth patterns are demonstrated
with a dominant cell type noted since it is unusual to see cells of inconsistent
nuclear grade within a single lesion.
High-grade DCIS is the easiest
to identify (Fig 1A-B). The tumor cells have pleomorphic nuclei, irregular nuclear
contours, prominent nucleoli, and frequent mitoses. Multiple growth patterns
may be apparent, often with central necrosis and calcifications. It is noted
that the tumor cell morphology is fundamental for this designation, even in
the absence of necrosis. Low-grade DCIS (Fig 2A-C) exhibits a uniform
population of cells that are generally in a cribriform or micropapillary pattern
and lack necrosis or cytologic atypia. Intermediate-grade DCIS (Fig 3)
consists of types that cannot easily be specified as either high or low nuclear
grade. The proliferating cells display mild to moderate cytologic atypia with
variable architectural growth patterns such as cribriform, micropapillary, or
solid. Central necrosis may be present.
 |
 |
Fig
1A-B. High-grade DCIS, comedocarcinoma.
(A) Multiple ducts with central necrosis and focal microcalcifications.
(B) Markedly atypical ductal cell proliferation with prominent nucleoli
and associated necrosis. |
 |
 |
 |
Fig
2A-C. Low-grade DCIS, noncomedocarcinoma.
(A) Cribriform growth pattern with a uniform cell population forming rounded
lumens.
(B) Predominantly solid growth pattern,
(C) Micropapillary pattern |
 |
| Fig 3. Intermediate-grade
DCIS. Multiple ducts with cribriform and micropapillary forms showing central
necrosis, microcalcifications, and mild cytologic atypia. |
Some architectural patterns of DCIS,
regardless of the nuclear grade, may be more extensive and often multicentric,
such as micropapillary and apocrine variants. Consequently, results of a DCIS
consensus conference on classification were described in 1997, which include
five categories: high grade, intermediate grade, low grade, pure or predominantly
micropapillary, and pure apocrine.4-6
Natural History and
Epidemiology
The natural history of a disease forms
the basis for recommended treatment and assessment of prognosis. However, few
studies are available on the natural history of DCIS. The best measures of the
course of this disease have been found in autopsy studies and in retrospective
reviews of biopsies for what was originally thought to be benign disease and
later was diagnosed as DCIS.
Seven major autopsy studies of women
not known to have had breast cancer have provided insight. Six studies found
an incidence of 4% to 18%.7 The seventh and largest study showed
a 0.2% incidence (1 in 519 cases).8 However, this study included
a significant proportion of groups known to have a smaller than usual risk of
breast cancer. Of the more than 1,000 cases comprising these seven studies,
only one case of invasive cancer was detected. Further analysis with fixed criteria
is needed.
In considering cases of DCIS followed
after biopsy alone, we know that the natural history of the lesion has been
modified. The Vanderbilt experience is the largest with adequate follow-up.9,10
Twenty-eight patients were identified as having DCIS after histologic re-review
of what was originally assessed as benign disease and followed for an average
of approximately 30 years. These women had small, noncomedocarcinoma-type, mostly
cribriform-variety DCIS tumors. Originally, seven women — and later two — developed
invasive cancer in the same breast quadrant that initially showed DCIS for a
rate of 32%. The first case of invasive cancer in this series presented some
15 years after the initial biopsy. Another woman developed distant metastases
with invasive cancer more than 30 years later. No cases of comedocarcinoma DCIS
were included in this series. It is striking that the natural history may require
more than 20 years to fully develop and that a patient who has not undergone
definitive treatment maintains a substantial risk. It is evident that some intraductal
lesions will progress, but identifying the subset at risk for a poor outcome
is difficult.
Clinical Features
The clinical presentation of DCIS
is varied. Prior to the widespread use of screening mammography, most patients
presented with nipple discharge, Paget’s disease, or a palpable mass. A more
recent review of patients participating in screening mammography found that
nearly 60% of DCIS cases were discovered solely by mammography.11
Currently, most cases of DCIS consist
of small lesions detected by mammography. In fact, while DCIS comprises approximately
5% of symptomatic breast cancers, it represents 15% to 20% of those detected
at radiologic screening.12,13 A change over time in a mammographic
finding is associated with malignancy approximately 18% of the time; of these,
most are in situ lesions. A mass that is greater than 1 cm on a mammogram
represents a malignancy in approximately 25% of cases. However, most of these
are invasive lesions.14 The palpable forms of DCIS are associated
with multicentricity, occult invasion, and an overall poorer prognosis.15
The finding on a mammogram that commonly leads to biopsy is a focus of microcalcifications,
which is seen in as many as 95% of cases of DCIS. Calcium deposits in DCIS are
dystrophic calcifications secondary to necrotic tumor cells. The number of clustered
microcalcifications and their presentation, such as branching or linear distribution,
are associated with the likelihood of finding malignancy (Figs 4-6). Studies
that have attempted to link pathologic and radiologic findings have largely
been unsuccessful. Overall findings agree that screening-detected DCIS is less
extensive, has smaller calcification cluster size, and has less retroareolar
and upper inner quadrant involvement than symptomatic DCIS.13 The
issue of recognizing cancers with extensive intraductal involvement has been
improved with mammography. The extent of calcium deposits is readily discernible
on today’s mammograms and aids in evaluating treatment options.
 |
 |
 |
| Fig 4A-C.
Mammogram (craniocaudal and magnification views) demonstrating numerous
scattered clusters of microcalcifications. |
 |
 |
 |
| Fig
5A-C. Mammogram (mediolateral oblique, mediolateral, and craniocaudal
views) exhibiting extensive branching microcalcifications. |
 |
 |
| Fig
6A-B. Mammogram (craniocaudal and mediolateral views) showing a linear
pattern of microcalcifications. |
Treatment of Ductal
Carcinoma In Situ
A wide array of treatment plans have
been developed to treat DCIS. This is partly the result of the uncertainty of
the natural history of the lesion and lack of pathologic standardization. Today,
the treatment and management of noninvasive carcinoma are among the most controversial
areas of breast cancer.
In the past, the removal of the breast
in its entirety was thought to be the only appropriate treatment of breast carcinoma,
and that was the traditional treatment of DCIS. Cure rates with this approach
were close to 100%. We are now detecting more cancer with mammography, and the
result has been a push toward breast conservation therapy. It is becoming more
difficult to recommend a highly invasive treatment for a lesion that has a risk
of cancer death of only 1% to 2%, although a mechanism to identify women at
high risk for developing recurrence of invasive carcinoma would be advantageous.
The National Surgical Adjuvant Breast
and Bowel Project (NSABP) has conducted two studies examining treatment outcomes
in women with DCIS randomized to treatment with excision alone or excision plus
radiation therapy.16,17 The NSABP protocol B06 found a recurrence
rate of 43% in patients treated with local excision alone. These patients were
originally misdiagnosed as having invasive cancer and were all clinically detected.
Mean follow-up was 83 months for the 76 patients.16 Lagios et al3
also studied 79 patients treated locally. They noted 13 recurrences (16%) at
a mean follow-up of 124 months. Seven were DCIS and six were invasive, which
is consistent with most studies on the management of DCIS. In general, when
local failures in the treatment of DCIS occur, the pathology is split evenly
between invasive and noninvasive ductal carcinoma.
In exploring the use of radiation
therapy to improve local control with excision, the NSABP B17 trial randomized
818 women to excision alone or excision plus 50 Gy of radiation.17
The irradiated group had an almost 60% decrease in the ipsilateral recurrence.
A recurrence rate of 16% was seen in patients receiving excision alone and 7%
in patients receiving excision plus radiation. Originally, follow-up was a median
of 43 months. Fisher and colleagues18 extended these findings to
a mean of 90 months in a 1998 report. Again, all cohorts benefited from radiation
independent of mammographic or clinical attributes. Since half of the recurrences
are invasive carcinoma, the result of salvage therapy is a substantial issue.
Solin et al19 reported high rates of salvage in 42 (15%) cases of
local failure in a total of 274 cases of DCIS treated with excision plus radiation.
The intraductal recurrences (19 patients, 45%) were predominately detected with
mammography, and all were disease-free for the median follow-up of 4.7 years.
Of those with invasive recurrence, five had distant metastases. In the entire
group of patients with local recurrence at a median follow-up of 3.7 years after
salvage, 36 (86%) were alive and free of disease, 1 was alive with disease,
and 4 (10%) died of disease. Another died of other causes.
Accurate assessment
of the extent of DCIS lesions is often complex. The status of the lumpectomy
margin in DCIS is a strong prognostic factor for recurrence.20,21
Several techniques have been used to assess the lumpectomy margins in DCIS,
including inked radial permanent section margins, tangential permanent section
margins, frozen section, and imprint cytology. An initial review of 894 women
with breast conservation and radiation therapy who were treated at our center
from 1984 to 1996 included 701 patients with lumpectomy margins evaluated by
imprint cytology and the remaining 193 by conventional histology. The overall
recurrence rate for all patient groups was 16 (2.27%) of the 701 patients assessed
by imprint cytology compared with 26 (13.5%) of the 193 patients assessed by
conventional histology (Table 1 Please see printed version for Table
1.)22
In this series, T0 lesions (DCIS) had a recurrence rate of 1.3% when evaluated
by imprint cytology vs 13.8% when conventional histology was used. Imprint cytology
was both sensitive (99%) and specific (98%) for the intraoperative evaluation
of surgical margins for DCIS with rapid feedback at the time of surgery.
Our experience with DCIS and imprint
cytology was recently updated.23 Of the 218 cases of DCIS reviewed
in this follow-up series, 96 patients (44%) were treated with breast conservation,
demonstrating an overall recurrence rate at 57.5 months of 6.15% and a specific
recurrence rate of 2% for pure DCIS without extensive intraductal component
(EIC) or microinvasion. Silverstein et al24 reported a 10% recurrence
rate at a median follow-up of 62 months in patients treated similarly but without
imprint cytology evaluation of margins.
Generally, axillary lymph node dissection
is not considered necessary in the treatment of DCIS.25 It has been
the widespread opinion that the risk of axillary metastases is less than 4%.
Since 1994, sentinel lymph node mapping with biopsy has gained expanding validation
and usage. Although a notable learning curve exists for surgeons who are training
to perform this new procedure,26 sentinel node mapping is highly
predictive of axillary nodal status with minimal morbidity.27 A significant
expansion of the precision of sentinel lymph node diagnostics has occurred with
the application of molecular and immunohistochemical markers to detect occult
metastases. More intensive examination of these nodes occurs and more accurate
staging results28 in DCIS patients with occult micrometastases to
the regional lymphatic basin staged with greater precision. Our studies have
shown that the seeming lack of microinvasion in the primary lesion does not
prevent the presence of nodal disease. Data from our consecutive prospective
series of 1,147 breast cancer patients who underwent lymphatic mapping are noted
in Table 2, which presents positive sentinel lymph nodes in relation to tumor
size. All patients with a preoperative diagnosis of DCIS, regardless of size
or pathologic staging, were evaluated with sentinel lymph node biopsy. Positive
sentinel lymph nodes were found in 8.6% of the T0 or presumed pure DCIS patients.28
We believe that sentinel lymph node evaluation is an excellent method for determining
whether microinvasion is present at the primary tumor site. Furthermore, it
may be a more sensitive method, as it has been in one case to date, of detecting
occult invasive cancer not otherwise identified on examination or mammography
in a patient diagnosed with DCIS. Additional investigation is necessary to assess
the clinical significance of micrometastatic nodal disease, the role of axillary
lymph node dissection in patients with micrometastases, and the true clinical
relevance of upstaging with cytokeratin (Fig 7).
|
Table
2. Tumor Size vs Positive Lymph Nodes
|
| Tumor
Size |
All
Patients
(1,143) |
Number
of Patients With
Positive Axillary Nodes |
Mapped
Patients
(1,094) |
Number
of Patients
With Positive SLNs |
| T0
(DCIS) |
208 |
18 (8.6%)
|
200 |
18
(9.0%) |
| T1a |
72 |
13 (18.0%)
|
69 |
13
(18.8%) |
| T1b |
239 |
46 (19.7%)
|
228 |
45
(19.7%) |
| T1c |
385 |
121 (31.4%)
|
370 |
118
(31.9%) |
| T2 |
211 |
112 (53.1%)
|
202 |
108
(53.5%) |
| T3 |
28 |
24 (85.7%)
|
25 |
22
(88.0%) |
Tumor
size in 1,143 breast cancer patients undergoing lymphatic mapping at Moffitt
Cancer Center related to the number of patients with positive SLNs (sentinel
lymph nodes).
Note: 49 patients failed mapping; 10 (20.4%) had positive nodes on complete
axillary dissection. |
 |
| Fig 7. Micrometastatic
ductal carcinoma in a sentinel node from a DCIS patient. |
There is no evidence to support the
use of cytotoxic chemotherapy in the treatment of DCIS, and it is currently
not indicated. However, hormonal manipulation with tamoxifen may benefit this
group. The NSABP Breast Cancer Prevention Trial (P-1) found that treatment of
high-risk women with tamoxifen for five years produced a 50% reduction in the
incidence of noninvasive carcinoma.29 Currently, the NSABP protocol
B24 is investigating the addition of tamoxifen to lumpectomy and radiotherapy
in the treatment of DCIS.30 Preliminary results show the addition
of tamoxifen reduces the cumulative five-year incidence of a subsequent invasive
tumor from 3.4% to 2.1%. Due to the risk of overlooking an area of invasion,
estrogen- and progesterone-receptor status is generally not performed on biopsy
tissue without a mass. Hormonal receptor data to guide treatment in patients
with DCIS are of unknown significance. Most literature indicates that histopathologic
prognostic factors have no clinical use and do not affect patient outcome. Life-long
observation is recommended for women with DCIS, beginning with a mammogram obtained
within six months of breast-conserving therapy to reestablish a baseline and
to verify the removal of any prior suspicious lesion; annual bilateral mammograms
are indicated thereafter.
Prognosis
As DCIS is a heterogeneous rather
than a uniform group of lesions, a single treatment program is not feasible.
A clear, concise approach to this entity was not available until recently. Investigators
at the Breast Center at Van Nuys, California, developed the Van Nuys Prognostic
Index (VNPI) to assist in the recommendation of a treatment plan.31
The scoring system parameters include three significant predictors of local
recurrence — margin width, tumor size, and pathologic classification. A score
of 1 (best) to 3 (worst) is assigned to each parameter to arrive at a final
score of 3 to 9. According to this index, patients with DCIS who score 8 or
9 on the VNPI should be considered for mastectomy because of their high local
recurrence rates of 60% at 8 years regardless of irradiation. Scores of 5 to
7 require radiation to reduce the local recurrence sufficiently after lumpectomy.
For patients with VNPI values of 4 or less, no statistical difference was found
whether or not radiation therapy was included. Used as a guideline, this index
highlights the diversity of DCIS and the need to review each case independently.
Determining the exact size of DCIS
as well as establishing accurate margin widths can be difficult. After review
of our local recurrence statistics for DCIS, subset analysis identified a group
with a particularly poor outcome. Patients with multifocal DCIS with microinvasion
have a five-year actuarial disease-free survival of 78% compared to 98% in patients
with simple DCIS.23 Our data also show that the chance of recurrence
of tumor following lumpectomy and radiation therapy correlates with the presence
of EIC and microinvasive disease. However, we have not identified any statistically
significant difference in recurrence among histologic subtypes of DCIS and surmise
that there is a fundamental difference in behavior of microinvasive and multifocal
tumors aside from their histologic subtype (Table 3).
|
Table
3. Characteristics of Seven Patients With DCIS
Who Recurred and Required Conversion to Mastectomy
|
Patient
Number |
Age
(Yrs) |
Tumor
Size
(cm) |
Mammogram
Finding |
Histology |
Location |
Residual |
|
1
|
60
|
5
|
Central
calcification
|
Comedo
|
Central
|
No
|
|
2
|
43
|
2.5
|
Clustered
calcification
|
Multifocal/microinvasive
comedo
|
UIQ
|
Yes
|
|
3
|
72
|
5
|
Multifocal/multicentric
calcification
|
Multifocal
comedo
|
UIQ
|
Yes
|
|
4
|
38
|
4.4
|
Clustered
calcification
|
Multifocal
noncomedo
|
UOQ
|
Yes
|
|
5
|
36
|
5
|
Clustered
calcification
|
Noncomedo
|
UOQ
|
No
|
|
6
|
66
|
5
|
Central
multifocal/multicentric calcification
|
Multifocal
comedo
|
Central
|
No
|
|
7
|
39
|
3
|
|