dcis

Ductal Carcinoma In Situ

DCIS, also known as intraductal carcinoma, is an entity distinct in
both its clinical presentation and its biologic potential from LCIS,
the other lesion classified as noninvasive carcinoma. The widespread
use of screening mammography has resulted in a significant increase in
the detection rate of DCIS, and the acceptance of breast-conserving
therapy for the treatment of invasive carcinoma has led to changes in
the management of women with DCIS. Uncertainty exists as to the
proportion of women with mammographically detected DCIS who will
develop invasive carcinoma during their lifetimes. This has led to a
debate regarding whether all DCIS should be treated as early-stage
carcinoma with either mastectomy or lumpectomy and irradiation, or
whether some DCIS can be excised and observed.
An abnormal mammographic report of clustered microcalcifications is
currently the most common presentation of DCIS. DCIS can also present
as a mass or pathologic nipple discharge, or can be identified as an
incidental finding in a breast biopsy. In many reports of
mammographically directed biopsies, DCIS accounts for one-half or more
of the malignancies identified. [ref: 140,150]
The widespread use of screening mammography has resulted in a
remarkable increase in the incidence (or detection rate) of DCIS.[ref:
151] This increase in the incidence of DCIS has been observed in women
both younger than and older than 50 years of age, and in both white and
African American women. This dramatic increase in the number of DCIS
cases has led some authors to suggest that screening results in the
detection of biologically indolent DCIS that is unlikely to become
clinically significant during a woman's lifetime. The findings that
patients with lesions detected by screening have a higher frequency of
grade 3 lesions than patients with lesions not detected by
screening[ref: 152] and that the risk factors for DCIS and invasive
carcinoma are similar [ref: 153] argue against this point.
DCIS is characterized pathologically by a proliferation of presumably
malignant epithelial cells within the mammary ductal-lobular system,
without light microscopic evidence of invasion into the surrounding
stroma. However, DCIS encompasses a heterogeneous group of pathologic
lesions that differ in their growth pattern and cytologic features. At
present, there is no universal agreement as to how best to subclassify
these lesions. Proposed classification schemes for DCIS have variously
emphasized (1) architectural features or growth pattern of the
neoplastic cells within the ductal-lobular system, (2) cytologic
features of the neoplastic cells, and (3) cellular necrosis, singly and
in combinations. The traditional system for classifying DCIS was based
primarily on architectural pattern and recognized five major subtypes:
comedo, cribriform, micropapillary, papillary, and solid. DCIS is
commonly subdivided into the comedo type and the noncomedo type (which
encompasses the other variants). This is based on the observations that
the comedo type usually appears more malignant cytologically and is
more often associated with invasion [ref: 154,155] than are the other
DCIS types. Classification systems based primarily on architecture have
a number of limitations: (1) many DCIS display a mixture of patterns,
(2) the correlation between architecture and nuclear grade is not very
high, and (3) interobserver reproducibility in the categorization of
DCIS lesions by architectural pattern is poor. [ref: 156] Several newer
systems classify DCIS lesions primarily on the basis of nuclear grade,
necrosis, or both, with architectural pattern given secondary or no
consideration.[ref: 156-160] In 1997, a consensus conference was
convened in an attempt to reach agreement on the classification of
DCIS. [ref: 161] While the panel did not endorse any one system of
classification, there was agreement that certain features be routinely
documented in pathology reports of DCIS lesions. These include nuclear
grade (low, intermediate, or high grade), the presence of necrosis
(comedo or punctate), cell polarization, and architectural pattern(s).
A number of biologic markers in DCIS lesions have been evaluated.
These studies have generally shown that comedo or high-grade lesions
more frequently than noncomedo or low-grade lesions lack estrogen and
PR,[ref: 162-164] overexpress the HER-2/neu (c-erbB-2) oncogene, [ref:
162-166] show mutations of the p53 tumor suppressor gene with
accumulation of its protein product,[ref: 162-167] and demonstrate
angiogenesis in the surrounding stroma. [ref: 168,169]
Axillary lymph node involvement in patients with mammographically
detected DCIS is a rare event. In one series of 189 patients with DCIS,
most of whose tumors were detected by mammography alone, none showed
metastases on axillary dissection. [ref: 170] A National Cancer Data
Base review of 10,946 patients with DCIS who had an axillary dissection
between 1985 and 1991 demonstrated that only 406 (3.6%) of this group
had axillary metastases. [ref: 171]
A frequently encountered issue related to DCIS is the identification
of small foci of invasive carcinoma, so-called microinvasion.
Unfortunately, this term has not been applied in a consistent,
standardized manner, and the histologic diagnosis of microinvasion is
not straightforward. In the 1997 edition of the AJCC Cancer Staging
Manual, [ref: 172] microinvasion is defined for the first time as "the
extension of cancer cells beyond the basement membrane into the
adjacent tissues with no focus more than 0.1 cm in greatest dimension"
and are staged as T1mic, a subset of T1 breast cancer. The staging
manual further states that "when there are multiple foci of
microinvasion, the size of only the largest focus is used to classify
the micro-invasion" and that the size of the individual foci should not
be added together. Given the problems with both the definition and
pathologic diagnosis of microinvasion, the clinical significance of
this lesion is controversial. The reported incidence of axillary lymph
node involvement in patients given the diagnosis of microinvasion
ranges from 0% to 20%. [ref: 173-179] The management of this condition
is discussed in the next section, Treatment Options.

Treatment Options

A variety of local treatments, ranging from excision alone to
mastectomy, have been proposed for DCIS. Making comparisons among
retrospective reports is difficult because of differences in patient
populations, lack of standardization of surgical and radiotherapeutic
techniques, and changes in treatment practice over time. Mastectomy is
a curative treatment for approximately 98% to 99% of patients with
DCIS, whether gross or mammographic. [ref: 180-182] Of note, patients
with initial biopsies that showed DCIS but who later had invasive
carcinoma identified in the mastectomy specimens were excluded from
these reports. Recurrences after mastectomy are almost all invasive
carcinomas and may present as a chest wall or axillary recurrence or as
distant metastases without evidence of local recurrence. Mastectomy is
a highly effective treatment for DCIS, but it is a relatively radical
approach to a lesion that may not progress to invasive carcinoma during
the patient's lifetime. It also seems somewhat paradoxical that a woman
with an invasive carcinoma should be able to preserve her breast,
whereas the reward for screening and early detection is a mastectomy.
The acceptance of breast-conserving therapy for the treatment of
invasive carcinoma has led to its use also as a treatment for DCIS.
Treatment of DCIS by mastectomy has not been directly compared with
treatment by excision and irradiation, and it is unlikely that such a
trial will ever be done. In many cases, the assumption has been made
that since these two treatments result in equivalent survival for
patients with invasive carcinoma, the same will be true for patients
with DCIS. This assumption is flawed, due to the difference in the risk
of metastatic disease between patients with invasive carcinoma and
those with DCIS. In patients with invasive carcinoma, the risk of
metastatic disease is largely present at diagnosis and is not greatly
altered by local recurrence in the breast. In patients with DCIS, on
the other hand, the risk of metastases at diagnosis is negligible, and
an invasive local recurrence carries with it the potential risk of
breast cancer mortality. Therefore, the anticipated incidence of
invasive recurrence and the results of salvage therapy should determine
the suitability of excision and irradiation as a treatment for DCIS. A
number of nonrandomized studies are available to address this
issue.[ref: 183-187] Solin and associates[ref: 183,184] reported the
results of 268 women with 271 breasts with DCIS treated with excision
and irradiation at ten institutions in Europe and the United States. At
a median follow-up of 10.3 years, the 15-year actuarial rate of local
failure was 19%. It is noteworthy that although the local failure rate
in this study was relatively high, the 15-year cause-specific survival
was 96%. The methods of mammographic and pathologic evaluation and the
extent of surgical resection employed in this study would probably not
be considered adequate today (e.g., only 15% underwent reexcision, and
margin status was unknown in 120 cases; 46%). In spite of these
caveats, this study is noteworthy for the large number of patients and
relatively long duration of follow-up, and the low cause-specific
mortality is reassuring. An examination of the subset of patients with
mammographically detected lesions from this series (n = 110) did not
reveal a significantly lower rate of local failure than that seen in
the group as a whole, [ref: 188] a finding also reported by Hiramatsu
et al. [ref: 185]
Because one-half of the local failures seen after breast-conserving
therapy for intraductal carcinoma are invasive carcinoma, the outcome
of salvage treatment of these recurrences is important. In a separate
report, Solin and coworkers[ref: 189] described 42 cases of local
failure in 274 cases of DCIS treated with excision plus irradiation.
The median follow-up after salvage treatment was 3.7 years. Nineteen of
the recurrences (45%) were DCIS, and 14 of these were detected by
mammography alone. All of the women with DCIS recurrences remain free
of disease after mastectomy, with a median follow-up of 4.7 years. Five
patients with invasive recurrence had developed distant metastases,
either simultaneously with the recurrence (one patient) or subsequently
(four patients). Chest wall recurrences were seen in three patients who
had salvage mastectomy for an invasive recurrence, and all of these
women developed distant metastases. Of the entire group of 42 women
with recurrence, 36 patients (86%) were alive and free of disease, 4
patients (10%) died of disease, 1 patient is alive with disease, and 1
patient died of other causes. Similarly high rates of salvage have been
reported in other studies [ref: 190]; however, the ultimate breast
cancer mortality resulting from breast-conserving therapy cannot yet be
assessed given the available follow-up in these studies.
A number of investigators have also examined the use of excision
alone as a treatment[ref: 190-195] (Table 37.2_5). Patients treated
with this approach are highly selected, usually on the basis of low
histologic grade, small lesion size, or both. The percentage of
patients with DCIS in the study population meeting these selection
criteria is usually not stated, making it unclear how many women with
DCIS are candidates for this type of treatment. In general, the results
show rates of local recurrence that are higher than that seen with
excision combined with irradiation. A 1999 publication by Silverstein
et al. suggests that the rate of local recurrence will be low if there
is an adequate margin of resection (defined as greater than 10 mm).
[ref: 194] There are, however, several limitations of the study that
are worth noting. First, the group of 93 patients treated by wide
excision alone who had margins greater than 10 mm is highly selected.
The median size of the lesion was only 9 mm, and only 23% showed comedo
necrosis. The patients were cared for by a dedicated team of surgeons,
radiologists, and pathologists, and the specimens were routinely
handled by total sequential embedding, an ideal technique for assessing
margins, but uncommonly used because of its expense. In addition, since
these patients were seen more recently in the series compared with the
irradiated patients, their follow-up time is shorter, estimated to be
approximately 5 years as a median, with many less than 3 years.
Therefore, this data set does not allow the conclusion that the full
range of DCIS lesions can be managed by wide excision alone.
To date, there have been two clinical trials with published results
in women with DCIS randomized to excision alone or excision plus
radiation therapy (RT)[ref: 190,196] (Table 37.2_6). Both trials
involved patients with DCIS treated with an excision yielding
histologically negative surgical margins defined as tumor-filled ducts
not touching an inked surface. The NSABP has reported the 8-year
results of trial B-17. [ref: 190] In this study, 818 women were
randomized to excision alone or excision plus 5000 cGy of irradiation
to the breast. Eighty percent of the women in the study had tumors
detected by mammographic screening. At 90 months of follow-up, a
persistent reduction was seen with RT. The 8-year incidence of invasive
recurrence was significantly reduced from 13.4% to 3.9% by irradiation,
and the incidence of recurrent DCIS was also significantly reduced from
13.4% to 8.2%. The European Organization for Research and Treatment of
Cancer has reported the 4-year results of trial 10853. [ref: 196] In
this study, 1010 women were randomized to excision alone or excision
plus 5000 cGy of irradiation to the breast. Seventy-one percent of the
women in the study had tumors detected by mammographic screening. With
a median follow-up of 51 months, a 38% reduction in the annual
incidence of ipsilateral breast recurrence was observed in the
irradiated group. The 4-year incidence of invasive recurrence was
significantly reduced from 8% to 4% by irradiation and the incidence of
recurrent DCIS was also reduced from 8% to 5%. The overall survival is
the same for the two groups, as is the incidence of distant metastases.
Of note, the baseline recurrence rate with excision alone was similar
in the two trials, but the reduction with RT was somewhat greater in
the NSABP trial (59% reduction) compared with the European Organization
for Research and Treatment of Cancer trial (38% reduction). In
addition, the local benefit of RT for both DCIS trials is lower than
that seen for trials of RT for invasive cancers treated by excision.
The identification of women at high risk of developing invasive
carcinoma after breast-conserving therapy for apparently localized DCIS
would be extremely helpful. The NSABP has reported the results of two
analyses of the pathologic features of 623 of the 824 patients enrolled
in protocol B-17.[ref: 197,198] In the initial report, moderate or
marked comedo necrosis and uncertain or involved margins were
associated with an increased risk of local failure. While radiation
reduced the risk of failure in all subgroups, the absolute benefit was
greatest in those patients at highest risk for recurrence.[ref: 197]
After 8 years, an analysis of nine histologic features, including
margins, histologic type, nuclear grade, tumor size, and comedo
necrosis, demonstrated that only comedo necrosis significantly
predicted for an increased risk of ipsilateral breast recurrence in
multivariate analyses. Breast recurrence was much greater in
unirradiated patients with moderate or marked comedo necrosis compared
with patients with absent or slight comedo necrosis. The addition of RT
eliminated most of the risk associated with this factor, with 13% of
those with absent or slight comedo necrosis and 14% with moderate or
marked comedo necrosis recurring after RT at 8 years. [ref: 198] Margin
involvement was of borderline significance, but only a minority of
patients had involved margins.
Several studies have suggested that age may influence the risk of
local recurrence after breast-conserving therapy. Solin et al.[ref:
184] noted a 25% incidence of local failure in patients aged 50 or
younger treated with excision and irradiation compared with 2% in
patients older than 50, in spite of the fact that nuclear grade, tumor
size, and margin status did not differ between groups. The median time
to local failure was also shorter in the younger patients (4.9 vs. 8.7
years). Similar findings using a cutoff of 40 years was noted by Van
Zee et al. and Fourquet et al. [ref: 199,200] Other studies have
suggested that a family history of breast cancer may affect the risk of
local failure after excision and irradiation. [ref: 185,186]
Attempts have been made to incorporate the size of the lesion, its
histologic features, and the extent of the surgical excision into a
prognostic index that would direct treatment selection. One such index
is the Van Nuys Prognostic Index, which assigns equally weighted scores
of 1, 2, or 3 for histologic type, width of the surgical margin, and
size of the lesion. [ref: 201] Lesions with low Van Nuys Prognostic
Index scores are said to be suitable for excision alone; those with
intermediate scores (5 to 7) require the addition of irradiation; and
those with high scores require mastectomy. While such a simplification
of the decision-making process is attractive, there are a number of
limitations to this index. [ref: 202] As noted previously, the latest
information from this group now suggests that margin width is the key
prognostic factor, with lesion size and histologic type much less
important. [ref: 194] Until the Van Nuys Prognostic Index is validated,
it should not substitute for an individualized assessment of the risks
and benefits of the available treatment options for DCIS.
Tamoxifen has been shown to reduce the risk of both invasive and
intraductal carcinoma in women at increased risk for breast cancer
development[ref: 112] and to reduce contralateral breast cancer
incidence when used as an adjuvant treatment in women with breast
cancer. [ref: 203] The initial results of NSABP protocol B-24, in which
1804 patients with DCIS treated by lumpectomy and RT were randomized to
tamoxifen (20 mg daily) or placebo for 5 years, have been reported with
a mean follow-up of 62 months[ref: 204] (Table 37.2_7). Overall, the
risk of ipsilateral recurrence of any type (invasive or noninvasive) or
of new contralateral breast cancers was reduced from 13.0% to 8.8% at 5
years, a highly significant reduction. These benefits need to be
weighed against the potential risks of treatment, which are lowest in
patients aged less than 50 [ref: 201] and those who have had a prior
hysterectomy.
The available information on DCIS suggests that, although all
patients can be treated with mastectomy, many are candidates for
treatment with excision and irradiation, and a smaller group may be
appropriately treated with excision alone. When thinking about
treatment selection, it is useful to consider (1) the risk for breast
cancer recurrence, (2) the risk for an invasive breast cancer, and (3)
the risk for dying of breast cancer as well as the patient's perception
of the risks and benefits of the treatment options. The available data
on breast-conserving treatment (BCT) with irradiation generally show
recurrence rates of 10% to 15% at 10 years. Approximately one-half of
these recurrences are invasive carcinoma, for a 10-year risk of 5% to
7%. Assuming that the risk of dying of breast cancer is one-third or
less the risk of developing an invasive cancer, the risk of breast
cancer death with BCT is approximately 2% at 10 years. (If the risk of
local recurrence is 5% to 10%, then the breast cancer mortality risk is
reduced proportionally.) The risk for death 10 years after a mastectomy
for DCIS is 1% to 2%, with nearly all breast cancer mortality seen by
that time. In contrast, given the long-term risk of a breast cancer
recurrence after BCT, comparisons of breast cancer mortality 30 years
after treatment could show greater differences in survival between
women having mastectomy and those treated with excision and RT.
However, the use of tamoxifen will significantly reduce the risk of
invasive recurrence. Whether RT is necessary for all patients with DCIS
treated with a breast-sparing approach remains uncertain. Retrospective
data indicate that highly selected patients, usually those with small,
low-grade (none or slight comedo necrosis) DCIS with widely negative
margins, have a low local recurrence rate after excision alone. The
effect of tamoxifen on recurrence when RT is not given is uncertain,
since this approach has not been directly studied in clinical trials.
While developments in molecular biology may one day allow us to
predict more precisely which lesions progress to invasive carcinoma,
efforts must now be directed toward minimizing local recurrence in
women treated with a breast-conserving approach. The initial step in
the evaluation of patients with DCIS is determination of the extent of
the lesion. Because most patients with DCIS have nonpalpable
mammographic lesions, careful mammographic evaluation before treatment
selection is critical. The routine use of magnification views as part
of the mammographic evaluation allows the detection of additional
calcifications that reduce the discrepancy between the pathologic and
the mammographic extent, particularly for well-differentiated DCIS. The
goals of surgery are to remove all suspicious microcalcifications and
to achieve negative margins of resection. Needle localization should be
used to guide the biopsy, and, if the calcifications are extensive,
bracketing wires are useful to aid in complete excision. Specimen
mammography is essential to confirm the excision of calcifications. In
cases in which calcifications are extensive or approach the edge of the
surgical specimen (even when the margins are negative), postexcision
mammography is useful to confirm the removal of all suspicious
calcifications. It is important to recognize that, although DCIS
lesions are not clinically detectable, they may be quite large. Morrow
et al. found that contraindications to breast preservation were present
in 33% of patients with DCIS compared with only 10% of patients with
stage I invasive carcinoma.[ref: 205] Extensive disease, which could
not be encompassed with a cosmetic resection, was the major
contraindication to BCT in patients with DCIS.
A detailed pathologic evaluation is also needed and should include
orientation and inking of the specimen before sectioning as well as
measurement of both specimen and, if present, tumor size. Because
accurate measurement of microscopic DCIS is often difficult, reporting
the number of blocks in which DCIS is present and the total number of
blocks is useful. If DCIS is present on only one slide, then it is
useful to note its size. The correlation of microcalcifications with
DCIS (i.e., calcifications noted in DCIS, calcifications in adjacent
benign breast tissue, or both) and the margin status should be noted.
If margins are involved, the extent of involvement should be stated,
and when negative, the proximity of the lesion to the margin should be
noted.
Clinical trials currently in design or open for accrual in the United
States include (1) a randomization following excision to clear margins
of 3 mm and tamoxifen to RT or no RT (Radiation Therapy Oncology Group,
Intergroup) and (2) trials of wide excision alone (Harvard, Eastern
Cooperative Oncology Group).

Microinvasive Carcinoma

As previously discussed, microinvasive carcinoma has been a poorly
defined pathologic entity. Similar to DCIS, it is being diagnosed more
frequently because of the increased use of screening mammography.
The limited available data on patients with microinvasive carcinoma
suggest that axillary lymph node metastases are infrequent and the
prognosis after surgical treatment is excellent. [ref: 173-
176,178,179,206-208] Because of variability in the definition of
microinvasion, results from the literature are applicable to an
individual patient only if microinvasion is defined in the same way.
Since the incidence of axillary node metastases is low, axillary
dissection is not routinely indicated. Survival in patients with
microinvasive carcinoma seems to be intermediate between that for DCIS
and that for small invasive carcinomas. The use of BCT in these
patients should follow the same guidelines for careful mammographic and
pathologic evaluation with the requirement for negative margins of
resection as for patients with an extensive intraductal component-
positive invasive carcinoma.

Summary

DCIS represents a heterogeneous group of lesions of varying malignant
potential. Total (simple) mastectomy is associated with a cure rate of
98% to 99% for all types of DCIS. Patients with localized DCIS are
candidates for breast-sparing surgery and irradiation. Detailed
mammography and careful pathologic evaluation are essential to confirm
the localized nature of the lesion and judge the adequacy of resection.
The goals of surgery are to remove all suspicious microcalcifications
and to achieve negative margins of resection. Excision alone may be an
appropriate treatment for selected women with small (less than 1 to 2
cm) low-grade DCIS lesions with clearly negative margins. Axillary
dissection is not indicated in DCIS. In women with large high-grade
lesions undergoing mastectomy, a low axillary sampling obviates the
need for reoperation if invasion is identified. The use of tamoxifen
should be considered to reduce the risk of ipsilateral breast tumor
recurrence after breast-conserving surgery and to reduce the risk of
contralateral breast cancer. A detailed discussion of the risks and
benefits of the various options must be undertaken to allow each woman
with DCIS to make an informed treatment choice.