Ductal Carcinoma
In Situ
357
correlation between the apoptotic index and p53 expression
in intraductal and invasive carcinoma, leading the authors to
speculate that p53 played a role in the regulation of apopto-
sis and the development of necrosis in DCIS.
Further evidence that altered control of apoptosis may
contribute to necrosis in DCIS comes from studies of
bcl-2
expression
. The
bcl-2
gene located on chromosome 18 plays
an important role in regulating growth by inhibiting apop-
tosis. Bcl-2 expression is inversely related to differentiation
as well as to the expression of the estrogen receptor (ER),
p53, and HER2 proteins in DCIS.
128
DCIS with biologic fea-
tures that are most often associated with necrosis are char-
acterized by downregulation of apoptosis inhibiting bcl-2
(Fig. 11.32).
Sneige et al.
129
correlated the frequency of central necro-
sis in DCIS with nuclear grade. Central necrosis was much
more frequent in lesions with poorly differentiated nuclear
grade (80%) than in those with intermediate (35%) or low
(22%) nuclear grade.
Marked periductal fibrosis
can, on occasion, be associated
with extensive obliteration of DCIS, a process referred to as
“healing” by Muir and Aitkenhead
130
(Fig. 11.33). The resid-
ual ductal structures typically consist of round-to-oval scars
composed of circumferential layers of collagen and elastic
tissue. The center of the duct may contain a few residual car-
cinoma cells, fragments of calcification, or histiocytes. End-
stage scars of periductal mastitis may not be distinguishable
from those of obliterated comedocarcinoma. After a study
of 425 breasts, Davies
131
concluded that “. . . ductal hyper-
elastosis, obliteration, and fibrous plaques are not limited to
breasts that are the seat of carcinoma. Indeed, the prevalence
of these three lesions in major ducts that are unaffected by
microscopic changes does not differ significantly in ‘normal’
and carcinomatous breasts.” At the other extreme, perhaps
also representing the result of host response to the tumor
or its products, one can encounter a severe inflammatory
reaction that may lead to a mistaken diagnosis of mastitis,
because DCIS is masked by the inflammation.
CD10 is a cell-surface metalloproteinase that is expressed
in a variety of normal cell types, including mammary myo-
epithelial cells and lymphoid precursor cells. Stromal CD10
expression has been associated with biologically aggressive
carcinomas. In an immunohistochemically analyzed tissue
microarray study, no CD10 immunoreactivity was found in
the stromal cells of the normal breast; however, CD10 re-
activity was detected in the stroma in about 10% of DCIS
cases and 50% of invasive carcinoma cases.
132
In this study,
CD10 expression correlated significantly with tumor size,
stage, grade, nodal involvement, and distant metastases, and
was also related to cytoplasmic β-catenin expression in the
invasive carcinoma cells.
Secreted protein acid rich in cysteine (SPARC) is a mul-
tifunctional glycoprotein that acts through several signaling
pathways to regulate extracellular matrix as well as tissue re-
modeling. It is possible that SPARC and CD10 play an inte-
gral role in the development of invasive carcinoma.
133
Solid DCIS
is formed by neoplastic cells that fill most or
all of the duct space (Fig. 11.34). Microlumens and papillary
structures are absent, but calcifications may be present. Ne-
crosis is not a conspicuous feature of solid DCIS, but small
foci may be present in affected ducts (Fig. 11.35). Patients
with comedocarcinoma often have coexistent foci of solid
DCIS. In contrast to solid intraductal hyperplasia, the po-
lygonal cells are typically of a single type with low to moder-
ate nuclear grade. The cytoplasm has a spectrum of cytologic
appearances, including clear, granular, amphophilic and
eosinophilic, and apocrine. Myoepithelial cells are variably
present at the periphery of ducts involved by solid DCIS.
LCIS, particularly of the florid type, can be mistaken for
DCIS; indeed, one description recently proposed for florid
LCIS was “solid-type DCIS that lacked E-cadherin expres-
sion.”
134
Additional immunostains that can be helpful in dis-
tinguishing LCIS from DCIS include p120, β-catenin, and
high molecular weight cytokeratins.
135
Papillary DCIS
is distinguished by the presence of a fibro-
vascular stromal architecture supporting one or more of the
foregoing structural patterns (see Chapter 14).
E
FIG. 11.31.
(Continued)
FIG. 11.32.
DCIS, bcl-2 expression.
Cytoplasmic and
membranous immunoreactivity for bcl-2 is present in DCIS
cells. Note cytoplasmic staining in periductal lymphocytes.
