Ductal Carcinoma
In Situ
375
FIG. 11.57.
DCIS, p53.
Nuclear immunoreactivity is evident
in almost all neoplastic cells in this DCIS with intermediate
nuclear grade.
FIG. 11.58.
DCIS, EGFR.
Membrane immunoreactivity for
EGFR forms slender beaded lines between cells in this
DCIS. Background cytoplasmic staining is also evident.
distinguished from HER2 (
+
) high-grade DCIS in routine
H&E sections. Livasy et al.
202
studied 245 examples of pure
DCIS and found that 19 (7.7%) qualified as basal like: (ER
[−], HER2 [−], and EGFR or CK5/6 [
+
]). This small subset
of DCIS displayed a variety of characteristics typically asso-
ciated with HER2 (
+
) DCIS, including a high Ki67 index,
expression of p53, and comedo histology. Thike et al.
203
ex-
amined the DCIS component in 241 triple-negative invasive
carcinomas and found that 151 (62.6%) DCIS were of high
nuclear grade, and 236 (97.9%) were also triple negative. The
basal phenotype, defined by immunoreactivity for CK14,
EGFR, and 34βE12, was expressed in 68% in the
in situ
and
invasive components of the same case. The authors con-
cluded that triple-negative DCIS is the likely precursor of
the corresponding invasive counterpart and that basal-like
expression is maintained in the majority of invasive cancers
associated with basal-like
in situ
disease.
p53:
Investigators employing a monoclonal antibody to
wild and mutant forms of the p53 protein have reported
nuclear reactivity in 10%,
204
18.5%,
205
19.2%,
195
25.2%,
206
and 37%
207
of DCIS examined (Fig. 11.57). In some stud-
ies, expression of p53 was significantly associated with large
or pleomorphic cell type, intraductal necrosis, and comedo
DCIS,
195,198,204–206
but others did not find a significant corre-
lation between grade or histologic subtype and p53 expres-
sion
207
or p53 mutations.
193
Nuclear p53 was found only
rarely in small cell DCIS.
206
No p53 reactivity was found
in 17 cystic papillary carcinomas studied by O’Malley et
al.
204
When present, p53 mutations have been identical in
most instances where intraductal and invasive carcinoma
samples from a single tumor have been examined.
208
In one
study, no p53 mutations were identified in microdissected
hyperplastic lesions from patients who had p53 mutations
in coexisting intraductal and invasive duct carcinoma.
208
Carcinomas expressing p53 tend to be ER and PR nega-
tive,
198,206
and they show evidence of a higher than median
proliferative rate manifested by a relatively high MIB1 la-
beling index.
198
Molecular analysis using direct sequencing
of PCR products revealed mutant p53 protein accumulation
in comedo DCIS.
151
There was not a significant trend for
coexpression of p53 and HER2 in any subset of carcinoma,
despite the independent association of p53 and HER2 with
large cell or comedo DCIS in some studies.
189,193,206,209
Other Markers
The
nm23 gene product
is associatedwith lowmetastatic poten-
tial in some cell culture systems and in invasive human breast
carcinomas.
210
Cytoplasmic immunoreactivity for nm23 is
found in normal breast epithelium and in most noninvasive
carcinomas.
211
Strong staining was found in LCIS. Comedo-
carcinomas without associated invasion exhibited more in-
tense nm23 reactivity than comedocarcinomas with invasion,
a difference not observed when noncomedo intraductal and
invasive carcinoma were compared.
211
These observations
suggest that reduced nm23 expression in comedo DCIS may
be a marker for the acquisition of invasive characteristics.
The relationship of growth factors and their receptors to
the morphology and prognosis of DCIS has not been exten-
sively explored. As noted earlier,
EGFR
expression has been
associated with the basal-like phenotype DCIS (Fig. 11.58).
E-cadherin
is a cell–cell adhesion molecule expressed by
epithelial cells. Loss of expression resulting frommutations in
the
E-cadherin
gene has been associated with invasive lobular
carcinoma and LCIS. E-cadherin expression may be reduced
in DCIS, but it is rarely absent. Vos et al.
212
studied 150 ex-
amples of DCIS and detected E-cadherin in all cases with re-
duced expression in 11%. In one study, there was significantly
less expression in high-grade than in low-grade lesions.
213
Bankfalvi et al.
214
also reported reduced E-cadherin reactivity
in high-grade DCIS and confirmed the absence of E-cadherin
expression in lobular carcinomas. The reduced cell–cell adhe-
sion in high-grade DCIS may contribute to the relatively high
frequency of microinvasion observed in these lesions.
