Invasive breast carcinoma - IARC

these added studies, the distinction can
remain impossible in some cases.
An unknown, but relatively small, prop
o rtion of intraepithelial neoplasias
cannot be easily separated into ductal
or lobular subtypes on the basis of pure
H&E morphology. Using immunostains
for E-cadherin and CK34βE12, some of
these will qualify as ductal (E-cadherin+,
CK34BetaE12-), some as lobular
(E-cadherin-, CK34βE12+), while
others are either negative for both
markers (negative hybrid) or positive for
both (positive hybrid) {337}. This important
group re q u i res further evaluation as
it may reflect a neoplasm of mammary
stem cells or the immediate post-stem
cells with plasticity and potential to
evolve into either ductal or lobular
lesions {338}.
Expression profiling
Gene expression profiling has become a
powerful tool in the molecular classification
of cancer. Recently, the feasibility
and reproducibility of array technology in
DCIS was demonstrated {1721}. More
than 100 changes in gene expression in
DCIS were identified in comparison with
control transcripts. Several genes, previously
implicated in human breast cancer
p ro g ression, demonstrated diff e re n t i a l
expression in DCIS versus non-malignant
breast epithelium, e.g. up-regulation of
lactoferrin (a marker of estrogen stimulation),
PS2 (an estrogen-responsive marker),
and SIX1 (a homeobox protein frequently
up-regulated in metastatic breast
cancer), and down-regulation of oxytocin
receptor {3148}.
Fig. 1.92 High grade ductal carcinoma in situ forming
a tumour mass. Large section, H&E.
A
C
1 cm
Fig. 1.93 High grade ductal carcinoma in situ. Low
power view shows extensive DCIS with calcification.
B
D
Genetic alterations
Most studies on somatic gene alterations
in premalignant breast lesions are based
on small sample numbers and have not
been validated by larger series {72}, with
the exceptions of the T P 5 3 tumour sup -
pressor gene and the oncogenes E R B B 2
and C C N D 1 {72,196}. Other genes, not
discussed here (e.g. oncogenes c - m y c,
f e s, c - m e t, and tumour suppresser gene
R B 1) may also play an important role in
breast carcinogenesis (for review see
{3048}).
Cytogenetics
Conventional cytogenetic analysis of
p remalignant lesions of the breast has
been carried out in only a small number
of cases, and, as with invasive ductal
E
F
Fig. 1.94 High grade ductal carcinoma in situ. A Multiple duct spaces with amorphous microcalcifications
and peripheral epithelial proliferations. B Comedo type. The proliferating cells show significant nuclear atypia,
mitotic figures and there is intraluminal necrosis. C Flat type. Significantly atypical cells have replaced
the native, normal mammary epithelium. D Flat type. A highly anaplastic cell population has replaced the
native epithelial cell layer. E Flat type with significant nuclear pleomorphism. F Flat type. A highly anaplastic
cell population has replaced the native epithelial layer, but there is no significant intraluminal proliferation.
c a rcinoma, abnormalities of chro m o-
somes 1 and 16 have been identified in
DCIS {1146,1567}. FISH-analyses using
DNA probes to centromeric sequences
of almost all chromosomes fre q u e n t l y
identified polysomy of chromosome 3,
10, and 17 and loss of chromosome 1,
16, and 18 in DCIS {1949}.
Chromosomal imbalance
CGH studies of DCIS have demonstrated
a large number of chro m o s o m a l
alterations including frequent gains on
1q, 6q, 8q, 17q, 19q, 20q, and Xq, and
losses on 8p, 13q, 16q, 17p, and 22q
{ 1 3 4 , 3 0 1 , 3 6 5 , 3 6 6 , 1 3 3 3 , 1 5 4 8 , 3 0 4 5 } .
Most of these chromosomal imbalances
72 Tumours of the breast