Invasive breast carcinoma - IARC

Table 4.03
Altered gene function in sporadic endometrioid (type I) and non-endometrioid (type II) endometrial
adenocarcinoma.
Gene Alteration Type I Type II References
Fig. 4.23 Endometrioid adenocarcinoma (type I).
Note the focal accumulation of mutant TP53 protein
within a TP53 wild-type carcinoma.
TP53 Immunoreactivity (mutant) 5-10% 80-90% {228,2647}
PTEN No immunoreactivity 55% 11% {1957}
KRAS Activation by mutation 13-26 0-10% {228,1512,1594,1787}
Beta-catenin Immunoreactivity (mutant) 25-38% rare {1787}
MLH1 Microsatellite instability /
epigenetic silencing 17% 5% {799,826,1594}
P27 Low immunoreactivity 68-81% 76% {2562}
Cyclin D1 High immunoreactivity 41-56% 19% {2562}
P16 Low immunoreactivity 20-34% 10% {2562}
Rb Low immunoreactivity 3-4% 10% {2562}
Bcl-2 Low immunoreactivity 65% 67% {1512}
Bax Low immunoreactivity 48% 43% {1512}
Receptors
ER and PR Positive immunoreactivity 70-73% 19-24% {1512}
Fig. 4.24 Serous intraepithelial carcinoma (type II)
expresses TP53 mutant protein.
ER = Estrogen receptor
PR = Progesterone receptor
detectable premalignant (type I) {1959}
or non-invasive malignant (type II) phases
of tumourigenesis {2647,2863}. A
c o m p rehensive model of sequential
genetic damage has not been formulated
for endometrial cancer despite a
growing number of candidate genes.
PTEN checks cell division and enables
apoptosis through an Akt-dependent
mechanism. Functional consequences of
PTEN mutation may be modulated in part
by the hormonal environment, as PTEN is
expressed only during the estrogen-driven
proliferative phase of the endometrium
{1957}. The use of PTEN immunohistochemistry
as a tool for diagnosis of
clinically relevant neoplastic endometrial
disease is limited by the fact that onethird
to one-half of type I cancers continue
to express PTEN protein, and loss of
PTEN function occurs as an early event
that may precede cytological and architectural
changes {1959}.
TP53 is the prototypical tumour suppressor
gene capable of inducing a stable
growth arrest or programmed cell death.
Mutant protein accumulates in nuclei,
where it can be readily demonstrated by
i m m u n o h i s t o c h e m i s t ry in most sero u s
(type II) adenocarcinomas {228}.
Staining for TP53 is not routinely indicated,
but the association of positive staining
with a poor clinical outcome may be
informative in suboptimal, scanty or fragmented
specimens.
Table 4.04
Essential diagnostic criteria of endometrial intraepithelial neoplasia (EIN).
EIN Criterion
Comments
Molecular delineation of premalignant
disease
Type I cancers begin as monoclonal outgrowths
of genetically altered premalignant
cells, and many bear genetic stigmata
of microsatellite instability, KRAS
mutation and loss of PTEN function that
a re conserved in subsequent cancer
{1642,1956}. The earliest molecular
changes, including PTEN, are detectable
at a stage before glands have undergone
any change in morphology {1959}.
The accumulation of genetic damage is
thought to cause emergence of histologically
evident monoclonal lesions. Further
elaboration of the histopathology of
endometrial precancers has been
accomplished through correlative histomorphometric
analysis of genetically
ascertained premalignant lesions {1958}.
Because these lesions were initially
defined by molecular methods, their
diagnostic criteria differ from those of
atypical endometrial hyperplasia. They
have been designated endometrial
intraepithelial neoplasia ("EIN") {1955},
1. Architecture Gland area exceeds that of stroma, usually in a localized region.
2. Cytological alterations Cytology differs between architecturally crowded focus
and background.
3. Size >1 mm Maximum linear dimension should exceed 1 mm.
Smaller lesions have unknown natural history.
4. Exclude benign mimics and cancer
Epithelial tumours and related lesions 231