world cancer report - iarc

Inheritance of high-penetrance genes
(DNA mismatch repair
genes, BRCA1-2 and p53)
and low-penetrance genes (CYP1A1,
MTHR)
ENDOMETRIUM
NON-ATYPICAL
HYPERPLASIA
Type I tumours
Polyclonal
proliferation
Fig. 5.66 A genetic model for endometrial tumorigenesis.
mal glands that have infoldings of their linings
into the lumens, disordered nuclear
chromatin distribution, nuclear enlargement,
a variable degree of mitosis and is
associated with necrosis and haemorrhage
[16]. Adenosquamous carcinoma, which
comprises 7% or less of cases, has a poor
prognosis. 5-10% of endometrial carcinomas
are uterine papillary serous carcinomas,
a very virulent type. Clear cell carcinoma
is more frequent in older women.
Endometrial cancer is a significant risk for
women affected by the dominantly inherited
hereditary nonpolyposis colorectal carcinoma
(HNPCC) syndrome and by Li-
Fraumeni syndrome, due to germline
mutations in mismatch repair genes and
p53 respectively [17]. An enhanced susceptibility
to endometrial cancer has also
been linked with an insertional p53 mutation,
a rare mutant in the methylenetetrahydrofolate
reductase gene and certain
germline variants of the CYP1A1 gene.
Endometrial tumours which occur in preand
perimenopausal women and are estrogen-related,
with hyperplasia ante- cedent
(adenomatous and atypical adenomatous
hyperplasias) are of stable behaviour (Type
II). Non-endometrioid tumours which
appear in postmenopausal women tend to
have a virulent behaviour (Type I). A model
Monoclonal proliferation
KRAS and PTEN mutation
Microsatellite instability
hMLH1 promoter methylation
ATYPICAL
HYPERPLASIA
Type II tumours
for the genetic alterations involved in
endometrial tumorigenesis is becoming
characterized (Fig. 5.66). Patients with
lesions which are positive for cytoplasmic
estrogen and progesterone receptors have
a better rate of disease-free survival than
those with no identifiable receptors [16].
PTEN mutations are associated with a
more favourable prognosis; tumours with
PTEN mutations tend to be of endometrioid
histology as opposed to clear cell
serous cell types and have fewer p53
mutations. Aneuploidy is associated with
poor prognosis, as is the overexpression of
c-erbB2/neu and p53 and mutations of
codon 12 or 13 of the KRAS gene.
Decreased expression of CD44 and E-cadherin
are associated with metastasis and
depth of myometrial invasion.
Management
Pre-cancerous lesions of the endometrium
and in situ tumours are treated by simple
hysterectomy. For frank carcinoma, total
abdominal hysterectomy and bilateral salpingo-oophorectomy
(removal of the fallopian
tubes and ovaries) are the definitive
treatment, although tailoring of therapy to
meet individual needs is important. More
than 50% of recurrences occur in the first
two years post-surgery. Thus regular and
KRAS
Microsatellite instability
PTEN/MMAC1
p16/INK4a
Cyclin D1
DCC
c-fms
Estrogen receptor
p53
c-erbB2/neu
MRP
1p LOH
ENDOMETRIAL
CARCINOMA
E-Cadherin
CD44v
DISSEMINATION
frequent follow-up is recommended. Postoperative
radiation therapy is currently
given to patients at a high risk of relapse
following surgery. In inoperable cases,
pelvic radiation therapy, usually external
beam and intracavity irradiation, may be
the sole treatment [16].
High levels of expression of MDR1 protein
(multi-drug resistance) or associated proteins
in a large number of endometrial
tumours and normal endometrial tissues
suggest there is a neoplasm which is
intrinsically resistant to chemotherapy [18]
(Box: Resistance to cancer chemo- therapy,
p285). In fact, use of chemo- therapy is
restricted to those with advanced or
recurrent metastatic disease, although
cisplatin, doxorubicin and cyclophosphamide
or a combination of methotrexate,
vinblastine, doxorubicin and cisplatin
can produce high response rates and
prolonged remissions. Response to high
dose progesterone therapy in receptorpositive
patients is about 70%. Estrogenreplacement
therapy is recommended
initially only in patients with in situ disease
or with low risk stage I tumours.
Survival is usually good, overall around
75-85% and for localized disease up to
90% (Fig. 5.65), although there is some
evidence to suggest that black women
Cancers of the female reproductive tract
219