world cancer report - iarc

Infection with S. haematobium is associated
with the development of squamous cell
carcinoma and in endemic areas, such as
Egypt, this type constitutes 90% of bladder
tumours [7].
A number of genes which regulate
enzymes involved in the metabolism of
bladder carcinogens have been identified
and it has been hypothesized that subjects
carrying specific genotypes could be
at an increased risk of bladder cancer [8].
For example, a dominant mutation in the
NAT2 gene causes slow metabolism of
aromatic amines, favouring their transformation
into active carcinogens; slow
metabolizers may be at a 40% increased
risk of bladder cancer. Similarly, individuals
who are null for the GSTM1 gene,
which encodes an enzyme involved in the
detoxification of polycyclic aromatic
hydrocarbons, have been reported to be
at increased risk of bladder cancer. There
is no evidence for high-penetrance gene
mutations that carry an elevated risk of
bladder cancer. The oncogene HRAS is
mutated at codon 12 in about 40% of
bladder tumours. Overexpression of the
epidermal growth factor receptor is associated
with invasive disease. The gene
encoding c-erbB2 (ERBB2) is amplified in
a small proportion of bladder tumours.
Cytogenetic and molecular techniques
have implicated aberration/partial loss of
chromosome 9 as a common feature in
Cyclin D1 amplification
Chromosome 9 LOH
TRANSFORMED
UROTHELIAL CELL
p53 gene inactivation
bladder cancer, and the cyclin-dependent
kinase inhibitors p16 INK4A and p15 are also
implicated in this context. Altered expression
of the phosphorylated form of the
retinoblastoma protein is common, and
most often encountered in invasive
tumours. Nuclear overexpression of p53
protein, essentially attributable to mutation
of the gene, is common and is associated
with disease progression (Fig. 5.86)
[9].
Management
Most patients with carcinoma in situ
progress to muscle invasion within 10
years, but can achieve good responses to
intravesical therapy - the administration of
a therapeutic agent directly into the bladder,
thereby exposing the mucosa to high
drug concentrations [10]. The most commonly
used agent in intravesical therapy
for superficial transitional cell carcinomas,
to prevent recurrence, and possibly
decrease progression and improve survival,
is bacille Calmette-Guérin (BCG), an
attenuated strain of the Mycobacterium
bovis bacterium which causes tuberculosis.
Cytotoxic drugs such as thiotepa, doxorubicin,
mitomycin C and/or ethoglucid
may be used for superficial tumours to
prevent recurrence.
The currently preferred treatment for
patients with invasive bladder cancer is
radical cystectomy. This involves excision
VEGF upregulation
Cyclin D activation
PAPILLARY
TRANSITIONAL CELL
CARCINOMA
“superficial”
CARCINOMA in situ
(pre-invasive transitional
cell carcinoma)
p53, RB gene inactivation
PDECGF expression
Fig. 5.87 Five-year relative survival rates after
diagnosis of bladder cancer.
of the bladder, prostate and seminal vesicles
in males or the bladder, ovaries,
uterus, urethra and part of the vagina in
females. Urinary diversion, and some
restoration of bladder function, may be
achieved through a range of reconstruction
options that continue to be refined
and improved. Adjuvant chemotherapy
(e.g with cisplatin, methotrexate and vinblastine,
or the latter combination plus
doxorubicin) may be employed. Several
new agents have been identified [11].
RECURRENT
TRANSITIONAL CELL
CARCINOMA
INVASIVE
TRANSITIONAL CELL
CARCINOMA
Fig. 5.86 Genetic alterations associated with the development of bladder cancer. LOH = loss of heterozygosity, VEGF = vascular endothelial growth factor,
PDECGF = platelet derived endothelial cell growth factor.
230 Human cancers by organ site