Eble JN, Sauter G., Epstein JI, Sesterhenn IA - iarc

Alterations of 9p21 and p15/p16 belong
to the few genetic alterations that are
equally frequent or even more frequent in
non-invasive low grade neoplasms than
in invasively growing/high grade
tumours.
A
Fig. 2.26 A Invasive urothelial cancer. Strong membranous expression of EGFR in a case of invasive urothelial
carcinoma. B Infiltrative urothelial carcinoma. Strong nuclear TP53 immunoreactivity in invasive urothelial
carcinoma.
since many TP53 mutations lead to protein
stabilization resulting in nuclear
TP53 accumulation. Immunohistochemical
TP53 analysis has practical utility
in surgical pathology. In addition to a
postulated role as a prognostic marker,
immunohistochemical TP53 positivity is a
strong argument for the presence of
genetically instable neoplasia in cases
with questionable morphology.
The PTEN (phosphatase and tensin
homology) gene also known as MMAC1
(mutated in multiple advanced cancers)
and TEP1 (TGFbeta regulated and
epithelial cell enriched phosphatase) is a
candidate tumour suppressor gene
located at chromosome 10q23.3. The relative
high frequency (20-30%) of LOH at
10q23 in muscle invasive bladder cancer
{1256} would make PTEN a good tumour
suppressor candidate. However, the frequency
of PTEN mutations is not clear at
present. In three technically well performed
studies including 35, 63, and 345
tumour samples, mutations were detected
in 0%, 0.6%, and 17% of cases {141,
359,2776}. These results leave the question
for the predominant mechanism of
inactivation of the second allele open, or
indicate that PTEN is not the (only) target
gene at 10q23.
B
inactivation and muscle invasion {360,
1177,2110,2112}. Some investigators
have reported an association between
altered Rb expression and reduced
patient survival {498,1530}.
Alterations of DNA repair genes are
important for many cancer types. In invasive
bladder cancer, alterations of mismatch
repair genes (mutator phenotype)
are rare. A metaanalysis of 7 studies
revealed that microsatellite instability
(MSI) was found only in 12 of 524 (2.2%)
of cases suggesting that MSI does not
significantly contribute to bladder cancer
development {1032}.
The genes encoding p16 (CDKN2A) and
p15 (CDKN2B) map to chromosome
9p21, a site that is frequently involved in
heterozygous and homozygous deletions
in urinary bladder cancer of all types.
Prognostic and predictive factors
Clinical factors
In general, individual prognosis of infiltrating
bladder tumours can be poorly predicted
based on clinical factors alone.
Tumour multifocality, tumour size of >3 cm,
and concurrent carcinoma in situ have
been identified as risk factors for recurrence
and progression {2215}. Tumour
extension beyond the bladder on bimanual
examination, infiltration of the ureteral
orifice {999}, lymph node metastases and
presence of systemic dissemination are
associated with a poor prognosis.
Morphologic factors
Morphologic prognostic factors include
grade, stage, as well as other specific
morphologic features.
Histologic grade probably has prognostic
importance for pT1 tumours. As most
pT2 and higher stage tumours are high
grade, its value as an independent prognostic
marker remains questionable.
Depth of invasion, which forms the basis
of pT categorization is the most important
prognostic factor. In efforts to stratify
category pT1 tumours further, sub-stag-
The retinoblastoma (RB1) gene product
was the first tumour suppressor gene to
be identified in human cancer. RB1
which is localized at 13q14, plays a crucial
role in the regulation of the cell cycle.
Inactivation of RB1 occurs in 30-80% of
muscle invasive bladder cancers
{360,1172,1530,2845}, most frequently
as a consequence of heterozygous 13q
deletions in combination with mutation of
the remaining allele {497}. A strong association
has been found between RB1
Fig. 2.27 Infiltrative urothelial carcinoma. Tumour suppressor genes and cell cycle control at the G1/S
checkpoint. Progression of the cell cycle depends on the release of pRb from transcription factors including
DP1 and E2Fs. For this purpose, pRb needs to be phosphorylated by cyclin dependent kinases (CDKs)
which are, in turn, actived by D and E cyclins. Cell cycle control may get lost if pRb or inhibitors of
cyclin/CDK complexes are inactivated, e.g. by mutation, deletion or methylation.
Infiltrating urothelial carcinoma 107