7° Congresso Nazionale

The role of fluorescent cystoscopy
with hexaminolevulinate in the diagnosis
of bladder cancer.
A. Volpe, F. Porpiglia, M. Billia, R.M. Scarpa
Urothelial carcinoma of the bladder is the sixth most common
malignant disease in the world. In 75–85% of cases,
bladder tumors are superficial at first diagnosis. However,
50–70% of patients presenting with superficial bladder
cancer will develop one or several recurrences after initial
treatment with transurethral resection (TUR), while 10-
20% will experience disease progression with infiltration of
the bladder muscle. White light cystoscopy (WLC) and urinary
cytology are the standard methods for detecting bladder
cancer, but their sensitivity and specificity are not completely
satisfactory, leading to a relatively frequent incomplete
detection of primary or recurrent tumors (1,2). Flat
urothelial lesions, such as CIS or urothelial dysplasia, are
particularly difficult to visualize endoscopically with classical
WLC because they are frequently located in unspecifically
inflamed or normal appearing mucosa. Even the use
of random biopsies does not result in a clinically relevant
improvement in the diagnosis of CIS (3). This is particularly
important since CIS is characterized by a higher risk
of progression to muscle invasive disease.
Furthermore, the risk of incomplete removal of tumour tissue
during transurethral resection of bladder tumour
(TURBT) is significant, either by overlooking flat dysplastic
lesions extending from the resected tumour, or tiny papillary
satellite tumours. Tumour remnants were found in up
to over 50% of cases at a second-look resection 4-6 weeks
after a first TURBT (4,5). The tumours that have been
missed during the resection will account for at least part of
the frequent positive cystoscopies 3-6 months after initial
treatment and may be responsible for a decreased survival.
To improve the sensitivity of WLC, especially for CIS, fluorescence
cystoscopy (FC) has been studied extensively in
the last few years (6). FC is a technique of photodynamic
diagnosis (PDD). PDD is based on the interaction between
a fluorochrome with a high selectivity for tumour cells and
light with an appropriate wavelength, which is absorbed by
the fluorochrome and reemitted with a different (longer)
wavelength. Since the early 1990s, 5-aminolaevulinic acid
(5-ALA) has been investigated for the fluorescent detection
of urothelial cancer. ALA is a precursor in the heme biosynthesis
pathway and induces an accumulation of fluorescent
endogenous porphyrins, mainly protoporphyrin IX (PPIX)
in tissues of epithelial origin (7).
The mechanisms that lead to an increased production of
fluorescent PPIX in cancerous tissue are currently not fully
understood. Several theories have been proposed, including
differences in the level of cellular metabolism, structur-
7° Congresso Nazionale Associazione Italiana di Endourologia
Divisione Universitaria di Urologia, ASO San Luigi Gonzaga, Orbassano, Università di Torino
al characteristics of diseased urothelium, inflammation
with consequent increase in permeability to ALA and
hyperproliferation of the urothelium, leading to a cumulative
effect. There are mainly two enzymes in the biosynthesis
of heme considered responsible for a tumour cell-specific
accumulation of PPIX: porphobilinogen deaminase
and ferrochelatase. The former is the rate limiting enzyme
and has been identified in greater concentrations in tumour
tissue. Clinical results with 5-ALA cystoscopy have been
very encouraging. Kriegmair et al. first evaluated the significance
and feasibility of the procedure, comparing endoscopic
findings under white light and fluorescent cystoscopy
and histology. A very high correlation was
observed between biopsies taken from areas with either
negative or positive fluorescence and histological findings.
In particular, a sensitivity of more than 95% and a specificity
of 68.5% was achieved (8). Other series have subsequently
confirmed these findings (9-12). Overall, FC
accounts for an increase in the tumor detection rate
between 18-76% as compared to WLC.
Zaak et al. have the largest experience with 5-ALA FC. In
their series tumors were detected only because of positive
fluorescence in 26.4% of cases. The incidence of CIS and
severe dysplasia in this patient group was 26.9%. Also, in
cases of suspicious cytological findings with negative WLC,
FC was able to considerably increase the tumor detection
rate (7).
In addition to flat urothelial lesions, the high rate of residual
tumor after TUR represents another reason for the high
recurrence rate of bladder tumors after the first resection. A
multicentre, randomized prospective trial including 165
patients was carried out in 1997-98 to investigate whether
FC-guided TURBT is able to reduce the rate of overlooked
tumors. The Authors compared the rate of residual
tumours 10-14 days after initial resection and found that
62% of patients were tumor-free after FC-guided TURBT
vs. 41% of cases after WLC-guided TURBT (p < 0.01).
Therefore, the rate of residual tumor could be reduced significantly
by nearly 40% under fluoroscopic guidance (13).
In another study of 191 patients with superficial bladder
cancer, the residual tumour rate at 5-6 weeks from the initial
resection was 25.2% in the WLC arm versus 4.5% in
the FC arm (p < 0.0001) (14).
Some studies have been also carried out to determine
whether FC-guided TUR is able to increase recurrence free
survival. Initial results showed a clear trend towards lower
recurrence rates in patients who had been resected under
Archivio Italiano di Urologia e Andrologia 2007, 79, 3, Supplemento 1
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