european urology 53 (2008) 1138–1150

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Review – Bladder Cancer

Photodynamic Diagnosis in Urology: State-of-the-Art

Dieter Jocham a,*, Herbert Stepp b, Raphaela Waidelich c

a
Department of Urology, University of Lübeck, Lübeck, Germany
b
Laser Research Laboratory, LIFE-Centre, University of Munich, Munich, Germany
c
Department of Urology, University of Munich, Munich, Germany

Article info Abstract

Article history: Objectives: To provide an overview on the methodology and clinical

Accepted November 28, 2007 relevance of fluorescence diagnosis with exogenous fluorochromes or
Published online ahead of fluorochrome prodrugs in urology.
print on December 21, 2007 Methods: The methodology is summarised on the basis of our experience
and the relevant literature. Clinical results and perspectives are reported
Keywords: and concluded after we scanned and evaluated sources from PubMed.
5-Aminolevulinic acid Search items were ‘‘aminolev*’’ or ‘‘hypericin’’ or ‘‘photodyn*’’ or ‘‘por-
Bladder cancer phyrin’’ or ‘‘fluorescence’’ or ‘‘autofluorescence’’ and ‘‘bladder’’ or ‘‘pros-
Hexaminolevulinate tate’’ or ‘‘kidney’’ or ‘‘peni*’’ or ‘‘condylo*’’. Some literature was also
Kidney tumour obtained from journals not indexed.
Penile carcinoma Results: A large number of clinical trials have shown that photodynamic
Photodynamic diagnosis diagnosis (PDD) improves the ability to detect inconspicuous urothelial
Prostate cancer carcinoma of the bladder. Fluorescence diagnosis has recently been
approved in Europe for the detection of bladder cancer after instillation
of a hexaminolevulinate (Hexvix1) solution. PDD is recommended by the
European Association of Urology for the diagnosis of carcinoma in situ of
the bladder. To date, the major weakness of PDD for the detection of
Please visit bladder cancer is its relatively low specificity. Initial results with PDD for
www.eu-acme.org/ the detection of penile carcinoma, prostate cancer, kidney tumours, and
europeanurology to read and urethral condylomata are promising.
answer questions on-line. Conclusions: To determine the actual impact of PDD on recurrence and
The EU-ACME credits will progression rates of bladder cancer, further long-term observational
then be attributed studies are necessary. These studies also will clarify whether PDD is
automatically. cost efficient.
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, University of Lübeck,

Ratzeburger Allee 160, D-23538 Lübeck, Germany. Tel. +49 451 500 2271; Fax: +49 451 500 3388.
E-mail address: [email protected] (D. Jocham).

0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.11.048
 european urology 53 (2008) 1138–1150 1139

1. Introduction a lower energy per photon, producing a shift in

colour between excitation and fluorescence light.
Photodynamic diagnosis (PDD) involves fluores- Optical filters can block backscattered excitation
cence to localise abnormal tissue. Therefore, this light and transmit selectively within the wavelength
procedure is also referred to as fluorescence bands of fluorescence emission. This is a well-
diagnosis or fluorescence photodetection. Repre- known procedure used in fluorescence microscopy.
senting an additional optical recognition criterion, Fluorescent markers, bound to antibodies or intra-
PDD reveals neoplastic lesions that cannot be seen cellularly synthesised, can be detected with high
by means of conventional methods. The value sensitivity because the unspecific background light
added depends on the selective accumulation is weak. Thus, these are the advantageous features
of fluorochrome and on how well interfering of fluorescence detection: lack of background signal
optical tissue inhomogeneities can be considered and specific targeting.
or eliminated. Specific targeting for medical diagnostic purposes
In urology, clinical interest in PDD mainly has implies a contrast in fluorescence of diseased versus
focussed on the improved detection of hardly visible normal tissue. This might be achieved with endo-
urothelial bladder cancer. Small papillary tumours genous tissue fluorochromes (autofluorescence) or
and flat urothelial lesions can easily be overlooked by delivering substances that cause specific fluor-
during conventional white light cystoscopy [1]. escence staining.
Preventing correct and early treatment, missed
diagnosis of high-grade flat lesions such as carci-
nomas in situ (CIS) has a decisive impact on case 3. Autofluorescence
outcome. In addition, incomplete resection results
in ‘‘recurrences,’’ that is, merely previously unde- Among the most efficient endogenous fluoro-
tected tumours. chromes are collagen, elastin, nicotinamide adenine
Within recent years, PDD of bladder cancer has dinucleotide, flavin adenine dinucleotide, lipofus-
found its way into widespread clinical use. The first cin, tryptophan, and keratin. Some of these
exogenous fluorochrome, hexaminolevulinate, has fluorochromes are located in the subepithelial
obtained approval for the detection of bladder connective tissue layer of the corresponding tissue.
cancer in 26 European countries. According to the The intensity of the perceptible autofluorescence is
2006 European Association of Urology (EAU) guide- thus partly determined by the thickness of the
lines, PDD has been accepted as a method to reveal epithelial cell layer covering connective tissue.
areas in the bladder that are suspicious of CIS or of Increased proliferative activity of malignant cells
developing papillary tumour that cannot be seen thereby results in reduced autofluorescence.
with white light cystoscopy. Nevertheless, ‘‘this Attempts to exclusively exploit endogenous fluor-
investigational method has not yet been implemen- escence for tumour recognition have been made
ted on a regular basis in daily practice’’ (EAU [2,3] and have gained some clinical acceptance with
guidelines on TaT1 [non–muscular-invasive] blad- regards to the detection of early-stage bronchial
der cancer, 2006). cancer.
To examine the current status of PDD in urology, Early clinical studies have shown that autofluor-
this review summarises development, methodol- escence may be a promising additional tool to
ogy, and clinical experience with special emphasis discriminate neoplastic from benign lesions of the
on fluorescence diagnosis of bladder cancer. bladder and penis [2,4]. To date, this diagnostic
method has not found its way into the routine
practice of urologists.
2. Physics behind PDD

Fluorescence is caused by the interaction of light 4. Exogenous drugs for fluorescence

(photons) with the outer electrons of molecules.
Molecules that are electronically excited by absorp- The application of exogenous drugs for fluorescence
tion of a photon of appropriate wavelength have diagnosis relies on a positive fluorescence staining
several possibilities to return to their ground state. of malignant or premalignant tissue. Most of the
One option is to emit a secondary photon. Molecules substances that already were applied in the clinic
making use of this relaxation path efficiently are environment are photosensitisers. Apart from
called fluorochromes. Fluorochromes absorb light showing fluorescence, photosensitisers also exert
with a high energy per photon and re-emit light with a phototoxic action, which is used for photodynamic
1140 european urology 53 (2008) 1138–1150

therapy (PDT). A recent review, dealing with PDT in autofluorescence, whereas suspicious tissue is
urology, is given by Pinthus et al [5]. PDT will not be identified by its red colour (Fig. 1).
explicitly included in this article, but readers may
keep in mind this additional potential of the 4.1. ALA and derivatives
fluorochromes discussed. Clinical experience in
the use of fluorescence diagnosis in urology has Among the substances available for porphyrin-
been reported for tetracycline, hypericin, and the based fluorescence imaging, 5-ALA is the most
porphyrin-related substances hematoporphyrin widely used. It is a small molecule containing five
derivative, Photofrin1, 5-aminolevulinic acid (5- carbon atoms, a zwitterion with an amino group on
ALA) and, most recently and successfully, its hexyl the one and a carboxylic acid group on the other end.
ester hexaminolevulinate (Hexvix1). For tetracy-
cline fluorescence excitation, UV excitation is
necessary and corresponding instruments were
developed in the early 1960s [6], but UV cystoscopy
was abandoned in the 1970s. Hypericin and por-
phyrins can efficiently be excited by visible violet
light (ca. 400 nm) and emit red fluorescence (590–
700 nm).
Detection of fluorescence signals from tissue is,
unfortunately, not as straightforward as in fluores-
cence microscopy. Excitation light incident on a
tissue surface penetrates several tissue layers where
it is multiply scattered and absorbed from inhomo-
geneously distributed absorbers, mainly haemoglo-
bin. The same is true for fluorescence light excited
somewhere inside the tissue. It is, therefore, not
astonishing that the detectable fluorescence inten-
sity from an endogenous or exogenous fluoro-
chrome is not a reliable quantitative measure of
its local concentration. Additionally, in most clinical
situations, the investigated tissue is excited inho-
mogeneously and from an arbitrary distance and
angle. By applying different wavelengths for excita-
tion or detection and establishing appropriate
algorithms, several groups have tried to generate
more reliable fluorescence signals for diagnostic
fluorescence imaging [7,8].
The currently used clinical instrumentation,
available from several manufacturers of endoscopes
and light sources, is especially designed for fluor-
escence cystoscopy and displays red porphyrin
fluorescence together with blue remitted light.
The blue light serves as a reference. It corrects
inhomogeneous illumination and distance varia-
tions. It also largely compensates for varying blood
absorption and observation angles [9]. The wave-
length of the blue reference light is chosen in a way
to experience intermediate absorption in tissue
Fig. 1 – Fluorescence (a) and white light (b) endoscopic
compared to the high absorption at the excitation
image of a flat pTaG1 lesion adjacent to a small papillary
wavelength and low absorption at the emission tumour that was classified pTaG1 as well. Fluorescence
wavelength. The identification of suspicious tissue staining was performed by instillation of 50 ml of a
by fluorescence occurs quite intuitively by the solution containing 1.5 g 5-aminolevulinic acid.
colour contrast of red fluorescence versus blue Reproduced by permission of the Royal Society of
reference light. Normal tissue thus appears blue Chemistry (RSC) on behalf of the European Society for
with a more or less greenish hue, originating from Photobiology [13].
 european urology 53 (2008) 1138–1150 1141

It plays a natural role in the intracellular biochem- active uptake via b-amino acid, g-aminobutyric acid
ical pathways as a heme precursor. or PEPT1 and PEPT2 membrane transport proteins
The administration of exogenous 5-ALA bypasses [15]. Passive diffusion, in this case, leads to a
the rate-limiting step in the biosynthesis of heme, considerably faster and more efficient uptake.
the synthesis of endogenous 5-ALA in the mito- Nonspecific esterases in the cells are believed to
chondria. It thereby forces each enzyme in the at least partly release the parent compound to enter
pathway to produce its product with maximum the heme biosynthesis pathway. It can, however,
available capacity. The critical bottleneck is the step not be excluded that the enzymes also may act on
from protoporphyrin IX (PpIX) to heme, the insertion the esters directly, finally producing esterified PpIX.
of a ferrous ion into the porphyrin ring, catalysed by For this reason, the fluorochromes synthesised on
the enzyme ferrochelatase. Thus, exogenously delivery of hexaminolevulinate are usually referred
applied 5-ALA can induce significant intracellular to more generally as ‘‘photoactive porphyrins’’
levels of PpIX. PpIX is an effective photosensitiser (PAPs). Unlike 5-ALA, hexaminolevulinate is not
and the only fluorescent substance in the pathway. suitable for systemic application.
The transient accumulation of excess PpIX
preferentially occurs in neoplastic or highly prolif- 4.2. Hypericin
erating cells [10]. Among the causes of this phenom-
enon, reduced activity of ferrochelatase and a Hypericin, a hydroxylated phenantroperylenequi-
relative enhancement of porphobilinogen deami- none, is one of the ingredients that causes the
nase activity are considered to be the decisive phototoxic effects of the Hypericum perforatum L
factors [11,12]. Thus, it is possible to use 5-ALA– plant (St John’s wort) [16]. Hypericin fluorescence
induced fluorescence to locate malignant and can be excited and detected with the same equip-
premalignant lesions. ment as used for porphyrin fluorescence. A con-
5-ALA can be administered topically in cream or siderable practical advantage of hypericin over
gel formulations, as an aerosol for inhalation, or as porphyrins is its significantly reduced photobleach-
an instillation liquid as well as systemically, pre- ing, allowing for longer investigation times. Pure
ferentially by oral delivery. A comprehensive over- hypericin, which is synthetically produced nowa-
view of the basic principles and clinical applications days, is characterised by a number of drawbacks,
of 5-ALA is given in the book by Pottier et al [13]. such as low solubility, costly production, and to
One of the drawbacks of 5-ALA–based PDD is the some extent lack of stability in solution [16]. In vitro
relatively fast photobleaching of PpIX. During studies have shown that methanolic extracts from
irradiation with fluorescence excitation light, the the H. perforatum plant may offer less expensive
photosensitiser PpIX can itself be a victim of the alternatives [17]. Solubility could successfully be
aggressive oxygen generated. It is then destroyed increased by nontoxic additives, such as pyrroli-
and lost for further ‘‘photodynamic purpose’’ (fluor- dones [18].
escence or phototoxicity). To prevent practical
limitations, instrumentation must be highly sensi-
tive for fluorescence detection and unnecessary 5. History of applying fluorescence diagnosis
light exposure must be avoided. in urology
Another drawback of 5-ALA is its low lipophilicity,
preventing thorough tissue penetration. With the First attempts with tetracycline fluorescence were
aim of enhancing lipophilicity, ester derivatives performed in 1957 [19]. In 1975, the haematopor-
have been synthesised. For use in dermatology, the phyrin derivative (HpD) was initially proposed for
methyl derivative gained approval (Metvix1, Photo- bladder cancer detection by Kelly [20]. Photofrin1,
cure ASA, Oslo, Norway), whereas for bladder cancer a drug derived from HpD, was first applied for
detection the hexylester hexaminolevulinate (Hex- bladder cancer imaging by Baumgartner et al in 1987
vix, GE Healthcare, London, United Kingdom) proved [7], after Jocham et al, Nseyo et al, and Dougherty
to be superior. Following intravesical application, had published early works on PDT of bladder cancer
hexaminolevulinate has shown deeper penetration with Photofrin in 1985 [21–23].
into the urothelium and production of a higher PpIX The main drawback associated with these syn-
concentration at significantly lower prodrug con- thetic porphyrins, at least for exclusively diagnostic
centrations compared to 5-ALA [14]. The ester application, is a prolonged skin photosensitisation.
derivatives of 5-ALA cross the cell membrane rather Low-dose drug regimes, which overcome this side-
by passive diffusion in contrast to the parent effect [24,25], necessitate complicated instrumenta-
compound, which is transported intracellularly by tion [25].
1142 european urology 53 (2008) 1138–1150

Following publication of first reports on the corresponding communication with the light
clinical suitability of the 5-ALA porphyrin pro- source.
drug by Kennedy et al in 1990 [26], topical
application of 5-ALA as an intravesically adminis- Although the equipment looks similar to stan-
tered solution was first implemented clinically by dard cystoscopy equipment, each of the compo-
Kriegmair et al in 1992 [27]. Because the fluores- nents is specialised and care must be taken to not
cence intensity obtained was much brighter than mix fluorescence equipment with standard compo-
with low-dose Photofrin, instrumentation could be nents.
simplified. In fluorescence mode, brightness is a limiting
factor because fluorescence efficiency of the fluor-
ochromes amounts to only a few percent. Thus, the
6. Fluorescence diagnosis of bladder cancer quality of the video images is somewhat reduced
compared to white light video, or motion artefacts
6.1. Equipment have to be considered due to frame integration.
Additionally, old lamps and light guides should
Some manufacturers of endoscopes and light readily be replaced. The surgeon should also provide
sources offer equipment for fluorescence cysto- for clear irrigation liquid and maintain sufficiently
scopy, comprising close distance to the bladder wall.
Urine shows bright green fluorescence, which
 Light source: high-power endoscopic light source results in blurring when in fluorescence mode, if the
with integrated excitation filter, providing excita- bladder was not accurately voided prior to cysto-
tion light in the range of 380–470 nm. The light scopy.
source can be switched between white light and Porphyrin fluorescence is quite efficiently
fluorescence modes and communicates with the bleached during light exposure, especially with
camera controller. excitation light, thereby contributing to limiting
 Light guide: special light guide for efficient the observation time. Hypericin fluorescence is
excitation light coupling to cystoscope. stable under practical conditions of fluorescence
 Cystoscope: including optimised fibre bundles for cystoscopy.
illumination and observation filter in the eyepiece
(alternatively, filter is inserted in the camera 6.2. Clinical studies
optics). Rigid and flexible versions are available.
Video endoscopes suitable for fluorescence ima- A large number of clinical trials have shown that
ging are in development. PDD improves detection of bladder cancer (Table 1).
 Camera: high-sensitivity version of the In the published studies, the sensitivity of fluores-
endoscopic camera, including a special ‘‘fluor- cence cystoscopy is consistently superior to white
escence mode’’ with preset gain values and light cystoscopy. The mean value of the sensitivities

Table 1 – PDD of urothelial carcinoma of the bladder versus WLC: sensitivity and specificity

Author, year of publication No. of patients Agent Sensitivity, % Specificity, %

PDD WLC PDD WLC

Kriegmair, 1996 [73] 104 ALA 96.9 72.7 66.6 68.5

Koenig, 1999 [52] 55 ALA 87 84 59 —
Riedl, 1999 [74] 52 ALA 94.6 76 43 —
Filbeck, 1999 [75] 120 ALA 96 67.5 35 66.4
Zaak, 2002 [76] 713 ALA 97 — 65 —
Grimbergen, 2003 [42] 160 ALA 97 69 49 78
Hungerhuber, 2007 [77] 875 ALA 92 76.3 41.4 —
Jichlinski, 2003 [78] 52 HAL 96 73 43 43
D’Hallewin, 2000 [48] 40 (CIS) Hypericin 93 — 98.5 —
D’Hallewin, 2002 [79] 87 Hypericin 94 — 95 —
Sim, 2005 [50] 41 Hypericin 82 62 91 98

The em dash indicates missing data.

PDD = photodynamic diagnosis; WLC = white light cystoscopy; ALA = 5-aminolevulinic acid; HAL = hexaminolevulinate; CIS = carcinoma in
situ.
 european urology 53 (2008) 1138–1150 1143

Table 2 – PDD using 5-ALA versus WLC: residual tumour rate at second-look TUR

Author, year of publication No. of patients Residual tumour rate, % p

PDD WLC

Riedl, 2001 [36] 102 16 39 0.005

Kriegmair, 2002 [35] 129 32.7 53.1 0.031
Filbeck, 2002 [34] 191 4.5 25.2 <0.001
Alken, 2007 [29] 604 29 29.2 —

The em dash indicates missing data.

PDD = following photodynamic diagnosis; WLC = following white light cystoscopy; TUR = transurethral resection.

for fluorescence cystoscopy is 93% (range: 82–97%), Urological Association [29,40], however, did not
compared to 73% (range: 62–84%) for white light reveal any difference in recurrence rates. Possibly
cystoscopy. Tritschler et al showed the sensitivity of biasing the evaluation of PDD as a diagnostic tool,
PDD to be higher than the sensitivity of the urine these trials have included topical recurrence pro-
marker NMP221BladderChek1 test, voided cytology, phylaxis. Publications interpreting the data are not
and washing cytology, respectively [28]. yet available.
Until now, five prospective multicentre studies Until now, results of two large prospective,
comparing fluorescence-guided transurethral resec- randomised trials on long-term benefit of 5-ALA–
tion (TUR) and conventional TUR using white light induced fluorescence diagnosis versus white light
cystoscopy have been published [29–33]. Three of cystoscopy have been published [37,39] (Table 3).
these trials [29,31,32] were randomised, whereas the Follow-up in these studies was 5 and 8 yr, respec-
remaining two studies [30,33] focussed on inter- tively. Both studies conclude that fluorescence-
patient comparison. All five studies showed that assisted TUR increases recurrence-free survival of
PDD is more effective than white light cystoscopy for patients suffering from non–muscle-invasive
detecting malignant bladder lesions, in particular urothelial carcinomas of the bladder.
CIS. As a consequence of the improved detection In the published clinical trials, the selection
rate, 17% of patients in the study managed by criterion for patient inclusion was suspected or
Jocham received more appropriate treatment fol- suspected or known urothelial carcinoma of the
lowing fluorescence-guided cystoscopy [32]. bladder. As far as data are available, both patients
The completeness of resection using PDD has with primary and recurrent bladder cancer were
been studied and three of the four controlled, phase included in all studies. The reported proportion of
3 studies proved that the number of tumours patients with primary cancer varied between 32%
detected at second-look TUR is significantly reduced [30] and 82% [37].
in patients following fluorescence-guided cysto- To date, the major weakness of PDD for the
scopy [29,34–36] (Table 2). detection of bladder cancer is its relatively low
With regard to the recurrence rate, the presented specificity. The specificity of fluorescence-guided
studies have conflicting results. Three of five studies cystoscopy reported in comparative studies is not
have shown that fluorescence-guided TUR better or even lower than the specificity of standard
enhances the recurrence-free survival rate after 24 white light cystoscopy (Table 1). In the study
mo (recurrence-free survival rate following PDD published by Tritschler et al, the specificity of PDD
versus white light cystoscopy: 40–88% vs. 28–64%, is even lower than the specificity of voided urine
respectively) [37–39]. Two studies recently presented cytology [28]. False-positive fluorescence may be
at the congresses of the EAU and the American induced by inflammation [41] or recent intravesical

Table 3 – PDD using 5-ALA versus conventional WLC: long-term follow-up

Author No. of patients available Recurrence-free survival rate, % Median follow-up, mo

for efficacy analysis
PDD WLC PDD WLC

Daniltchenko [39] 102 41 25 42 39

Denzinger [37] 191 71 45 86 83

PDD = following photodynamic diagnosis; WLC = following white light cystoscopy.

1144 european urology 53 (2008) 1138–1150

therapy [42]. In addition, normal mucosa may Following intravesical instillation, 5-ALA, hexamino-
contain a minimal amount of endogenous PpIX. levulinate, and hypericin are absorbed systemically
Viewed with an acute angle, the thin normal mucosa in very low concentration only [53–55]. Therefore, the
represents a thick layer for the observer and may side-effects of PDD are mainly limited to local
thus cause the impression of fluorescence. This symptoms such as dysuria, haematuria, bladder
preferentially occurs when investigating the bladder pain, and bladder spasm [32]. With regard to these
neck, trigone, or diverticula [43]. symptoms, there is no difference between patients
Whether fluorescence of histologically proven undergoing fluorescence endoscopy and white light
benign lesions is caused by early malignant genetic cystoscopy [35]. The recently reported case of
alterations is still the object of research. Molecular anaphylactic shock 5 h after intravesical exposure
analyses indicate that at least some of the false- to hexaminolevulinate, however, clearly necessitates
positive hyperplastic urothelial lesions may have to further assessment [56].
be considered tumour precursors missed by conven-
tional cystoscopy [44]. Immunohistochemical stain- 6.5. Fluorescence cytology
ing for p53 and p16, however, did not show a
difference between false-positive fluorescent lesions Initial investigations have been made with fluores-
and benign lesions [43]. cence microscopy. In a standard setting (405–435 nm
Two clinical studies compared the technical excitation, detection with long-pass filters at
equipment. These studies indicate that PDD using approximately 460 nm), porphyrin-containing cells
rigid cystoscopes results in a higher tumour detec- show red fluorescence, whereas unstained cells are
tion rate than using flexible cystoscopes (85–94% vs. identified by their weak green autofluorescence. Red
70–89%, [45,46]). blood cells appear as small dark spots.
Prospective randomised trials that compare the In an attempt to simplify the analysis of bladder
efficacy of the different exogenously applied fluor- washing specimens, a special instrument was
ochromes for PDD of urothelial carcinomas are still designed to spectrally resolve porphyrin fluores-
lacking. A study comparing hexaminolevulinate and cence [57].
5-ALA for the detection of bladder cancer specified Preliminary results with ex vivo fluorescence
the derivative to be superior by showing higher cytology using 5-ALA or hypericin and flow cyto-
tumour selectivity, lower efficient concentration, metry using hexaminolevulinate suggest that this
shorter administration time needed and deeper diagnostic modality may be a useful adjunct to
tissue penetration obtained [47]. Evidence indicates conventional urinary cytology in detecting malig-
that specificity of hypericin is superior to specificity nant urothelial cells [57–59].
of 5-ALA and hexaminolevulinate [48–50].

6.3. Guidelines and recommendations 7. Fluorescence diagnosis of non-urothelial

tumours
Due to the superior sensitivity of this diagnostic
modality, PDD is recommended by the EAU as well Because the principle of tumour-selective fluores-
as the Austrian Association of Urology. According to cence upon delivery of 5-ALA is not restricted to
the EAU guidelines, fluorescence cystoscopy should bladder cancer, it was investigated for other urologic
be considered for the diagnosis of CIS of the bladder applications, too. Urethral condylomata acuminata
(grade B recommendation; EAU guidelines [51]). The detection was first reported by Schneede et al [60],
consensus board of the Austrian Association of after Fehr et al and Ross et al had shown selective
Urology recommends performing fluorescence- staining of such lesions on the vulva and the shaft of
guided cystoscopy in patients with cytology results the penis [61,62]. Fluorescence diagnosis of the
suspicious of urothelial carcinomas but normal urethra is performed 1 h after urethral instillation
findings in white light cystoscopy and in follow- of 0.1% solution of 5-ALA. In a single-institution trial,
up cystoscopy for high-risk urothelial carcinomas, fluorescence urethroscopy detected additional sub-
especially for CIS. clinical human papilloma virus (HPV) lesions in 13 of
43 men [60]. A study of neodymium:yttrium-alumi-
6.4. Side-effects num-garnet (Nd:YAG) laser coagulation of urethral
condylomata following conventional white light
All studies concurrently available showed that PDD urethroscopy alone and white light endoscopy in
of bladder cancer using exogenous drugs for fluor- addition to fluorescence urethroscopy after topical
escence diagnosis is well tolerated [31–33,50,52]. application of 5-ALA showed fewer recurrences in
 european urology 53 (2008) 1138–1150 1145

the fluorescence-controlled group (21.3% vs. 47.3%) long-term follow-up studies are available. Unan-
[63]. imously, all studies report that fluorescence cysto-
Early clinical experience indicates that fluores- scopy significantly improves the endoscopic
cence-guided Nd:YAG laser therapy using topically detection of bladder cancer as compared to standard
applied 5-ALA assists in better discriminating the white light cystoscopy. The enhanced diagnosis of
tumour margin, thus resulting in more reliable the sometimes hardly visible CIS by PDD is one of the
destruction of all neoplastic tissue in penile-sparing most remarkable benefits of this method and
surgery [4]. Because, following the oral administra- improves management of patients suffering from
tion of 5-ALA, PpIX is also accumulated in tumour- this disease. Multivariate analyses have shown that
bearing lymph nodes of patients with penile carci- presence of CIS is an independent unfavourable
nomas, PDD may also provide a useful adjunct to prognostic factor, increasing the risk of progression.
localise metastatic disease in lymphadenectomy [64]. Particularly bacillus Calmette-Guérin failures need
Fluorescence diagnosis of renal cell carcinoma was meticulous follow-up and individualised therapy
first reported by Popken et al in 1999 [65]. In a clinical [69]. Therefore, fluorescence cystoscopy should be
pilot study, 5-ALA had been applied systemically considered particularly for the diagnosis of CIS of
4–6 h prior to organ-preserving tumour resection. In the bladder and in follow-up cystoscopy for high-
eight of nine renal tumours, resection borders could risk urothelial carcinomas. The high sensitivity of
be clearly demarcated by PpIX fluorescence. Despite PDD makes it feasible to refrain from taking random
these promising results, no further clinical experi- biopsies or TUR, if there is no suspicious fluores-
ence with PDD of kidney cancer has been reported to cence in PDD.
date. Because surrounding tissue precludes fluores- Patients with multifocal stage Ta bladder
cent photodetection, PDD of renal cell carcinoma is tumours also profit from PDD. Tumour ‘‘recurrence’’
limited to peripheral tumours. may be due to the persistence of residual tumour in
Applicability for diagnosis and treatment of the bladder after an incomplete TUR or a lesion that
prostate carcinomas is a matter of ongoing clinical has been overlooked during first endoscopy [70]. The
studies. First cases were already reported by more complete first resection under PDD control can
Zaak et al in 2003 [66]. Fluorescence microscopy of make a second-look resection in patients with Ta
cryosections obtained from cancer-bearing pros- bladder tumours unnecessary. Because 5-ALA and
tates after radical surgery showed highly selective hexaminolevulinate do not penetrate much deeper
PpIX accumulation in cancer epithelium versus than 1 mm, however, fluorescence cannot indicate
normal glandular epithelium and connective tissue. invasion depth. Therefore, a second transurethral
resection is indicated in T1 tumours to rule out
muscle invasion.
8. Future perspectives The adequacy of the TUR also has an important
impact on the percentage of patients with super-
Instrumentation for fluorescence diagnosis will ficial bladder cancer having a recurrence at first
follow the general trend towards improved resolution follow-up cystoscopy after initial TUR [70]. It has
(high-definition TV-standard cameras, video endo- been shown that the recurrence at any site in the
scopy). The development of semiconductor-based bladder at the first follow-up cystoscopy after TUR is
light sources for fluorescence excitation in combina- one of the most important prognostic factors for
tion with video endoscopy may provide a user- time to progression [70–72]. Therefore, PDD might
friendly equipment. Digital image processing on be most advantageous for patients with primary
fluorescence images and overlay on intermittently tumours. Large and multicentre studies, however,
acquired white light images may further improve comparing the outcome of patients with primary
diagnostic accuracy [67,68]. Especially for systems and recurrent cancer following PDD are still
used in an outpatient environment, a ‘‘quality check warranted.
feature’’ is important to avoid false diagnosis due to To determine the actual impact of PDD on
improperly working equipment. The major task will recurrence and progression rates, further long-
be to enhance the specificity of PDD. term observational studies are necessary. These
studies also will clarify whether PDD is cost
efficient.
9. Discussion and conclusions Promising initial results with PDD for the detec-
tion of penile carcinoma, prostate cancer, kidney
PDD of bladder cancer has entered the era of tumours, and urethral condylomata justify further
prospective randomised trials. First results of clinical studies.
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Editorial Comment on: Photodynamic Diagnosis scopy using 5-aminolevulinic acid or hexylester
in Urology: State-of-the-Art hexaminolevulinate improves the detection of
Marko Babjuk bladder cancer as is thoroughly summarized by
Department of Urology, General Teaching Hospital, Jocham et al [1]. Its efficacy was observed in different
Charles University, Praha, Czech Republic clinical situations and using both rigid and flexible
[email protected] endoscopes [1]. There is, thus, no surprise that PDD
is routinely used in an increasing number of centers.
Early cancer detection is an essential prerequisite However, many aspects remain that must be
of successful therapy. Despite an effort in many considered to be able to exploit the method entirely:
organ locations the principles of photodynamic
diagnosis (PDD) have been applied mostly in bladder 1. Although some smaller prospective randomized
cancer. There is no doubt that fluorescence cysto- trials showed its positive impact on recurrence
 european urology 53 (2008) 1138–1150 1149

rate in non–muscle-invasive tumors, no infor- totally and improve its specificity [2]. Together
mation is available about progression and with development of new technologies we could
survival rates. In fact, the major benefit of the expect more sophisticated detection tools that
method is expected in aggressive tumors where can overcome the user dependence of currently
the aspects of progression and survival must be used techniques and even offer the possibility of
considered. The results of prospective random- real-time assessment of tissue pathology in vivo
ized multicenter trials based on clearly defined [3].
end points and patient population are absolutely
required.
2. The cost efficiency of PDD used in individual References
situations along with initial detection, transur-
ethral resection, or follow-up cystoscopy must [1] Jocham D, Stepp H, Waidelich R. Photodynamic diagno-
be determined. This will help us specify its sis in urology: state-of-the-art. Eur Urol 2008;53:1138–50.
indications and incorporate it precisely in [2] Zaak D, Stepp H, Baumgartner R, et al. Ultraviolet-
excited (308nm) autofluorescence for bladder cancer
currently used schedules of bladder cancer
detection. Urology 2002;60:1029–33.
management.
[3] D’Hallewin M-A, Khatib SE, Leroux A, et al. Endoscopic
3. The biologic background of the method is not confocal fluorescence microscopy in normal and tumor
completely understood. The explanation of prin- bearing rat bladder. J Urol 2005;174:736–40.
ciples of selective accumulation of protopor-
phyrin IX in tumor cells, of laser-induced
DOI: 10.1016/j.eururo.2007.11.049
autofluorescence, and of interactions between
light and tissue are necessary to use the method DOI of original article: 10.1016/j.eururo.2007.11.048

Editorial Comment on: Photodynamic Diagnosis and allowing better detection of carcinoma in situ
in Urology: State-of-the-Art (CIS), the impact of PDD on the progression of these
Jehonathan H. Pinthus tumors remains to be determined. Another caveat
Department of Surgery, Division of Urology, of PPD of urothelial bladder carcinoma is its
McMaster University, Hamilton, ON, Canada relatively low specificity. Although this may
[email protected] impede its use for diagnostic purposes in patients
who undergo their first work-up for hematuria, it is
The ultimate goal in the management of super- not the case for patients with high-risk urothelial
ficial bladder cancer is the prevention of disease cancer (eg, patients with previous CIS or multifocal
recurrence and progression. Recent advances in or large Ta bladder cancers). Although not pub-
photodynamic diagnosis (PDD) render this cur- lished yet, PDD can be potentially very useful in the
rently underused diagnostic technique an addi- investigation of positive urine cytology in the
tional important tool in achieving this goal. Many absence of evident disease in white light cysto-
of the recurrent superficial bladder cancers are scopy and normal upper tracts.
probably undetected tumors that were not initially In the current era of organ-sparing approaches
resected rather than recurrent new lesions. Con- in surgical uro-oncology, PDD can be an exciting
sequently, it is reasonable to state that fluores- potential adjunctive tool. Accordingly, the man-
cence-guided cystoscopy has significantly higher agement of penile cancer can be complemented by
tumor detection rates than standard surveillance PDD, specifically in defining the true margins of
cystoscopy and that this can be translated to better the lesion in penile-sparing surgery [3]. Similarly,
patient care [1]. It seems, however, that the main preliminary promising results were demonstrated
obstacle in adopting PDD to routine urologic for partial nephrectomy of peripherally located
practice is the general lack of familiarity with it. kidney cancers [4]. Whether PDD can be used
The comprehensive review of Jocham et al clearly for the intraoperative detection of positive mar-
assists in easing this task [2]. It should be gins at the time of radical prostatectomy for
emphasized that, though efficient in reducing prostate cancer or even in those selected cases
recurrence rates of superficial bladder cancer of prostate-sparing radical cystectomy for bladder
1150 european urology 53 (2008) 1138–1150

cancer remains to be determined in specially [3] Frimberger D, Schneede P, Hungerhuber E, et al. Auto-
designed clinical trials. fluorescence and 5-aminolevulinic acid induced fluores-
cence diagnosis of penile carcinoma—new techniques to
monitor Nd:YAG laser therapy. Urol Res 2002;30:295–300.
References [4] Popken G, Wetterauer U, Schultze-Seemann W. Kidney-
preserving tumour resection in renal cell carcinoma
[1] Filbeck T, Pichlmeier U, Knuechel R, Wieland WF, Roess- with photodynamic detection by 5-aminolaevulinic
ler W. Clinically relevant improvement of recurrence- acid: preclinical and preliminary clinical results. BJU
free survival with 5-aminolevulinic acid induced fluor- Int 1999;83:578–82.
escence diagnosis in patients with superficial bladder
tumors. J Urol 2002;168:67–71.
DOI: 10.1016/j.eururo.2007.11.050
[2] Jocham D. Photodynamic diagnosis in urology: state-
of-the-art. Eur Urol 2008;53:1138–50. DOI of original article: 10.1016/j.eururo.2007.11.048