Bladder cancer is a very common malignancy of the urinary tract in the Western world, especially in men, three times more than women [1].

North America and Western Europe have very high incidence rates of bladder cancer in contrast with Asian countries and Central Africa where the incidence rates are very low [2,3]. Most (75-85%) bladder cancers incidences are non–muscle invasive at first diagnosis (pTa, pT1, carcinoma in situ [CIS]) [4]. In non-muscle-invasive bladder cancer (NMIBC), approximately 70% of patients present as pTa, 20% as pT1, and 10% as CIS lesions [1]. Generally, the prognosis of NMIBC is good, although 30-80% of cases will recur and 1-45% of cases will progress to muscle invasion within 5 yr [1,5]. Early detection of bladder cancer is therefore mandatory in order to reduce the mortality rate. It has been estimated that 10-20% of bladder tumors are overlooked in conventional WLC [6].

Hexaminolevulinate acid (HAL), an ester derivative of 5-ALA (ALA-Aminolevulinic acid) bioavailability is better, thus a higher tissue accumulation of photoactive porphyrins is achieved and this advantage is added to the diagnostic value of WLC [7]. Clinical trials of phases 1-3 led to the approval of HAL (Hexvix) for the detection of bladder cancer in 26 European countries. The aim of our study was to compare WLC and PDD (photodynamic diagnosis) with HAL in the diagnosis of bladder tumors.

The study was a case series and was conducted between October 2008 and May 2012. Fifty patients (43 men and 7 women) with primary bladder cancer were included in the study. All patients have been admitted and investigated for hematuria and/or positive urinary cytology (Table 1) [8-11]. A standard investigative protocol which included general clinical examination, blood tests, urine culture, abdominal ultrasonography, IVP (intravenous pyelography) and eventually a CT scan was applied in all cases. The study was approved by the Hospital Ethical Committee and informed consent was obtained by all patients.

Table 1: Patients characteristics.

A standard WLC was always performed as a first step of the evaluation and all suspicious areas were accurately described and reported on a bladder map. Thereafter, a fluorescence cystoscopy was accurately performed and any suspicious area was reported on the same map. Biopsies were collected from any suspicious area either under blue or white light and resection of the tumors identified (TUR) [13-16].Whenever no suspicious areas could be seen, a standard random mapping including 8 biopsies overall was completed. All WLCs and BLCs were performed by the same expert urologist (Table 2) [17].

Table 2: WLC and BLC findings and diagnosis.

Patients with acute or chronic urinary tract infection, urinary tract lithiasis, multi-drug allergies as well as patients underwent recent BCG installation, radiotherapy and multi bladder catheterizations were excluded [12].

For BLC, patients received 85mg HAL- Hexvix^® bladder instillation (85 mg dissolved in 50 mL phosphate buffer solution), using a 14Ch bladder catheter 1 hour prior to cystoscopy [18-22]. The Storz D-light- C system with a xenon arc lamp as source was used in all cases.

Bladder biopsies were performed in selected cases from bladder mucosa areas considered suspicious at WLC or BLC as well as from normal bladder mucosa [23].

Within six hours after TUR all patients included in the study underwent a postoperative chemotherapy instillation of 50 mg Epirubicin. All patients received an adjuvant intravescical immunotherapy with BCG vaccine as all patients had high or intermediate-risk cancer.

Categorical data were examined by chi-square test, while continuous variables were evaluated by the t-test. Specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with the usual mathematical formulas (Table 3) [24].

Table 3: Sensitivity, Specificity, PPV and NPV of WLC and BLC respectively.

The patient’s characteristics are shown in Table1. Forty-three males and seven females were included; in the study. The mean age of the patients was 64.8 ± 8.4 years. All patients had primary bladder cancer diagnosed. We extracted 220 specimens and more information are shown in Table 2. Bladder cancer was diagnosed in 137 specimens, and non-bladder cancer was diagnosed in 83 specimens. In non cancer tissue, 33 were normal tissue and 50 were chronic inflammation. Of the chronic inflammation specimens, 44 were positive in BLC, compared with 31 positive in WLC. There were 17 CIS lesions. All CIS lesions were detected with BLC (100%) and only 11 lesions (64.7%) by WLC.

One hundred-forty specimens were showed positive with WLC from which 109 were confirmed bladder cancer. Thirty-one specimens showed negative with WLC. The positive and negative predictive value of WLC was 77.9% and 65%, respectively. The sensitivity and specificity of WLC were 79.6% (109/137) and 62, 6% (52/83), respectively (Table 3).

One hundred- sixty nine specimens showed positive with BLC. One hundred- twenty five of these cases were histologically confirmed bladder cancer. Forty-four specimens showed negative for cancer. The positive predictive value of BLC was 73.9%. Fifty-one specimens showed negative results with BLC. After examination of these lesions, thirty-nine were not bladder cancer. The negative predictive value of BLC was 76, 5%. BLC sensitivity was 91.2% (125/137) and specificity 46.9% (39/83) (Table 3).

Eighty specimens were negative with WLC where forty-four of them were positive with BLC (42.5%). Within this group, 22 specimens were revealed to be bladder cancer. The sensitivity of BLC was higher than WLC, whereas the specificity of WLC and BLC showed no significant difference.

We missed 28 positive biopsies with WLC: 6 were Ca in situ and dysplasia, 15 were Ta and 7 were T1.

Overlooking of smaller flat and papillary lesions in conventional WLC during primary transurethral resection causes a major problem in the treatment of bladder cancer. Patients with undetected highgrade flat lesions who don’t receive the appropriate early treatment, had negative therapeutic outcomes. In addition, the incomplete resection of papillary tumors is simply undetected tumor and not a recurrence as maybe considered. It has been estimated that 10-20% of bladder tumors are overlooked in conventional WLC [6]. Various studies report residual tumor rates after TUR of superficial bladder tumors between 30% and 70% [8,9].

Not detecting concomitant or carcinoma in situ only results in a higher risk of progression and death from bladder cancer [10]. To avoid re-resection of persisting Ta and T1 lesions and to detect CIS with direct implications for prognostic and therapeutic reasons the diagnosis of both papillary and flat lesion has to be optimized. ALA based rigid fluorescence cystoscopy for detection and resection of superficial bladder tumors has been investigated extensively [11]. In addition, Hexvix (PhotoCure ASA, Oslo, Norway) HAL, a potent ester of ALA, has better selectivity, more intense fluorescence and needs shorter instillation time [12]. HLA penetration and accumulation in neoplastic cells is better than ALA. Lange et al. [13] found a high level of demarcation between red fluorescence malignant cells and blue light normal tissues.

In previous reports, the sensitivity of PDD and WLC ranged from 82% to 97% and from 62% to 84%, respectively [14]. Juan Palou et al. [15] showed that sensitivity of the BLC group was 90,6% and the specificity was 74,1%, with 76,5% and 87,3% in the WLC group. Kausch et al. [16] showed similar results in the BLC group for sensitivity and specificity in the WLC group.

Schmidbauer et al. [17] in a study of 52 patients with bladder cancer they found a BLC sensitivity of 96% compared with 73% for WLC. Several studies showed that BLC provides better detection rates in superficial bladder cancer. A meta-analysis by Savino et al, showed a better detection rate by PDD with HAL with an increased benefit for CIS [18].

Jichlinski et al. [19], reported that among 45 patients, 43 were diagnosed by BLC compared with 33 diagnosed by WLC for sensitivity of 96% and 73%. BLC was proved very useful for detecting CIS in 13 patients, because all except 1 were diagnosed or confirmed by BLC. For Jocham et al. [20] 96% of all tumors were detected with BLC whereas only 77% by WLC. This difference was also showed for dysplasia (93% vs. 48%), CIS (95% vs. 68%), and superficial papillary tumors (96% vs. 85%). More appropriate treatment was received by 17% of patients. The diagnostic accuracy in our study was significantly improved for BLC (91.2%) compared with WLC (79.6%).

Geavlete et al. [21] described a CIS detection rate of 95.7% for BLC whereas WLC diagnosed only 51% of the CIS lesions. Other studies described similar results of CIS detection of 97% for BLC and 58% for WLC. Our study also showed that 100% (17/17 lesions) of CIS lesions were detected with BLC and 64,7% (11/17 lesions) were detected with WLC.

The benefit of BLC was highest in CIS. It has become evident that BLC detects more tumour lesions. As for the data on papillary tumors, strongly heterogeneous results were also found for CIS. In fact, Jichlinski et al. [19] report a significantly higher fraction (77% and 78%) of CIS tumors detected by BLC and not by WLC.

Patients with CIS have a higher risk factor for disease progression because specific survival is strongly affected by the presence of CIS alone or associated with papillary superficial bladder cancer and non papillary T1 tumors [22,23]. An earlier diagnosis is necessary when mucosal changes are still a precursor of CIS.

DYS (dysplasia) is an epithelial abnormality which appears as a flat lesion on the bladder mucosa and is a precursor of CIS [24]. This premalignant lesion might have important implications in the early diagnosis of bladder cancer progression. Recent studies have shown that concomitant or single DYS is associated with a higher risk for disease progression [25]. Diagnosis is difficult in the early stages because both lesions are indistinguishable from the normal-appearing bladder mucosa and urine cytology testing might not be sufficiently sensitive [25]. The situation can be improved with the intravescical use of HAL which makes these flat lesions more visible within an otherwise normal bladder mucosa.

Our results confirm the advantage in the diagnosis of CIS on the bladder mucosa examined by BLC rather than classic WLC. As in previous observations [19,20], we also found a benefit in the diagnosis of early superficial papillary tumors that were not yet visible.

In our study, the incidence of DYS and CIS was 44% and 34%, respectively. This means that 78% of our patients had a potential evolving flat lesion. With WLC the incidence of such lesions would have been only 38%. This suggests the careful consideration of all therapeutic possibilities, such as careful endoscopic resection and immunoprophylaxis in these high risk patients. Bladder cancer is often multicentre and particularly when there are flat lesions a WLC might miss invisible tumors. The detection rate of these otherwise undiagnosed lesions is higher with photodynamic screening.

The limitations of this study are the small number of patients included. Further studies about the diagnostic value of BLC and costeffectiveness are needed to determine whether this important and not inexpensive diagnostic tool must be use for primary diagnosis in patients with non-muscle invasive bladder cancer.

Hexaminolevulinate-guided cystoscopy is a valuable diagnostic method, with considerably improved accuracy and improvement in diagnosis of non-muscle-invasive bladder cancer and especially CIS.

Consent: All patients have given their informed consent for the study. All signed forms are available on request.