PHOTODYNAMIC DIAGNOSIS OF NON MUSCLE INVASIVE BLADDER CANCER: PRELIMINARY EXPERIENCE

Giorgio Napodano1, Antonio Campitelli1, Tommaso Realfonso1, Umberto Di Mauro1, Maria Addesso1, Roberto Sanseverino1
  • 1 Ospedale Umberto I - ASL Salerno, U.O.C. Urologia (Nocera Inferiore)

Objective

Bladder cancer is one of the most common cancers in the Western world. Despite a better understanding of the disease’s biology, the diagnosis and surgical treatment of NMIBC, based on cystoscopy and Turb, has remained relatively unchanged over the past decades. The WLC Turb outcomes are far from optimal considering that residual tumor rate ranges from 28 to 76% [1-2] and understaging rate ranges from 9 to 49% [3]. It has been demonstrated that second TURB (ReTURB) is a valid tool to improve staging accuracy, recurrence-free and progression-free survival [4-5]. Current EUA and AUA guidelines support Re-TURB for a diagnosis of high grade or T1 bladder cancer. Fluorescence endoscopy was first introduced in the 1960s and subsequently photosensitive drugs where introduced in the 1990s in an attempt to improve quality of diagnosis and surgical tretment of NIMBC. Several studies have demonstrated that Haexaminolevulinate exogenous fluorescence (PDD) offered improved tumour detection, reduced residual tumour rates, and prolonged recurrence-free survival [6]. We report our preliminary experience with PDD, comparing Hexaminolevulinate fluorescence cystoscopy with white light cystoscopy for detecting papillary and flat lesions both in patients with suspected bladder cancer and in patients undergoing ReTurb after primitive T1HG TCC.

Materials and Methods

Patients underwent bladder instillation with Hexaminolevulinate (Hexvix) (85 mg) for 1 hour. Cystoscopy was then performed using standard white light followed by blue light cystoscopy (PDD). Lesions or suspicious areas identified under the two illumination systems were mapped and biopsied for histological examination (cold biopsy or TURB). We compared histological evaluation of lesion detected at WLC and PDD cystoscopy.

Table 1. Group 1: false positive and false negative: per lesion analysis
WLC PDD
False positive 6.1% (4/66) 13.6% (9/66)
False negative 22.7% (15/66) –
New CIS 1 4

Table 2. Group 1: false positive and false negative: per patient analysis
WLC PDD
False positive 7.5% (4/53) 15.1% (8/53)
False negative 1.9% (1/53) –
New CIS 1 4

Table 3. Group 1: reasons for changing prognosis after PDD
PTS (n)
From single to multiple TCC 4
From <3 to >3 lesions 1
New diagnosis of T1HG 1
New CIS 3
Total pts 9

Table 4. Group 2: false positive and false negative: per lesion analysis
WLC PDD
False positive 21.0% (8/38) 18.4% (7/38)
False negative 36.8% (14/38) –
New CIS 1 4

Table 5. Group 2: false positive and false negative: per patient analysis
WLC PDD
False positive 19.0% (8/42) 7.1% (3/42)
False negative 19.0% (8/42) –
New CIS 1 4

Table 6. Group 2: reasons for changing prognosis after PDD
PTS (n)
From single to multiple TCC 1
New diagnosis of Dysplasia 1
New diagnosis of T1HG 4
New CIS 3

Results

A total of 95 patients (78 male, 17 female) underwent combined cystoscopy (WL + PPD). Of the patients, 53 had primitive known or suspected bladder cancer (Group 1), while 42 underwent PPD-Returb after primitive T1HG bladder cancer (Group 2). Of Group 1 patients, at WLC cystoscopy, 11 (20.7%) patients had no lesions, 22 (41.5%) had single and 20 (37.8%) had multiple tumours, respectively. Histological evaluation of WLC lesions revealed: inflammation (4 pts), hyperplasia (1), dysplasia (2 pts), TaG1 (16 pts), T1G1 (2 pts), T1G2 (1 pts), T1G3 (9 pts), T1G3 + CIS (2 pts), CIS alone (1 pts), T2G3 (4 pts). PDD cystoscopy revealed 24 suspected areas in 19 patients (35.8%): inflammation (9), hyperplasia (2), dysplasia (2), TaG1 (5), T1G3 (1), CIS (3), T2G3 (2). False negative rate of WLC and false positive rate of PDD were 22.7% and 13.6%, respectively [tables 1-2]. After PDD evaluation, prognosis changed in 9 out of 53 patients (17.0%) [table 3]. 9/Of Group 2 patients,, at WLC cystoscopy, 25 (59.5%) patients had no lesions, 12 (28.6%) had single and 5 (11.9%) had multiple tumours, respectively. Histological evaluation of WLC lesions revealed: inflammation (8 pts), dysplasia (2 pts), TaG1 (1 pts), TaG1 + CIS (1 pts), T1G3 (5 pts). PDD cystoscopy revealed 21 suspected areas in 13 patients (31%): inflammation (7), hyperplasia (1), dysplasia (2), T1G3 (8), CIS (3). False negative rate of WLC and false positive rate of PDD were 36.8% and 18.4%, respectively [tables 4-5]. After PDD evaluation, prognosis changed in 9 out of 42 patients (21.4%)[table 6].

Discussions

Transurethral resection (TURB) is the cornerstone approach in the diagnosis, initial staging and therapy of transitional cell carcinoma (TCC). Ideally, all bladder lesions should be identified and completely removed during WLC Turb. However the rate of residual tumour after TURB of neoplasms ranges from 28% to 76% [1-2]. These outcomes may be the results of limits of WLC Turb, as misdiagnosed tumours and untreated positive margins. Fluorescence endoscopy has been developed to enhance tumor detection by labeling neoplastic cells with drug that generate photoactive compounds. The concept relies on the greater uptake of haexaminolevulinate by neoplastic cells and its reaction to specific light wavelength to generate detectable fluorescence [7]. Recent review has reported that PDD Turb offers higher tumor detection rate, reduced resisual tumor and prolonged recurrence free survival than WLC [6]. In particular, PDD cystoscopy improved the detection of both papillary bladder cancer and carcinoma in situ. Sensitivity for PDD ranged from 92 to 100% and from 93 to 100% for Ta and T1 tumors, respectively, compared with 81-100% and 50-96% of WLC. Moreover, sensitivity of PDD for multiple tumors was 97.8% versus 69.6% of WLC [8]. A meta-analysis by Kausch et al. showed that PDD consent to identify an additional 20% of papillary tumors than WLC alone [9]. In our study, PDD cystoscopy revealed 29 lesions more than WLC in 21 of 95 (22.1%) patients. Particuarly, PDD allowed to identify additional Carcinoma in situ in 6 of 95 (6.3%) patients. Several studies investigated benefit of PDD in the detection of CIS; they reported a CIS detection rate of 49-100% for PDD compared to 5-68% for WLC alone [10-16]. The meta-analysis by Kausch et al. found an 39% advantage in the detection of CIS with PDD over WLC [9].
The main limit of PDD is low specificity (43-82%) due to false positive rate. In 8 trials false positive rate was 7-47% for PDD versus 9-62% for WLC [13,14, 17-22]. In all these trials except one [21], false-positive rate was higher for PDD than WLC . False positive results are related to flogosis due to a recent TURB, previous BCG bladder instillation and urinary tract infection [23-24]. In our experience, false positive rate was 11.6%. After PDD evaluation, prognosis and treament planning changed in 18 out of 95 patients (19%). However, a longer follow up and larger series of patients are essential to demonstrate whether PDD can offer an advantage in the management of these patients in terms of recurrence and progression

Conclusion

Transurethral resection (TURB) is the cornerstone approach in the diagnosis, initial staging and therapy of transitional cell carcinoma.. However WLC Turb outcomes are far from optimal considering that residual tumor rate ranges from 28 to 76%. Hexaminolevulinate fluorescence cystoscopy can be used in conjunction with white light cystoscopy to improve detection of bladder cancer. Several studies have demonstrated that Haexaminolevulinate exogenous fluorescence (PDD) offered improved tumour detection, reduced residual tumour rates, and prolonged recurrence-free survival. In our preliminary experience, PDD cystoscopy allowed to identify at least one more tumor than WLC in approximately a third of the patients. After histological evaluation, prognosis changed in 19% of patients. Whether this would translate to better outcomes in terms of recurrence and progression free survival has yet to be determined.

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