Carcinoma in Situ of the Bladder: Why Is It Underdetected?

José D. Subiela; Óscar Rodr&ıacute; guez Faba; Félix Guerrero-Ramos; Julia Aumatell; Alberto Breda; Joan Palou


Curr Opin Urol. 2020;30(3):392-399. 

In This Article

Current Evidence on Diagnosis of Carcinoma in Situ of the Bladder

White light cystoscopy (WLC) and urine cytology represent the standard diagnostic strategy for CIS; however, WLC can miss lesions that are not visible. This is particularly true in CIS, which may vary from normal-appearing mucosa to a lesion indistinguishable from an inflammatory process. Owing to this issue, new tools have been developed to increase the detection rate. However, the definitive diagnosis of CIS remains histological and requires performance of biopsies of the bladder mucosa.

Biopsies of Suspected Zones, Random Biopsies, and Biopsies of the Prostatic Urethra

According to the EAU guidelines, biopsies should be performed in all areas that are suspicious on WLC and random biopsies should be performed in patients with nonpapillary tumors and/or positive urine cytology.[5] This recommendation is based on studies with a low incidence of CIS (EORTC protocols 30863 and 30911, which included patients with low-risk and intermediate-risk/high-risk tumors with incidences of positive biopsies of 1.5 and 3.5%, respectively).[9] The results of a meta-analysis involving 10 975 patients with NMIBC who underwent random biopsies showed a pooled incidence of CIS of 17.35%, with a higher detection rate in patients with positive cytology [odds ratio (OR): 5.60; 95% confidence interval (CI): 3.49–8.99], multiple tumors (OR: 2.51; 95% CI: 1.98–3.18), nonpapillary tumors (OR: 5.01; 95% CI: 2.31–10.86), stage T1 tumors (OR: 2.54; 95% CI: 2.11–3.07), and histological grades G2 and G3 (OR: 3.76; 95% CI: 2.96–4.79), as well as when the random biopsies had been performed according to the EAU guidelines. These variables are related to the EORTC intermediate-risk and high-risk groups; therefore, the authors suggested that the maximum performance of random biopsies is observed in these groups of patients.[2]

With respect to CIS in the prostatic urethra, the EAU guidelines support performance of biopsies in patients with bladder neck tumors, presence or suspicion of CIS, positive cytology without evidence of tumor, and presence of abnormalities in the prostatic urethra.[5] Biopsies of the prostatic urethra in the paramontanal zone using the resection loop have shown a better diagnostic performance, allowing the assessment of prostatic urethra mucosa, paraurethral ducts, and possible stromal invasion;[10] in addition, this strategy seems to prepare the prostatic urethra for eventual treatment with BCG, resulting in an improvement in the response rate (RR).[11]

Narrow Band Imaging

The most recent clinical data on the usefulness of narrow band imaging (NBI) in the diagnosis of CIS are reflected in two meta-analyses that show that NBI significantly improves the detection rate compared with WLC [the additional detection rate was 25.1% (95% CI: 0.09–0.42) in per-patient analysis and 31.1% (95% CI 0.24–0.39) in per-lesion analysis]. This diagnostic strategy improves the recurrence rate at 3 and 12 months of follow-up [RR = 0.43 (95% CI: 0.23–0.79) and 0.81 (95% CI: 0.69–0.95), respectively].[12,13]

Photodynamic Diagnosis

There is a growing body of evidence on the basis of multiple clinical trials and meta-analyses that shows an improvement in the CIS detection rate with photodynamic diagnosis (PDD) compared with WLC. The additional detection rate with respect to CIS could reach 50% according to some authors.[14] A meta-analysis of individual patient data from three prospective nonrandomized clinical trials designed to assess the cumulative difference in detection of CIS between PDD and WLC confirmed PDD to be superior [detection rate with PDD vs. WLC: 0.87 (95% CI: 0.82–0.92) vs. 0.75 (95% CI: 0.69–0.82); P = 0.006].[15] Moreover, other meta-analyses involving patients in different clinical stages have likewise demonstrated superiority of PDD over WLC for the detection of CIS. Thus, Kausch et al.[16] showed an additional detection rate of 39% with PDD (95% CI: 0.23–0.57), whereas Mowatt et al.[14] found that PDD improved the detection rate sensitivity by 51 and 36% in per-patient and per-biopsy analysis, respectively. Similarly, Burger et al.[17] reported an additional CIS detection rate of 40.8%.

Although clinical trials have not been designed to evaluate the impact of CIS detection by PDD on recurrence rate, a subanalysis derived from Burger et al.'s[17] meta-analysis showed a relative risk reduction of 31% at 12 months of follow-up.

Developing Technologies

Currently there are no clinical data on optical coherence tomography; however, it has shown promise in an animal model, with a significant improvement in CIS detection.[18] The Storz Professional Image Enhancement System is a relatively recent technology, and although it has been validated for visualization of bladder tumors,[19] the acquisition of clinical data is still ongoing ( identifier NCT02252549). Confocal laser endomicroscopy has recently also been validated in bladder tumors, but various difficulties have been described in its use for the characterization of flat lesions.[20]

A recent study investigated dynamic contrast-enhanced MRI (DCE-MRI) combined with PDD for the detection of CIS and showed a sensitivity and specificity of 37.5 and 91.7%, respectively, when both PDD and DCE-MRI were test-positive. Despite the limitations, the authors indicate that their goal is to establish 'MRI-PDD fusion transurethral resection of the bladder tumor ' as an approach in the clinical management of high-risk NMIBC.[21]

Although multiple technologies have been developed, it remains the case that little is known about their efficacy; therefore, further prospective studies will be needed to determine their usefulness in detecting CIS of the bladder in a real clinical scenario.