Advances in imaging technologies in the evaluation of high-grade bladder cancer

Abstract

Bladder cancer ranges from a low-grade variant to high-grade disease. Assessment for treatment depends on white light cystoscopy, however because of its limitations there is a need for improved visualization of flat, multifocal, high-grade, and muscle-invasive lesions. Photodynamic diagnosis and narrow-band imaging provide additional contrast enhancement of bladder tumors and have been shown to improve detection rates. Confocal laser endomicroscopy and optical coherence tomography enable real-time, high-resolution, subsurface tissue characterization with spatial resolutions similar to histology. Molecular imaging offers the potential for the combination of optical imaging technologies with cancer-specific molecular agents to improve the specificity of disease detection.

Keywords: Bladder cancer; Confocal laser endomicroscopy; Fluorescence cystoscopy; Molecular imaging; Narrow band imaging; Optical coherence tomography; Photodynamic diagnosis.

Figure 1

Photodynamic diagnosis (PDD) of high-grade papillary and flat bladder cancer. (A) White light cystoscopy (WLC) showed a large broad-based papillary tumor. (B) PDD showed diffuse pink fluorescence over the tumor. Subsequent pathology for the lesion imaged in (A) and (B) confirmed non-invasive high-grade urothelial carcinoma. In a different patient, (C) WLC showed minimal erythema on the bladder mucosa along the left lateral wall, however (B) PDD showed a pink fluorescence over the region that was confirmed to be non-invasive high-grade urothelial carcinoma and CIS on histopathology.

Figure 2

Narrow band imaging (NBI) of the bladder. (A) WLC of the left lateral wall regions showed only mild erythema. (B) Under NBI, brown fluorescence delineated the extent of more vascularized neoplastic areas, subsequently confirmed on pathology to be high-grade non-invasive urothelial carcinoma.

Figure 3

Optical biopsy of the bladder using confocal laser endomicroscopy (CLE). Normal, low-grade, high-grade papillary bladder cancer, CIS and inflammation CLE images are shown with corresponding WLC images and hematoxylin and eosin (H&E) staining from subsequent biopsy. Low-grade cancer shows characteristically organized papillary structures, in contrast to high-grade cancer and CIS that display pleomorphic cells and distorted microarchitecture. (From Hsu, M., Gupta, M., Su, L. M. et al.: Intraoperative optical imaging and tissue interrogation during urologic surgery. Curr Opin Urol, 24: 66, 2014; with permission.)

Figure 4

Endoscopic molecular imaging of human bladder cancer using fluorescein labeled anti-CD47 as the imaging agent and CLE as the imaging modality. (A) Immediately after radical cystectomy, the ex vivo intact bladder was instilled with the molecular imaging agent via a urinary catheter and incubated for 30 minutes to allow antibody binding. After irrigation with saline, bound anti-CD47 was detected by endoscopic imaging of the bladder mucosa and normal and suspicious regions were biopsied for histopathological analysis. (B) Representative frames of CLE videos acquired from normal and cancer lesions in 5 bladders (Bl) with corresponding H&E images. Scale bars, 50 mm. (From Pan, Y., Volkmer, J. P., Mach, K. E. et al.: Endoscopic molecular imaging of human bladder cancer using a CD47 antibody. Sci Transl Med, 6: 260ra148, 2014; with permission.)

Figure 5

Endoscopic molecular imaging of human bladder cancer using anti-CD47 labeled with a quantum dot nanocrystal (Qdot₆₂₅) and imaged with blue light cystoscope from a clinical PDD system. Representative WLC and PDD images with corresponding H&E staining for co-localization of anti-CD47-Qdot₆₂₅ binding and histopathology. (A) Cancer-specific binding of anti-CD47-Qdot₆₂₅ in a bladder with normal mucosa and a CIS lesion. (B) Benign regions of normal urothelium, squamous metaplasia, inflammation, and ulcer with no detectable anti-CD47-Qdot₆₂₅ binding. (C) Anti-CD47-Qdot₆₂₅ binding detected under PDD on urothelial carcinomas. (D) Anti-CD47-Qdot₆₂₅ bound to adenocarcinoma of the bladder. (E) In a bladder with a history of BCG treatment, anti-CD47-Qdot₆₂₅ bound to a region with recurrent carcinoma but did not bind to a region of cystitis. (F) Anti-CD47-Qdot₆₂₅ bound to residual tumor in a prior resection bed but not to benign scar tissue. Scale bars, 50 mm. (Adapted from Pan, Y., Volkmer, J. P., Mach, K. E. et al.: Endoscopic molecular imaging of human bladder cancer using a CD47 antibody. Sci Transl Med, 6: 260ra148, 2014; with permission.)