Detection of early bladder carcinoma by fluorescence cystoscopy with Hexvix(R): Improvement of the specificity by microcystoscopy

Our long-term activity in the development of fluorescence imaging for the detection of early superficial bladder cancer aimed at optimizing the selective production and accumulation of photoactivable porphyrins (PaP), mainly protoporphyrin IX (PpIX), after the instillation of derivatives of aminolevulinic acid (ALA) within cancerous tissues. This research eventually led to the approval of hexylaminolevulinate (HAL, Hexvix(R)) in 27 European countries. Although the selective production of PpIX and the sensitivity of this procedure are outstanding, its specificity is limited due to false positive lesions that are mainly associated with inflammations of the bladder mucosa. Therefore, our current research focuses on the improvement of the specificity of this detection method. New methods, using high magnification (HM) endoscopy, are being investigated by our group in order to discriminate false from true positive findings, and hopefully resulting in a reduced number of biopsies. In this study, we are using a dedicated magnification cystoscope, allowing conventional magnification during "macroscopic" white light and fluorescence observation, as well as image acquisition with HM when the endoscope is in contact with the tissue. This is realized by an optical setup directly integrated in the cystoscope. The diameter of the field of view of the images is 500 microns in the HM mode and the resolution is about 3 microns. With this optical setup, our on going study is aimed at observing and characterizing the neo*-vascularization of the flat fluorescing sites in order to distinguish (pre-)cancerous tissue from inflammation. Thirty nine biopsies were taken on fluorescence-positive sites. The vascular patterns observed on CIS (n = 7) were significantly altered in 5 of them (71%), as compared to normal and inflamed mucosa where such alterations were never observed.

Detection of early bladder carcinoma by fluorescence cystoscopy with Hexvix: optical characterization of a high magnification cystoscope

Blaise Lovisa, Hubert van den Bergh, Georges Wagnières

Fluorescence detection of early superficial bladder cancer has been well established over the last years. This technique exploits the selective production and accumulation within cancerous tissues of photoactive porphyrins (PaP), mainly protoporphyrin IX (PpIX), after the instillation of hexaminolevulinic acid (Hexvix (R)) in the bladder. Although the selective production of PpIX and the sensitivity of this procedure are outstanding, its specificity is still limited by a relatively important proportion of false positive (FP) lesions. Cancerization process often combines with changes in vascular architecture. It is likely that the visualization of these modifications should allow us to differentiate false and true positive (TP). Therefore, our current research focuses on the characterization of positive sites by high magnification (HM) cystoscopy. This new method is investigated by our group to reduce the number of biopsies. In this study, we are using a dedicated rigid cystoscope, allowing conventional magnification during "macroscopic" white light and fluorescence observation, as well as image acquisition with HM when the endoscope is in contact with the tissue. This is realized by an optical setup directly integrated in the cystoscope. We describe here an off-clinics calibration procedure that will allow us to assess the vessel architecture and size once we use this optics to observe the bladder mucosa.

SPIE2009

High-magnification vascular imaging to reject false-positive sites in situ during Hexvix® fluorescence cystoscopy

Blaise Lovisa, Hubert van den Bergh, Georges Wagnières

Fluorescence imaging for detection of non-muscle-invasive bladder cancer is based on the selective production and accumulation of fluorescing porphyrins-mainly, protoporphyrin IX-in cancerous tissues after the instillation of Hexvix (R). Although the sensitivity of this procedure is very good, its specificity is somewhat limited due to fluorescence false-positive sites. Consequently, magnification cystoscopy has been investigated in order to discriminate false from true fluorescence positive findings. Both white-light and fluorescence modes are possible with the magnification cystoscope, allowing observation of the bladder wall with magnification ranging between 30 X for standard observation and 650 X. The optical zooming setup allows adjusting the magnification continuously in situ. In the high-magnification (HM) regime, the smallest diameter of the field of view is 600 microns and the resolution is 2.5 microns when in contact with the bladder wall. With this cystoscope, we characterized the superficial vascularization of the fluorescing sites in order to discriminate cancerous from noncancerous tissues. This procedure allowed us to establish a classification based on observed vascular patterns. Seventy-two patients subject to Hexvix (R) fluorescence cystoscopy were included in the study. Comparison of HM cystoscopy classification with histopathology results confirmed 32/33 (97%) cancerous biopsies and rejected 17/20 (85%) noncancerous lesions. c 2010 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3484257]

2010

Bladder cancer detection by fluorescence imaging with Hexvix®: Analysis and processing of images obtained during high magnification cystoscopy

Blaise Lovisa, Hubert van den Bergh, Georges Wagnières

Fluorescence cystoscopy has been recently acknowledged as a useful method to detect early superficial bladder cancer, even flat lesions. After the instillation of hexaminolevulinic acid (Hexvix®) in the bladder for about an hour, photoactivable porphyrins (PaP), mainly protoporphyrin IX (PpIX) accumulate in the cancerous cells. Although we observe a selective production of PpIX and an outstanding sensitivity of this method, false positive (FP) lesions negatively impact its specificity. Carcinogenesis often combines with angiogenesis, and thus changes in vascular architecture. Therefore, the visualization of the vascular modifications on the fluorescence positive sites is likely to differentiate false and true positive (TP). New methods including high magnification (HM) cystoscopy are being investigated by our group, and will yield a reduced number of biopsies and a better characterization of the fluorescence positive sites. In this study, we are using a dedicated rigid cystoscope, allowing conventional magnification during "macroscopic" observation, as well as image acquisition with HM when the endoscope is in contact with the tissue. Each observed site is biopsied and described by histopathological analysis. The vascular organization (tortuosity, vascular loops, vascular area and diameter) of the fluorescence positive sites was characterized in parallel with an in situ visual grading and a dedicated software procedure. We describe here a simple image processing prototype that classifies the HM images into two classes, according to their pixel distributions. For that purpose, we developed an algorithm in the image spatial and frequency domain, so that the vascular architecture could be described objectively and quantitatively. © 2009 Copyright SPIE - The International Society for Optical Engineering.

Spie-Int Soc Optical Engineering, Po Box 10, Bellingham, Wa 98227-0010 Usa2009

Bladder cancer detection by fluorescence imaging with Hexvix®: Analysis and processing of images obtained during high magnification cystoscopy

Blaise Lovisa, Hubert van den Bergh, Georges Wagnières

Spie-Int Soc Optical Engineering, Po Box 10, Bellingham, Wa 98227-0010 Usa2009