Fluorescence Diagnosis in GI Endoscopy

• Introduction
• Autofluorescence of Gastrointestinal Tissues
• Exogenous Fluorophores
• Technical Background of Fluorescence Endoscopy
• Endoscopic Fluorescence Spectroscopy
• Endoscopic Fluorescence Imaging
• Clinical Results of Fluorescence Endoscopy
• Esophagus and Stomach
• Bile Ducts
• Colon
• Surveillance of Gene Transfer
• Conclusions
• Acknowledgments
• References

Introduction

Undoubtedly, diagnostic gastrointestinal endoscopy faces a challenge from new methods, e. g. magnetic resonance imaging and computerized tomographic techniques. Because of the discomfort associated with endoscopy, noninvasive alternatives for diagnostic procedures are welcome. Colonoscopy is still superior to double-contrast barium enema in detecting colonic polyps [1]. However, computerization has already resulted in fascinating reports on virtual colonoscopy [2] [3] . The sensitivity and specificity of magnetic resonance cholangiopancreatography now approach those of endoscopic retrograde cholangiopancreatography [4]. Hence, conventional diagnostic gastrointestinal endoscopy is challenged by stimulating alternatives. Only if the detection of early carcinoma, dysplasia, or of other precancerous lesions can be improved will diagnostic gastrointestinal endoscopy survive this confrontation.

Several new technologies have recently been introduced to improve the capability of conventional endoscopy for subtle diagnostics. Chromoendoscopy, optical coherence tomography, Raman spectroscopy, elastic scattering spectroscopy, and fluorescence endoscopy have all been studied recently. Among these new techniques, diagnostic fluorescence endoscopy is the method which has been investigated most intensively, and is reviewed here. Since photodynamic therapy has been summarized recently in Endoscopy [5] , this technique will not be covered here.

Fluorescence detection is an exciting new tool which has only recently gained much interest from gastroenterologists (Figure [1]). Interestingly, reports on photodynamic therapy preceded papers on diagnostic approaches using fluorescence [6]. Hence, the search for improved therapeutic procedures may have resulted in the development of a new diagnostic method. Colonic tissue [7] [8] [9] [10] [11] [12] [13] was examined earlier than the upper gastrointestinal tract [13] [14] [15] [16] [17] [18] [19] [20] . The bile ducts were examined by fluorescence endoscopy only recently [21], while photodynamic treatment of bile-duct cancer had been described earlier [22] [23] .

Autofluorescence of Gastrointestinal Tissues

Tissue autofluorescence is based on the excitation of endogenous fluorophores by light. Endogenous fluorophores used for autofluorescence endoscopy include collagen, nicotinamide adenine dinucleotide (NAD/NADH), flavins, tryptophan, elastin, porphyrins, lipofuscin, and possibly other molecules [6] [24] . These fluorophores absorb light of specific wavelengths, and re-emit it partially at longer wavelengths as fluorescence. Depending on the fluorophore, the excitation wavelength is in the range of 300 - 450 nm, while the emission wavelength is between 350 and 600 nm [25] [26] . In the case of porphyrins, application of blue excitation light will result in red fluorescence [25].

Although tissue autofluorescence has been studied for several years, the mechanisms of tumor-selective changes in the intensity of autofluorescence are still a matter of debate [9] [10] [12] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] . Porphyrins as endogenous fluorophores are present in gastrointestinal tumors, depending on the tumor's grading [37]. The ratio of fluorescence intensity of tryptophan to NADH is different in metastatic vs. nontumorigenic cell lines [38]. One of the major sources of tissue autofluorescence is collagen. A decreased fluorescence intensity of collagen due to mucosal thickening or to replacement of the submucosa by tumorous cells can also contribute to the altered autofluorescence of malignant tissues [39] [40] [41] . In adenomatous colonic polyps, submucosal fluorescence is reduced, and the increased red fluorescence is associated with fluorescence by dysplastic crypt cells [41]. The illumination and detection geometry is also of importance. Inflammatory changes, metabolic alterations, the microenvironment, the hemoglobin content, and absorption by the blood flow also modify the intensity of autofluorescence [6] [26] [41] [42] [43] [44] [45] .

Exogenous Fluorophores

Exogenous fluorophores may accumulate in malignant tissues by several mechanisms [46] [47] . Many tumors exhibit abnormalities in heme synthesis [48] [49] . Particularly, ferrochelatase activity is reduced in malignant or premalignant cells [49] [50] . This difference from normal tissue is exploited by applying 5-aminolevulinic acid (5-ALA) as an exogenous prodrug [48]. Exogenous 5-ALA is metabolized up to protoporphyrin IX. The lack of ferrochelatase then results in the accumulation of protoporphyrin IX which exhibits strong fluorescence [51] [52] [53] . Thus, 5-ALA-induced protoporphyrin IX can induce a high ratio in fluorescence between tumors and normal tissue [13] [42] . 5-ALA causes a stronger porphyrin accumulation in a colon carcinoma model than synthetic porphyrin mixture (Photofrin, Axcan Pharma, Mont-Saint-Hilaire, Canada) [53]. In many countries, unfortunately, Photofrin is the only substance approved so far, while 5-ALA still is an investigational drug for most gastrointestinal applications.

Whether 5-ALA should be applied topically or systemically in gastrointestinal fluorescence endoscopy is still a matter of debate [51] [54] [55] [56] . While oral or topical application of 5-ALA has already been studied to a certain extent, concerns still exist about adverse effects arising from its systemic application [54]. Depending on the route of administration of 5-ALA, peak levels of protoporphyrin IX will be reached within a few hours (usually 2 - 6 hours) in the stomach or in the colonic tissue, while peak concentrations in serum are reached within less than 1 hour [54] [56] [57] . Following oral administration of 5-ALA, the plasma half-life of protoporphyrin IX is 8 hours, and protoporphyrin IX is undetectable or has returned to baseline values within about 48 hours [58] [59] . Plasma clearance is faster after topical administration than after oral administration [42]. Recently, a 5-ALA bioadhesive gel has been tested for applications in the esophagus and stomach [60].

The adverse effects of 5-ALA are minor. Depending on the applied dose (usually in the range of 20 to 60 mg/kg), nausea and/or vomiting occur in about 20 % of patients, and transient elevation of liver enzymes in 25 - 70 %, but photosensitization of the skin is observed infrequently [13] [50] [59] [61] [62] . Sensitization of the skin is more pronounced after oral administration than after topical application [42] [63] . Surprisingly, no attacks of porphyria have been reported after the administration of 5-ALA. For safety reasons, however, care should still be taken to exclude from studies using 5-ALA those patients with known porphyria or known severe liver disease.

Porfimer sodium (Photofrin) is an alternative exogenous fluorophore which is nearly exclusively used for therapeutic purposes [23]. Nevertheless, excess accumulation of this fluorophore is observed in malignant tissues. Consequently, an increased fluorescence of malignant tissues as compared with normal tissues is detected after intravenous administration of Photofrin [64]. Since the elimination half-time of Photofrin is about 3 weeks, it may be retained in the skin for up to several weeks [65]. Severe phototoxicity of the skin can occur after its application [66] [67] [68] . The high costs and the sensitization of the skin impede its use in diagnostic fluorescence endoscopy in man, except under rare circumstances [69].

There is an ongoing search for improved exogenous fluorophores. 5-ALA has been modified by esterification: accumulation of protoporphyrin IX in tumor cells was induced at the same level as by unmodified 5-ALA, but at a much lower dosage [70]. New molecules for enhanced fluorescence imaging of malignant tissues are currently being investigated [71].

Technical Background of Fluorescence Endoscopy

Endoscopic detection of autofluorescence, or of fluorescence induced by exogenously applied fluorophores or prodrugs, is based on various techniques. Tissue autofluorescence may be detected by specialized optical devices using laser light, or by incoherent light sources equipped with optical filters for fluorescence excitation. Initially, autofluorescence was investigated by point fluorescence spectroscopy using an optical fiber probe. More recently, devices became available enabling imaging of autofluorescence of larger areas. In gastrointestinal diseases, detection of fluorescence may be facilitated by the application of exogenous photosensitizers [6] [7] [25] [26] [45] [46] [47] [50] [51] [53] [55] [56] [57] [58] [61] [65] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] .

Endoscopic Fluorescence Spectroscopy

Using fluorescence spectroscopy, characteristic fluorescence emission bands of fluorophores are measured. Usually, a small optical fiber probe is inserted via the working channel of a conventional endoscope. Some fibers within this probe deliver the excitation light to the tissue surface, and other fibers detect the emanating fluorescence, which then is further processed by optical multichannel analyzers. These devices display the intensity of the fluorescence vs. the wavelength [26] [53] [79] . The data can be further processed using different algorithms [10] [16] [36] [42] [83] . Among the mathematical models applied, the differential normalized fluorescence (DNF) index has gained special interest. With this model, average fluorescence spectra from patients with normal tissues are used as baseline values [84] [85] . Using a novel image-processing procedure, fluorescence spectroscopy has recently been applied also to video-endoscopes [86].

The point measurements achieved by endoscopic fluorescence spectroscopy have the advantage of relative technical simplicity. Inserting a small probe via the working channel of a conventional endoscope is easy. However, subsequent data analysis may be cumbersome [87]. The most important factor is that the point measurements rely on proper targeting with the probe. Thus, the endoscopist first has to detect suspicious areas, and may then apply the probe for fluorescence spectroscopy. Since only a very small area (50 - 1000 μm) of tissue surface is covered [6], the possibility of an optical sampling error is the major drawback of this technique.

Endoscopic Fluorescence Imaging

In contrast to point fluorescence spectroscopy, processing of the whole endoscopic image by specialized filters and/or by specialized detection cameras has the advantage that it theoretically detects fluorescence of suspicious areas within the whole tissue surface visualized during the endoscopic procedure [6] [78] . Endoscopic fluorescence imaging may thus be less dependent on the experience of the endoscopist. Like fluorescence spectroscopy, endoscopic fluorescence imaging is capable of detecting either autofluorescence or exogenously induced fluorescence. In contrast to fluorescence spectroscopy, on the other hand, it cannot differentiate between fluorophores emitting fluorescence within the same range of wavelengths. Using optical filters, however, certain wavelengths of the emitted fluorescence can be selected.

The devices developed for endoscopic fluorescence imaging generate real-time fluorescence images of large areas. Furthermore, switching between the conventional white-light image and the fluorescence image is possible in real time. Using a laser of a selected wavelength as the light source, such a system is called laser-induced fluorescence endoscopy (LIFE). A detailed discussion of light sources and delivery systems for fluorescence endoscopy has been published [88], and an overview has recently been given on light-delivery systems [89].

Two systems for endoscopic fluorescence imaging are presently commercially available (D-Light; Storz, Tuttlingen, Germany, and LIFE-GI; Xillix Technologies, Richmond, Canada). The D-Light system uses the wavelength range of 375 to 440 nm for excitation, and is optimized for the detection of fluorescence by 5-ALA-induced protoporphyrin IX. Images of a high color contrast are provided by specialized filter balancing. With the D-Light system, fluorescence excitation light or conventional white light can be chosen. Optical filters (for direct inspection) or a specialized camera equipped with filters (for screen display and computerization) are attached to conventional fiberoptic gastrointestinal endoscopes [6]. With 5-ALA-induced fluorescence, suspicious areas will exhibit fluorescence in red, while normal tissue shows green fluorescence. For sufficient image quality, however, the acquisition time in fluorescence mode should be limited to 2 - 8 images per second. Thus, low fluorescence intensities require a very slow action of the endoscope.

The LIFE-GI system uses blue laser light with a wavelength of 437 nm for excitation. Fluorescence is detected in two separate channels (green, wavelength 490 - 560 nm; red, wavelength 630 nm or longer), and is then processed and displayed [25] [26] [90] . A newly developed experimental fluorescence imaging system applying a longer wavelength has recently been applied to detect deep-seated tumors [91]. The clinical efficacy of endoscopic fluorescence detection systems is proven by histological comparison of biopsies taken from fluorescent areas and from nonfluorescent areas. Areas of suspicious fluorescence are usually targeted by conventional biopsy forceps to confirm or exclude malignancy or dysplasia.

Clinical Results of Fluorescence Endoscopy

Esophagus and Stomach

A mathematical model for fluorescence spectroscopy was adjusted to detect esophageal cancer in vitro [16]. When this technique was applied to patients with known Barrett's esophagus, all patients with high-grade dysplasia were classified correctly [85] (Table [1]). In addition, in an application of fluorescence spectrometry and DNF modelling during routine esophageal endoscopy in more than 100 patients, only very few samples were misclassified by fluorescence spectrometry, as compared with histology [15] [84] (Table [1]). After sensitization by Photofrin, adenocarcinoma was detected with high accuracy in resected specimens of Barrett's esophagus. Applied in vivo to five patients, this technique also differentiated dysplastic from benign lesions [69].

Using 5-ALA (20 mg/kg body weight) as an exogenous fluorophore, dysplasias in two patients with known Barrett's esophagus were correctly detected using the D-light fluorescence imaging system [63] (Table [1]) (an example of such an examination, performed at our institution, is shown in Figure [2]). Published only in abstract form, these authors have extended their experience to 40 patients with histologically proven long Barrett's esophagus. These patients were examined after various doses of 5-ALA applied orally or sprayed locally [92]. As shown in another abstract, 11 patients with Barrett's esophagus exhibiting high-grade dysplasia were examined successfully using fluorescence spectroscopy after sensitization by 5-ALA [93]. In contrast, endoscopic autofluorescence imaging has been found to be less reliable in detecting low-grade dysplasia in Barrett's esophagus [94].

Little information is yet available on the clinical value of fluorescence endoscopy in the detection of gastric malignancies. Studying resected specimens of 50 patients with gastric cancer by endoscopic fluorescence imaging (LIFE-GI), the overall detection rate of malignancy has been found to be 95 %. However, the detection rate was dependent on the depth of infiltration of the tumors. The detection rate was 58 % if the tumors were restricted to the mucosa, 74 % if the submucosa was infiltrated, but 88 % if the tumors reached into the muscularis propria or into deeper layers [90] (Table 1). Hence, these in vitro data are disappointing for the detection of early gastric malignancy by fluorescence endoscopy. Using a modification of this system, a sensitivity of 95 % in detecting early gastric cancer, but a specificity of only 56 %, was reported in abstract form [95], while another abstract showed a sensitivity of 94 % and a specificity of 86 % [96]. In one patient with a known gastric adenoma, the D-Light fluorescence imaging system correctly detected malignant tissue areas [97].

Bile Ducts

Very little has been reported so far on tumor detection by fluorescence endoscopy in the biliary tree. Recently, data on nine patients with bile-duct cancer were reported [21]. Photodynamic therapy of bile-duct cancer using exogenously induced fluorescence and laser light therapy had earlier been reported [22] [23] , and a multicenter trial to further evaluate photodynamic treatment of cholangiocellular carcinoma is on its way.

Colon

Basic work such as in vitro spectroscopy of colonic adenomas and of normal tissues (10,12), or fluorescence localization of dysplasia after application of exogenous fluorophores in animal experiments [11] preceded the clinical application of fluorescence detection of colonic dysplasias.

Autofluorescence spectroscopy with and without photosensitization by oral administration of 5-ALA has been applied successfully to patients with colonic adenomatous polyps or with hyperplastic polyps [98] (Table [2]). Using novel image-processing software and a specialized video colonoscope, fluorescence spectroscopy correctly identified adenomatous polyps by decreased fluorescence as compared with the surrounding tissue, with the threshold set at 80 % of the intensity of normal mucosa [86]. Using time-resolved endoscopic spectroscopy in patients with polyps, adenomatous polyps were accurately distinguished from nonadenomatous polyps [99]. By autofluorescence spectroscopy at 370 nm, normal mucosa, hyperplastic polyps, and adenomatous polyps were differentiated [83]. In patients with familial adenomatous polyposis, colectomy specimens were examined by spectroscopy. With the threshold value set to 75 % of the fluorescence of normal tissue, adenomas were detected with a high accuracy [36]. Using ultraviolet laser-induced fluorescence spectroscopy in patients with hyperplastic polyps or with adenomatous polyps, the histological diagnosis was correctly predicted in nearly all cases [100]. Earlier reports had already observed that adenomas can be distinguished from normal tissue or from hyperplastic polyps by fluorescence spectroscopy [9] (Table [2]).

In a prospective pilot study, our group successfully applied endoscopic autofluorescence imaging (using the D-Light system) to patients with adenoma, with a history of carcinoma, or with inflammatory bowel disease [101]. Subsequently, we are testing the D-light system in patients with long-standing inflammatory bowel disease, to detect dysplasia by autofluorescence imaging or by fluorescence imaging after oral administration of 5-ALA (20 mg/kg). The initial results show a high sensitivity and a good correlation with histological findings. Owing to the limited number of patients included so far, specificity values have not yet been determined [102] (Figures [3] [4] ). In patients with long-standing inflammatory bowel disease, application of D-light fluorescence imaging using 5-ALA has also been reported by another group [103]. In previous animal experiments, this group had detected dysplastic lesions in model colitis with high sensitivity but with low specificity [104].

Surveillance of Gene Transfer

A novel application of fluorescence endoscopy is the surveillance of gene transfer into malignant cells. Using bronchoscopy, this has been described recently in an animal model [105]. If such methods can be transferred to therapeutic situations, new fields might be open for fluorescence endoscopy in the future.

Conclusions

Fluorescence spectroscopy and fluorescence imaging have been introduced into gastrointestinal endoscopy only recently. Both methods have their pros and cons, but comparative data are not available. From a clinical point of view, however, fluorescence imaging presently shows several advantages. The choice between using autofluorescence or exogenously induced fluorescence still has to be determined by comparisons of the diagnostic accuracy of the two methods [106]. The optical instruments available for gastrointestinal fluorescence endoscopy are continually being improved, but hitherto are not applicable to daily clinical routine.

Knowledge on endogenous and exogenous fluorophores is increasing rapidly. It can be expected that the differences in fluorescence between dysplastic or malignant tissue and normal tissue will soon be elucidated in detail. Novel photosensitizers will also be produced.

Initial clinical data on diagnostic fluorescence endoscopy of the gastrointestinal tract are encouraging. However, there is a strong need for prospective trials on fluorescence endoscopy in larger groups of unselected patients. At present, this is the major prerequisite to establish the role of fluorescence endoscopy in the detection of dysplasia or early malignancies.

Acknowledgments

The author is indebted to Dr R. Baumgartner for reading the manuscript critically and making very helpful suggestions and comments. The superb collaboration of all the scientists at the Laserforschungslabor of the Urological Department of the University of Munich (R. Baumgartner, H. Stepp, R. Sroka) is gratefully acknowledged. Ms R. Schinkmann's help in gathering the literature was invaluable.

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M. Sackmann,M.D. 

II Dept. of Medicine Klinikum Grosshadern Ludwig-Maximilians University

81366 Munich Germany

Fax: Fax:+ 49-89-7004418

Email: E-mail:misa@med2.med.uni-muenchen.de

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M. Sackmann,M.D. 

II Dept. of Medicine Klinikum Grosshadern Ludwig-Maximilians University

81366 Munich Germany

Fax: Fax:+ 49-89-7004418

Email: E-mail:misa@med2.med.uni-muenchen.de