- Email: [email protected]
Photodynamic diagnosis in the gastrointestinal tract
Gastrointest Endoscopy Clin N Am 14 (2004) 475 – 485
Photodynamic diagnosis in the gastrointestinal tract Esther Endlicher, MDa, Helmut Messmann, MDb,* a
Department of Internal Medicine I, University of Regensburg, 03042 Regensburg, Germany b Department of Internal Medicine III, Klinikum Augsburg, PO Box 101920, 86009 Augsburg, Germany
Because of the multistep neoplastic progression in developing cancer with excellent therapeutic modalities in superficial growth stages lacking metastasis, an early diagnosis of precancerous lesions is of essential benefit for our health service system and particularly for the individual patient. Photodynamic diagnosis is a new technique which may improve the detection of nonvisible or difficult-to-detect malignant and premalignant lesions. Exogenously applied sensitizers accumulate selectively in malignant lesions and induce fluorescence after illumination with light of adequate wavelength. However, endogenous fluorophores, induce different autofluorescence in malignant and benign lesions. Meanwhile photodynamic diagnosis is a widely spread technique in urology, using 5-aminolevulinic acid (5-ALA) sensitization. Fluorescence cystoscopy, after local instillation of 5-ALA into the bladder, has significantly enhanced the diagnosis of malignant and premalignant lesions. In the gastrointestinal track, there are promising results in the detection of early cancers or dysplasia in patients with Barrett’s esophagus or ulcerative colitis, but no randomized study has been performed to evaluate this method in comparison with conventional white-light endoscopy. This article focuses on the technical basis of this interesting method and reviews the preclinical and clinical results available for the gastrointestinal tract so far. Possible indications for photodynamic diagnosis in gastroenterology are listed in Box 1.
* Corresponding author. E-mail address: [email protected] (H. Messmann). 1052-5157/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2004.03.009
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Box 1. Possible indications for photodynamic diagnosis in gastroenterology
Longstanding and extensive ulcerative colitis Barrett’s esophagus Primary sclerosing cholangitis Surveillance of patients after polypectomy, photodynamic therapy, mucosal resection Differentiation of malignant and benign mucosal lesions (ulcers, stenosis, polyps)
Autofluorescence Autofluorescence of different tissues is based on the typical excitation and emision spectrum of endogenous fluorophores (Table 1). These endogenous fluorophores include collagen, elastin, flavins, tryptophane, porphyrins, and nicotinamide adenine dinucleotide (NAD/NADH). Different excitation wavelengths activate different fluorophores. Inflammation, ischemia, hemoglobin content, and also neoplastic alterations influence the metabolic and the oxidative status of the cells and therefore autofluorescence of the tissue. Collagen is probably one of the most important contributors for tissue autofluorescence. Depending on mucosal thickness—average thickness of the mucosa is 460 mm— the penetration depth at 400 nm excitation is about 500 mm. Therefore collagen and elastin of the mucosa will be excited at this wavelength. Thickening of the mucosa, typical for tumor growth, results in a decreased autofluorescence of elastin and collagen [1].
Exogenous photosensitization: photosensitizers Exogenous photosensitization is based on the administration of a photoactive compound that accumulates selectively in tumors.
Table 1 Excitation and emission wavelengths of various fluorophores in tissue Fluorophores
Excitation (nm)
Emission (nm)
NADH Flavin Collagen Elastin Porphyrin
350 455 250 285 405
500 495 330 350 610
Data represent maximum values at optimum excitation/emission condition.
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exogenous administration
477
mitochondrion
GLY + SCoA ALAsynthetase
ferrochelatase
PPIX
2+
Heme
Fe
5-ALA PROTO 5-ALA
5-ALA PBG
URO extra-
COPRO
cytoplasm
intracellular
Fig. 1. Porphyrin biosynthesis after exogenous application of 5-ALA. There are several possibilities for selectivity of Protoporphyrin IX in tumor cells: (1) enhanced cellular uptake of 5-ALA into the cell, (2) enhanced activity of the porphyrin-synthesis, (3) reduced activity of the enzyme ferrochelatase. Abbreviations: 5-ALA, 5-aminolevulinic acid; COPRO, coproporphyrinogen; GLY, glycine; PBG, porphobilinogen; PPIX, protoporphyrin IX; PROTO, protoporphyrinogen; SCoA, Succinyl-CoA; URO, uroporphyrinogen.
5-Aminolevulinic acid With respect to side effects (length of skin sensitivity) and tumor selectivity, 5-aminolevulinic acid (5-ALA) is the most interesting substance for photodynamic diagnosis compared with other sensitizers [2,3]. Not a sensitizer itself, 5-ALA is converted intracellularly into the photoactive compound protoporphyrin IX (PPIX) (Fig. 1). The cellular uptake of 5-ALA is still being investigated, but in vitro studies indicate that 5-ALA seems to be taken up by active transport mechanisms [4]. It can be assumed that the major cause for selective retention of 5-ALA in malignant tissue is based on the biosynthetic pathway. Tumors tend to have an increase in porphobilinogen deaminase activity, resulting in greater production of PPIX. Furthermore, a reduced ferrochelatase activity results in a greater retention of PPIX by the tumor because of reduced conversion of PPIX into heme [5,6]. 5-ALA can be given topically or by mouth. Depending on the application mode, peak levels of PPIX will be reached within 4 to 6 hours after systemic sensitization and 1 to 2 hours after local administration in the esophagus, stomach, or in the colonic tissue [7,8]. The plasma half-life of PPIX is 8 hours, and PPIX values return to baseline levels within about 48 hours after oral administration of 5-ALA [9]. This may even be faster after topical administration. Compared with other sensitizers such as Photofrin and hematoporphyrin derivative (HPD), 5-ALA shortened the interval of skin photosensitization making it possible to investigate the patients on an outpatient basis.
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The tissue distribution of PPIX is found to be predominantly in the mucosa—also quite different from that of most other photosensitizers [10,11]. Besides photodynamic diagnosis, this makes 5-ALA particularly attractive for photodynamic therapy of superficial lesions such as intraepithelial neoplasia in Barrett’s esophagus. Depending on the doses (20 to 60 mg/kg) of 5-ALA, minor side effects such as nausea and vomiting, transient increase in liver enzymes, photosensitization of the skin, and hyper/hypotension can be observed [12]. Hematoporphyrin derivative and porfimer sodium (Photofrin) Hematoporphyrin derivative (HPD) and a more recently introduced and more pure preparation of HPD, Photofrin, are nearly exclusively used for therapeutic purposes and therefore only mentioned briefly. Photofrin is an effective photosensitizing agent but has the disadvantage of prolonged skin photosensitization, which requires patients to avoid sunlight for as long as 4 to 6 weeks after receiving the substance [13]. 5-ALA-esters Hydrophilic properties of 5-ALA limit the amount of uptake and penetration, particularly after topical administration of 5-ALA. Therefore chemical modification into its more lipophilic esters seems to be promising to overcome these limitations of local application of 5-ALA. Esterified 5-ALA derivatives have been used both in vitro [14 –18] and in vivo [11,19], and better effects were achieved compared with the application of unmodified 5-ALA. In particular, administration of different 5-ALA esters, depending on the aliphatic length of the alcohol used for esterification, led to significantly higher mean mucosal fluorescence intensity values after significantly shorter incubation times compared with 5-ALA. In urology, there are promising data, using the 5-ALA-hexylester for the photodetection of early human bladder cancer [19]. The results of this study indicate that with 5-ALA-hexylester, a two fold increase of PPIX fluorescence intensity can be observed using a 20 fold lower concentration as compared with 5-ALA. For the gastrointestinal tract, there are no clinical data evaluating the 5-ALA esters for fluorescence endoscopy available so far.
Technical background of photodynamic diagnosis The principle of photodynamic diagnosis is based on the interaction of light and tissue. Irradiation of tissue with light of a specific wavelength leads to excitation of endogenous or exogenous fluorophores, causing electrons to be raised to a higher energy level. Subsequent relaxation induces emission of a typical fluorescent light. As already mentioned, photodynamic diagnosis can use the detection of autofluorescence or exogenously induced fluorescence. Endoscopy is performed using fiberscopes connected to a light source delivering white
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or blue light 375 to 440 nm. During endoscopy it is possible to switch between the conventional white light mode and the blue light mode. Furthermore the endoscope is adapted to a camera with an imaging processing module delivering real-time fluorescence pictures. There are several devices available for the gastrointestinal tract (for example D-Light, Storz, Germany and LIFE-GI, Xillix, Canada). While the Xillix laser-induced fluorescence endoscopy gastrointestinal (LIFE-GI) system is based on detecting tissue autofluorescence, the D-Light system is optimized for the detection of 5-ALA –induced fluorescence. Premalignant and malignant lesions will exhibit red fluorescence, whereas normal tissue shows blue fluorescence.
Clinical results of fluorescence endoscopy Autofluorescence Because of technical problems with detection systems in the beginning, using a prototype of the second generation (Xillix) seems to reach a better contrast with shorter examination times [20]. Haringsma et al [21] found a sensitivity and specificity of 87% for the detection of high-grade dysplasia and early cancers in 80 patients with Barrett’s esophagus, using the Xillix-LIFE-system. The sensitivity and specificity were 76% and 93% for the conventional with light endoscopy. In contrast, low-grade dysplasia could be correctly diagnosed in only four of 22 cases. Furthermore this group demonstrated in 65 patients a sensitivity and specificity of 96% and 70% for the discrimination of dysplastic versus nondysplastic colonic lesions [22]. Using another prototype of the LIFE system (Tricam SL PAL, Storz, Tuttlingen, Germany) Brand et al [23] reached a sensitivity of 91% and a specificity of 90% for the detection of dysplastic lesions in the colon. Additionally, the capability of autofluorescence endoscopy to detect the presence and extent of occult malignant and premalignant gastrointestinal lesions has been demonstrated in further studies [24]. The diagnosis of early gastric cancers was also possible with a high sensitivity (95%) but low specificity (56%) [25]. Limited data are available for the diagnosis of bile duct cancers with autofluorescence. Izuishi et al [26] examined nine patients with bile duct cancer with the Xillix LIFE-GI system, and they could demonstrate a successful differentiation of neoplastic from nonneoplastic tissue. Recently published data on autofluorescence showed diverse results. The data of Borovicka et al [27] demonstrated that autofluorescence-aided endoscopy (using the Storz system) enhances the ability to visualize and localize neoplastic lesions in Barrett’s esophagus. One additional neoplastic lesion out of 10 patients with dysplasia or cancer was found, which may have been missed by standard endoscopy. However, the results of two other investigations studying a higher number of patients were disappointing. Egger et al [28] assessed the value of autofluorescence compared with four quadrant biopsies for the detection of premalignant and malignant lesions in 35 patients with Barrett’s esophagus. A
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total of 345 biopsies showed low-grade dysplasia in 88 biopsies, high-grade dysplasia in 19 biopsies, and carcinoma in 12 biopsies. Accordingly sensitivity and specificity rates for diagnosis of cancer or dysplasia versus intestinal metaplasia without dysplasia were only 21% and 91%. Four quadrant biopsies revealed five cancer/high-grade dysplasia and 76 low-grade dysplasia not detected by autofluorescence. Unfortunately the nonrandomized study design of this investigation has to be criticized. Biopsies were taken after evaluation of autofluorescence in comparison with methylene blue staining and conventional white light endoscopy. Therefore, the results of this study have to be considered cautiously. The second study by Bergman et al [29] included 47 patients with Barrett’s esophagus, evaluating the Xillix LIFE-II-system for the detection of premalignant and malignant lesions. LIFE did not improve the detection of highgrade dysplasia or carcinoma compared with standard endoscopy in this randomized cross-over study. Both LIFE and standard endoscopy missed three of 15 (20%) patients with high-grade dysplasia or carcinoma diagnosed after the other procedure. To improve the quality of autofluorescence imaging fiberscope systems, a new Auto-Fluorescence Imaging (AFI) videoendoscope system has been developed by Olympus Optical Co., Ltd. Namishia et al [30] recently investigated this system for the detection of colonic neoplasms. The AFI image provided better brightness and resolution than the autofluorescence fiberscope image; resolution and clearness were similar to those of conventional videoscopes. Adenoma and hyperplasia could be distinguished from each other due to different colors with a sensitivity of 81%.
5-ALA-induced fluorescence endoscopy Because of technical problems with autofluorescence detection systems, exogenous photosensitization has been used to enhance the fluorescent signal and therefore the detection of premalignant and malignant lesions. Fluorescence endoscopy, using 5-aminolevulinic acid (5-ALA) sensitization, is widely used in urology and even neurosurgery [31,32]. In the gastrointestinal tract we could demonstrate for the first time that dysplastic lesions in a dextrane sulfate sodium (DSS) colitis model in rats were detectable with the naked eye under an ultraviolet A light source after systemic sensitization with 5-ALA [33]. A total of 56 fluorescent specimens exhibited either low-grade dysplasia or probably dysplastic mucosa. High-grade dysplasia was not found in this study. Amounts of 10 and 25 mg/kg 5-ALA given intravenously induced no fluorescence of any tissue, whereas 200 mg/kg 5-ALA intravenously led to general fluorescence of all tissues. Therefore the animals were sensitized with 50, 75, and 100 mg/kg 5-ALA. With 100 mg/kg 5-ALA intravenously, all dsyplasic lesions were detected (sensitivity was 100%). However, specificity was low (22%) due to a high rate of false-positive fluorescence mainly caused by inflammation. Sensitization with 50 mg/kg 5-ALA resulted in a sensitivity of only 42% and a
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Table 2 Sensitivity, specificity, positive, and negative predictive value per biopsies to detect dysplastic lesions in Barrett’s esophagus after different sensitization forms using 5-aminolevulinic acid (5-ALA) 5-ALA application mode
Examinations (biopsies) (n)
500 mg locally 5 mg/kg orally 10 mg/kg orally 20 mg/kg orally 30 mg/kg orally
22 4 13 13 6
(96) (20) (56) (44) (27)
Sensitivity (%) 60 80 100 100
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
69 70 56 51 27
18 0 40 13 23
94 100 88 100 100
From: Endlicher E, Knu¨chel R, Hauser T, Szeimies R, Scho¨lmerich J, Messmann H. Endoscopic fluorescence detection of low and high grade dysplasia in Barrett’s oesophagus using systemic or local 5-aminoluevulinic acid. Gut 2001;48:314 – 9; with permission.
specificity of 56%. Using 75 mg/kg 5-ALA intravenously seemed to be a good compromise, leading to a sensitivity of 92% and a specificity of 35%. In the next step, we were able to transfer this knowledge to patients with Barrett’s esophagus. In 47 patients with Barrett’s esophagus, 10 of them with known dysplasia, 58 fluorescence endoscopies were performed after sensitization with different concentrations of 5-ALA given orally (5, 10, 20, 30 mg/kg) or locally (500 to 1000 mg) by spraying the mucosa via a catheter. Fluorescence endoscopy was performed 4 to 6 hours after systemic and 1 to 2 hours after local sensitization using a special light source delivering white or blue light (D-light, Storz, Tuttlingen, Germany). A total of 243 biopsies of red fluorescent (n = 113) and nonfluorescent areas (n = 130) was performed. In three patients, two early cancers and dysplasia, not visible during routine endoscopy, were detected by fluorescence endoscopy. Thirty-three biopsies revealed either low- or high-grade dysplasia. Sensitivity to detect dysplastic lesions ranged from 60% after local
Fig. 2. Conventional white light endoscopic image of a patient with Crohn’s disease and no macroscopic suspicious lesion. (See also Color Plate 17).
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Fig. 3. Corresponding fluorescence endoscopic image shows a selective red fluorescent area that revealed high-grade dysplasia on histology. (See also Color Plate 18).
sensitization with 500 mg to 80%, 100%, and 100% after systemic application of 10, 20, and 30 mg/kg, respectively. However, specificity was best for local sensitization with 70% while systemic administration revealed values between 27% and 56% (Table 2). Using 5 mg/kg, no red fluorescence in dysplastic lesions was found. No severe side effects were noted [34]. Brand et al [35] acquired PPIX fluorescence intensities by measurement of quantitative fluorescence spectra in 20 patients with Barrett’s esophagus. They found a sensitivity and specificity of 100% for the detection of nodular highgrade dysplasia, using the fluorescence intensity ratio of 635nm/480nm. By using the protoporphyrin IX fluorescence alone, high-grade dysplasia was distinguished from nondysplastic tissue with 77% sensitivity and 71% specificity. Gossner et al [36] studied 35 patients with upper gastrointestinal dysplasia and early cancers. Patients were examined 3 hours after sensitization with 10 mg/kg 5-ALA. Neoplasias were detected with a sensitivity and specificity of 85% and 70%, respectively. Mayinger et al [37] reached a sensitivity and specificity of 85% and 53% in the detection of premalignant and malignant esophageal lesions in 22 patients 6 to 7 hours after sensitization with 15 mg/kg 5-ALA orally. Inflammatory bowel disease, especially ulcerative colitis, is another important possible indication for fluorescence endoscopy. Our experience with 37 patients who had ulcerative colitis showed that local administration of 5-ALA either with an enema or using a spray-catheter is superior to a systemic sensitization with 20 mg/kg 5-ALA orally [38]. Sensitivity after sensitization with 20 mg/kg 5-ALA orally was low 43%. However, local sensitization increased sensitivity to 87% to 100%, whereas specificity after sensitization with 20 mg/kg orally was 73% and therefore higher compared with the local sensitization mode with enema (51%) and spray-catheter (62%). Fig. 2 demonstrates a conventional white light endoscopic image of a patient with Crohn’s disease and no macroscopic suspicious lesion. The corresponding fluorescence endoscopic image (Fig. 3) shows a selective red fluorescent area which revealed high-grade dysplasia on histology.
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Summary Clinical data on photodynamic diagnosis for the detection of premalignant and malignant lesions in the gastrointestinal tract are encouraging so far. A major benefit of using autofluorescence is the lack of side effects because no sensitizer has to be applied. However, highly sophisticated detection systems are needed to enhance the weak autofluorescence-based fluorescent signal. New prototypes of autofluorescence videoendoscopes are under way [30] and will be decisive for further clinical use, especially because results of recently published studies have been disappointing. Preliminary data on exogenously induced fluorescence using 5-ALA are promising for screening patients with ulcerative colitis and Barrett’s esophagus. Whereas systemic sensitization in a dose of approximately 15 mg/kg orally seems to be suitable for patients with Barrett’s esophagus, topical application of 5-ALA with an enema seems to be the method of choice for patients with ulcerative colitis. Side effects such as photosensitization, transient increase in liver enzymes, nausea, and vomiting are negligible. In the future the clinical use of fluorescence endoscopy will depend on new developments especially with respect to high resolution video endoscopes. Fluorescence endoscopy only on the basis of fiberscopes available so far will soon become out of date. Furthermore there are other methods, for example methylene blue aided chromoendoscopy with promising results for the early detection of intraepithelial neoplasia and colorectal cancer in patients with ulcerative colitis [39].
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comparing light induced fluorescence endoscopy (LIFE) with standard endoscopy for detection of early neoplasia in Barrett’s esophagus (BE). Gastroenterology 2003;124(Suppl.I):A49. Namihisa A, Ogihara T, Nakaniwa N, Ohkawa A, Sakamoto N, Abe S, et al. Newly developed autofluorescence imaging videoendoscope system for the detection of colinic neoplasms. Gastrointest Endosc 2003;57:AB175. Kriegmair M, Zaak D, Knuechel R, Baumgartner R, Hofstetter A. 5-Aminolevulinic acid-induced fluorescence endoscopy for the detection of lower urinary tract tumors. Urol Int 1999;63: 27 – 31. Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen H. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 2002;93:1003 – 13. Messmann H, Kullmann F, Wild T, Knu¨chel-Clarke R, Ru¨schoff J, Gross V, et al. Detection of dysplastic lesions by fluorescence in a model of colitis in rats after previous photosensitization with 5-aminolaevulinic acid. Endoscopy 1998;30:333 – 8. Endlicher E, Knu¨chel R, Hauser T, Szeimies R, Scho¨lmerich J, Messmann H. Endoscopic fluorescence detection of low and high grade dysplasia in Barrett’s oesophagus using systemic or local 5-aminolaevulinic acid sensitization. Gut 2001;48:314 – 9. Brand S, Wang T, Schomacker K, Poneros J, Lauwers G, Compton C, et al. Detection of highgrade dysplasia in Barrett’s esophagus by spectroscopy measurement of 5-aminolevulinic acidinduced protoporphyrin IX fluorescence. Gastrointest Endosc 2002;56:479 – 87. Gossner L, Stepp H, Sroka R, May A, Stolte M, Ell C. Photodynamic diagnosis (PDD) of high grade dysplasia and early cancer in Barrett’s esophagus using 5-aminolevulinic acid (ALA). Gastroenterology 1998;114:A136. Mayinger B, Neidhardt S, Reh H, Martus P, Hahn E. Fluorescence induced with 5-aminolevulinic acid for the endoscopic detection and follow up of esophageal lesions. Gastrointest Endosc 2001;54:572 – 8. Messmann H, Endlicher E, Freunek G, Rummele P, Scholmerich J, Knuchel R. Fluorescence endoscopy for the detection of low and high grade dysplasia in ulcerative colitis using systemic or local 5-aminolaevulinic acid sensitisation. Gut 2003;52:1003 – 7. Kiesslich R, Fritsch J, Holtmann M, Koehler HH, Stolte M, Kanzler S, et al. Methylene blueaided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;48:880 – 8.
Photodynamic diagnosis in the gastrointestinal tract Esther Endlicher, MDa, Helmut Messmann, MDb,* a
Department of Internal Medicine I, University of Regensburg, 03042 Regensburg, Germany b Department of Internal Medicine III, Klinikum Augsburg, PO Box 101920, 86009 Augsburg, Germany
Because of the multistep neoplastic progression in developing cancer with excellent therapeutic modalities in superficial growth stages lacking metastasis, an early diagnosis of precancerous lesions is of essential benefit for our health service system and particularly for the individual patient. Photodynamic diagnosis is a new technique which may improve the detection of nonvisible or difficult-to-detect malignant and premalignant lesions. Exogenously applied sensitizers accumulate selectively in malignant lesions and induce fluorescence after illumination with light of adequate wavelength. However, endogenous fluorophores, induce different autofluorescence in malignant and benign lesions. Meanwhile photodynamic diagnosis is a widely spread technique in urology, using 5-aminolevulinic acid (5-ALA) sensitization. Fluorescence cystoscopy, after local instillation of 5-ALA into the bladder, has significantly enhanced the diagnosis of malignant and premalignant lesions. In the gastrointestinal track, there are promising results in the detection of early cancers or dysplasia in patients with Barrett’s esophagus or ulcerative colitis, but no randomized study has been performed to evaluate this method in comparison with conventional white-light endoscopy. This article focuses on the technical basis of this interesting method and reviews the preclinical and clinical results available for the gastrointestinal tract so far. Possible indications for photodynamic diagnosis in gastroenterology are listed in Box 1.
* Corresponding author. E-mail address: [email protected] (H. Messmann). 1052-5157/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2004.03.009
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Box 1. Possible indications for photodynamic diagnosis in gastroenterology
Longstanding and extensive ulcerative colitis Barrett’s esophagus Primary sclerosing cholangitis Surveillance of patients after polypectomy, photodynamic therapy, mucosal resection Differentiation of malignant and benign mucosal lesions (ulcers, stenosis, polyps)
Autofluorescence Autofluorescence of different tissues is based on the typical excitation and emision spectrum of endogenous fluorophores (Table 1). These endogenous fluorophores include collagen, elastin, flavins, tryptophane, porphyrins, and nicotinamide adenine dinucleotide (NAD/NADH). Different excitation wavelengths activate different fluorophores. Inflammation, ischemia, hemoglobin content, and also neoplastic alterations influence the metabolic and the oxidative status of the cells and therefore autofluorescence of the tissue. Collagen is probably one of the most important contributors for tissue autofluorescence. Depending on mucosal thickness—average thickness of the mucosa is 460 mm— the penetration depth at 400 nm excitation is about 500 mm. Therefore collagen and elastin of the mucosa will be excited at this wavelength. Thickening of the mucosa, typical for tumor growth, results in a decreased autofluorescence of elastin and collagen [1].
Exogenous photosensitization: photosensitizers Exogenous photosensitization is based on the administration of a photoactive compound that accumulates selectively in tumors.
Table 1 Excitation and emission wavelengths of various fluorophores in tissue Fluorophores
Excitation (nm)
Emission (nm)
NADH Flavin Collagen Elastin Porphyrin
350 455 250 285 405
500 495 330 350 610
Data represent maximum values at optimum excitation/emission condition.
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exogenous administration
477
mitochondrion
GLY + SCoA ALAsynthetase
ferrochelatase
PPIX
2+
Heme
Fe
5-ALA PROTO 5-ALA
5-ALA PBG
URO extra-
COPRO
cytoplasm
intracellular
Fig. 1. Porphyrin biosynthesis after exogenous application of 5-ALA. There are several possibilities for selectivity of Protoporphyrin IX in tumor cells: (1) enhanced cellular uptake of 5-ALA into the cell, (2) enhanced activity of the porphyrin-synthesis, (3) reduced activity of the enzyme ferrochelatase. Abbreviations: 5-ALA, 5-aminolevulinic acid; COPRO, coproporphyrinogen; GLY, glycine; PBG, porphobilinogen; PPIX, protoporphyrin IX; PROTO, protoporphyrinogen; SCoA, Succinyl-CoA; URO, uroporphyrinogen.
5-Aminolevulinic acid With respect to side effects (length of skin sensitivity) and tumor selectivity, 5-aminolevulinic acid (5-ALA) is the most interesting substance for photodynamic diagnosis compared with other sensitizers [2,3]. Not a sensitizer itself, 5-ALA is converted intracellularly into the photoactive compound protoporphyrin IX (PPIX) (Fig. 1). The cellular uptake of 5-ALA is still being investigated, but in vitro studies indicate that 5-ALA seems to be taken up by active transport mechanisms [4]. It can be assumed that the major cause for selective retention of 5-ALA in malignant tissue is based on the biosynthetic pathway. Tumors tend to have an increase in porphobilinogen deaminase activity, resulting in greater production of PPIX. Furthermore, a reduced ferrochelatase activity results in a greater retention of PPIX by the tumor because of reduced conversion of PPIX into heme [5,6]. 5-ALA can be given topically or by mouth. Depending on the application mode, peak levels of PPIX will be reached within 4 to 6 hours after systemic sensitization and 1 to 2 hours after local administration in the esophagus, stomach, or in the colonic tissue [7,8]. The plasma half-life of PPIX is 8 hours, and PPIX values return to baseline levels within about 48 hours after oral administration of 5-ALA [9]. This may even be faster after topical administration. Compared with other sensitizers such as Photofrin and hematoporphyrin derivative (HPD), 5-ALA shortened the interval of skin photosensitization making it possible to investigate the patients on an outpatient basis.
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The tissue distribution of PPIX is found to be predominantly in the mucosa—also quite different from that of most other photosensitizers [10,11]. Besides photodynamic diagnosis, this makes 5-ALA particularly attractive for photodynamic therapy of superficial lesions such as intraepithelial neoplasia in Barrett’s esophagus. Depending on the doses (20 to 60 mg/kg) of 5-ALA, minor side effects such as nausea and vomiting, transient increase in liver enzymes, photosensitization of the skin, and hyper/hypotension can be observed [12]. Hematoporphyrin derivative and porfimer sodium (Photofrin) Hematoporphyrin derivative (HPD) and a more recently introduced and more pure preparation of HPD, Photofrin, are nearly exclusively used for therapeutic purposes and therefore only mentioned briefly. Photofrin is an effective photosensitizing agent but has the disadvantage of prolonged skin photosensitization, which requires patients to avoid sunlight for as long as 4 to 6 weeks after receiving the substance [13]. 5-ALA-esters Hydrophilic properties of 5-ALA limit the amount of uptake and penetration, particularly after topical administration of 5-ALA. Therefore chemical modification into its more lipophilic esters seems to be promising to overcome these limitations of local application of 5-ALA. Esterified 5-ALA derivatives have been used both in vitro [14 –18] and in vivo [11,19], and better effects were achieved compared with the application of unmodified 5-ALA. In particular, administration of different 5-ALA esters, depending on the aliphatic length of the alcohol used for esterification, led to significantly higher mean mucosal fluorescence intensity values after significantly shorter incubation times compared with 5-ALA. In urology, there are promising data, using the 5-ALA-hexylester for the photodetection of early human bladder cancer [19]. The results of this study indicate that with 5-ALA-hexylester, a two fold increase of PPIX fluorescence intensity can be observed using a 20 fold lower concentration as compared with 5-ALA. For the gastrointestinal tract, there are no clinical data evaluating the 5-ALA esters for fluorescence endoscopy available so far.
Technical background of photodynamic diagnosis The principle of photodynamic diagnosis is based on the interaction of light and tissue. Irradiation of tissue with light of a specific wavelength leads to excitation of endogenous or exogenous fluorophores, causing electrons to be raised to a higher energy level. Subsequent relaxation induces emission of a typical fluorescent light. As already mentioned, photodynamic diagnosis can use the detection of autofluorescence or exogenously induced fluorescence. Endoscopy is performed using fiberscopes connected to a light source delivering white
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or blue light 375 to 440 nm. During endoscopy it is possible to switch between the conventional white light mode and the blue light mode. Furthermore the endoscope is adapted to a camera with an imaging processing module delivering real-time fluorescence pictures. There are several devices available for the gastrointestinal tract (for example D-Light, Storz, Germany and LIFE-GI, Xillix, Canada). While the Xillix laser-induced fluorescence endoscopy gastrointestinal (LIFE-GI) system is based on detecting tissue autofluorescence, the D-Light system is optimized for the detection of 5-ALA –induced fluorescence. Premalignant and malignant lesions will exhibit red fluorescence, whereas normal tissue shows blue fluorescence.
Clinical results of fluorescence endoscopy Autofluorescence Because of technical problems with detection systems in the beginning, using a prototype of the second generation (Xillix) seems to reach a better contrast with shorter examination times [20]. Haringsma et al [21] found a sensitivity and specificity of 87% for the detection of high-grade dysplasia and early cancers in 80 patients with Barrett’s esophagus, using the Xillix-LIFE-system. The sensitivity and specificity were 76% and 93% for the conventional with light endoscopy. In contrast, low-grade dysplasia could be correctly diagnosed in only four of 22 cases. Furthermore this group demonstrated in 65 patients a sensitivity and specificity of 96% and 70% for the discrimination of dysplastic versus nondysplastic colonic lesions [22]. Using another prototype of the LIFE system (Tricam SL PAL, Storz, Tuttlingen, Germany) Brand et al [23] reached a sensitivity of 91% and a specificity of 90% for the detection of dysplastic lesions in the colon. Additionally, the capability of autofluorescence endoscopy to detect the presence and extent of occult malignant and premalignant gastrointestinal lesions has been demonstrated in further studies [24]. The diagnosis of early gastric cancers was also possible with a high sensitivity (95%) but low specificity (56%) [25]. Limited data are available for the diagnosis of bile duct cancers with autofluorescence. Izuishi et al [26] examined nine patients with bile duct cancer with the Xillix LIFE-GI system, and they could demonstrate a successful differentiation of neoplastic from nonneoplastic tissue. Recently published data on autofluorescence showed diverse results. The data of Borovicka et al [27] demonstrated that autofluorescence-aided endoscopy (using the Storz system) enhances the ability to visualize and localize neoplastic lesions in Barrett’s esophagus. One additional neoplastic lesion out of 10 patients with dysplasia or cancer was found, which may have been missed by standard endoscopy. However, the results of two other investigations studying a higher number of patients were disappointing. Egger et al [28] assessed the value of autofluorescence compared with four quadrant biopsies for the detection of premalignant and malignant lesions in 35 patients with Barrett’s esophagus. A
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total of 345 biopsies showed low-grade dysplasia in 88 biopsies, high-grade dysplasia in 19 biopsies, and carcinoma in 12 biopsies. Accordingly sensitivity and specificity rates for diagnosis of cancer or dysplasia versus intestinal metaplasia without dysplasia were only 21% and 91%. Four quadrant biopsies revealed five cancer/high-grade dysplasia and 76 low-grade dysplasia not detected by autofluorescence. Unfortunately the nonrandomized study design of this investigation has to be criticized. Biopsies were taken after evaluation of autofluorescence in comparison with methylene blue staining and conventional white light endoscopy. Therefore, the results of this study have to be considered cautiously. The second study by Bergman et al [29] included 47 patients with Barrett’s esophagus, evaluating the Xillix LIFE-II-system for the detection of premalignant and malignant lesions. LIFE did not improve the detection of highgrade dysplasia or carcinoma compared with standard endoscopy in this randomized cross-over study. Both LIFE and standard endoscopy missed three of 15 (20%) patients with high-grade dysplasia or carcinoma diagnosed after the other procedure. To improve the quality of autofluorescence imaging fiberscope systems, a new Auto-Fluorescence Imaging (AFI) videoendoscope system has been developed by Olympus Optical Co., Ltd. Namishia et al [30] recently investigated this system for the detection of colonic neoplasms. The AFI image provided better brightness and resolution than the autofluorescence fiberscope image; resolution and clearness were similar to those of conventional videoscopes. Adenoma and hyperplasia could be distinguished from each other due to different colors with a sensitivity of 81%.
5-ALA-induced fluorescence endoscopy Because of technical problems with autofluorescence detection systems, exogenous photosensitization has been used to enhance the fluorescent signal and therefore the detection of premalignant and malignant lesions. Fluorescence endoscopy, using 5-aminolevulinic acid (5-ALA) sensitization, is widely used in urology and even neurosurgery [31,32]. In the gastrointestinal tract we could demonstrate for the first time that dysplastic lesions in a dextrane sulfate sodium (DSS) colitis model in rats were detectable with the naked eye under an ultraviolet A light source after systemic sensitization with 5-ALA [33]. A total of 56 fluorescent specimens exhibited either low-grade dysplasia or probably dysplastic mucosa. High-grade dysplasia was not found in this study. Amounts of 10 and 25 mg/kg 5-ALA given intravenously induced no fluorescence of any tissue, whereas 200 mg/kg 5-ALA intravenously led to general fluorescence of all tissues. Therefore the animals were sensitized with 50, 75, and 100 mg/kg 5-ALA. With 100 mg/kg 5-ALA intravenously, all dsyplasic lesions were detected (sensitivity was 100%). However, specificity was low (22%) due to a high rate of false-positive fluorescence mainly caused by inflammation. Sensitization with 50 mg/kg 5-ALA resulted in a sensitivity of only 42% and a
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Table 2 Sensitivity, specificity, positive, and negative predictive value per biopsies to detect dysplastic lesions in Barrett’s esophagus after different sensitization forms using 5-aminolevulinic acid (5-ALA) 5-ALA application mode
Examinations (biopsies) (n)
500 mg locally 5 mg/kg orally 10 mg/kg orally 20 mg/kg orally 30 mg/kg orally
22 4 13 13 6
(96) (20) (56) (44) (27)
Sensitivity (%) 60 80 100 100
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
69 70 56 51 27
18 0 40 13 23
94 100 88 100 100
From: Endlicher E, Knu¨chel R, Hauser T, Szeimies R, Scho¨lmerich J, Messmann H. Endoscopic fluorescence detection of low and high grade dysplasia in Barrett’s oesophagus using systemic or local 5-aminoluevulinic acid. Gut 2001;48:314 – 9; with permission.
specificity of 56%. Using 75 mg/kg 5-ALA intravenously seemed to be a good compromise, leading to a sensitivity of 92% and a specificity of 35%. In the next step, we were able to transfer this knowledge to patients with Barrett’s esophagus. In 47 patients with Barrett’s esophagus, 10 of them with known dysplasia, 58 fluorescence endoscopies were performed after sensitization with different concentrations of 5-ALA given orally (5, 10, 20, 30 mg/kg) or locally (500 to 1000 mg) by spraying the mucosa via a catheter. Fluorescence endoscopy was performed 4 to 6 hours after systemic and 1 to 2 hours after local sensitization using a special light source delivering white or blue light (D-light, Storz, Tuttlingen, Germany). A total of 243 biopsies of red fluorescent (n = 113) and nonfluorescent areas (n = 130) was performed. In three patients, two early cancers and dysplasia, not visible during routine endoscopy, were detected by fluorescence endoscopy. Thirty-three biopsies revealed either low- or high-grade dysplasia. Sensitivity to detect dysplastic lesions ranged from 60% after local
Fig. 2. Conventional white light endoscopic image of a patient with Crohn’s disease and no macroscopic suspicious lesion. (See also Color Plate 17).
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Fig. 3. Corresponding fluorescence endoscopic image shows a selective red fluorescent area that revealed high-grade dysplasia on histology. (See also Color Plate 18).
sensitization with 500 mg to 80%, 100%, and 100% after systemic application of 10, 20, and 30 mg/kg, respectively. However, specificity was best for local sensitization with 70% while systemic administration revealed values between 27% and 56% (Table 2). Using 5 mg/kg, no red fluorescence in dysplastic lesions was found. No severe side effects were noted [34]. Brand et al [35] acquired PPIX fluorescence intensities by measurement of quantitative fluorescence spectra in 20 patients with Barrett’s esophagus. They found a sensitivity and specificity of 100% for the detection of nodular highgrade dysplasia, using the fluorescence intensity ratio of 635nm/480nm. By using the protoporphyrin IX fluorescence alone, high-grade dysplasia was distinguished from nondysplastic tissue with 77% sensitivity and 71% specificity. Gossner et al [36] studied 35 patients with upper gastrointestinal dysplasia and early cancers. Patients were examined 3 hours after sensitization with 10 mg/kg 5-ALA. Neoplasias were detected with a sensitivity and specificity of 85% and 70%, respectively. Mayinger et al [37] reached a sensitivity and specificity of 85% and 53% in the detection of premalignant and malignant esophageal lesions in 22 patients 6 to 7 hours after sensitization with 15 mg/kg 5-ALA orally. Inflammatory bowel disease, especially ulcerative colitis, is another important possible indication for fluorescence endoscopy. Our experience with 37 patients who had ulcerative colitis showed that local administration of 5-ALA either with an enema or using a spray-catheter is superior to a systemic sensitization with 20 mg/kg 5-ALA orally [38]. Sensitivity after sensitization with 20 mg/kg 5-ALA orally was low 43%. However, local sensitization increased sensitivity to 87% to 100%, whereas specificity after sensitization with 20 mg/kg orally was 73% and therefore higher compared with the local sensitization mode with enema (51%) and spray-catheter (62%). Fig. 2 demonstrates a conventional white light endoscopic image of a patient with Crohn’s disease and no macroscopic suspicious lesion. The corresponding fluorescence endoscopic image (Fig. 3) shows a selective red fluorescent area which revealed high-grade dysplasia on histology.
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Summary Clinical data on photodynamic diagnosis for the detection of premalignant and malignant lesions in the gastrointestinal tract are encouraging so far. A major benefit of using autofluorescence is the lack of side effects because no sensitizer has to be applied. However, highly sophisticated detection systems are needed to enhance the weak autofluorescence-based fluorescent signal. New prototypes of autofluorescence videoendoscopes are under way [30] and will be decisive for further clinical use, especially because results of recently published studies have been disappointing. Preliminary data on exogenously induced fluorescence using 5-ALA are promising for screening patients with ulcerative colitis and Barrett’s esophagus. Whereas systemic sensitization in a dose of approximately 15 mg/kg orally seems to be suitable for patients with Barrett’s esophagus, topical application of 5-ALA with an enema seems to be the method of choice for patients with ulcerative colitis. Side effects such as photosensitization, transient increase in liver enzymes, nausea, and vomiting are negligible. In the future the clinical use of fluorescence endoscopy will depend on new developments especially with respect to high resolution video endoscopes. Fluorescence endoscopy only on the basis of fiberscopes available so far will soon become out of date. Furthermore there are other methods, for example methylene blue aided chromoendoscopy with promising results for the early detection of intraepithelial neoplasia and colorectal cancer in patients with ulcerative colitis [39].
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