American Journal of Obstetrics and Gynecology
Volume 183 • Number 1 • July 2000
Copyright © 2000 Mosby, Inc.

GENERAL OBSTETRICS AND GYNECOLOGY

Dr.sinan DOĞANTÜRK

Ankara

Assessment of 5-aminolevulinic acid-induced porphyrin fluorescence in patients with peritoneal endometriosis

 

Peter Hillemanns MD^a

Helmut Weingandt ^a

Herbert Stepp PhD^b

Reinhold Baumgartner PhD^b

Wei Xiang PhD^a

Matthias Korell MD^a

 

Key words

5-Aminolevulinic acid

diagnosis

endometriosis

photodynamic

protoporphyrin

 

From the Department of Obstetrics and Gynecology^a and the Urology Laser Research Laboratory,^b Klinikum Grosshadern, Ludwig-MaximiliansUniversitat.

Supported by the BIOMED project of the European community (grant BMH4-CT97-2260). Peter Hillemanns, MD, was supported in part by a grant from the K.L. Weigand Stiftung.
Received for publication May 19, 1999.
Revised December 2, 1999.
Accepted January 18, 2000.

Reprint requests: Peter Hillemanns, MD, Department of Obstetrics and Gynecology, Klinikum Grosshadern, Ludwig-Maximilians-Universitat, 81377 Munchen, Germany.

Copyright © 2000 by Mosby, Inc.

0002-9378/2000 $12.00 + 0  6/1/105897



Munich, Germany

Objective: The purpose of this study was to examine the diagnostic potential for patients with endometriosis of porphyrin fluorescence after oral administration of 5-aminolevulinic acid.
Study Design: Fifteen women referred for laparoscopy because of suspected endometriosis received 1 or 10 mg/kg 5-aminolevulinic acid orally. After 1.5 to 6 hours endoscopic fluorescence spectral analysis and video inspection were performed.
Results: With 10 mg/kg 5-aminolevulinic acid and application intervals of >3 hours we observed a significantly higher porphyrin fluorescence in active peritoneal endometriosis than in adjacent normal peritoneum. Pigmented and nodular endometriosis showed weak to negative fluorescence. A strong fluorescence of the fimbrial mucosa was seen. A 1-mg/kg dose of 5-aminolevulinic acid was insufficient for fluorescence diagnosis. No side effects were recorded.
Conclusion: Porphyrin fluorescence after oral administration of 5-aminolevulinic acid may be beneficial in diagnosis of peritoneal endometriosis. The strong fluorescence of fimbrial mucosa may limit the applicability of this technique in young women, however, because phototoxic damage cannot be excluded at present. (Am J Obstet Gynecol 2000;183:52-7.)

 

Endometriosis is a frequent clinical problem for women of reproductive age that can markedly influence both reproductive prognosis and quality of life. Typically, this disorder causes dysmenorrhea, chronic or cyclic pelvic pain, and infertility, resulting in prolonged medical treatment and repeated hospitalizations for surgery. Histologically, this disorder is characterized by the presence of endometrial glands and cytogenic stroma in extrauterine locations. Estimates of the prevalence of endometriosis depend on the study population; for example, reported prevalences are 18% among women undergoing laparoscopic sterilization, 30% among women with infertility and pelvic pain, and as high as 50% among teenagers with severe dysmenorrhea.^{[1] [2]}

The main diagnostic technique remains laparoscopy. Other techniques, such as serum CA 125 assay, magnetic resonance imaging, and ultrasonography, have not proved adequately sensitive or specific. Laparoscopic diagnostic accuracy is influenced by several variables, including the quality of the endoscopic equipment and the operator's experience and skill.^[3] However, endometriosis has a large variety of forms and color manifestations, such as nodular implants and black or red peritoneal lesions. In consequence some lesions may be easily missed, which may lead to recurrent endometriosis with all its clinical consequences.

Light-induced fluorescence is a relatively new technique with unique properties that make it attractive for the diagnosis of endometriosis. It uses fluorescent drugs that concentrate preferentially in tumors and other hyperproliferative tissues. A number of photosensitizers are currently under investigation, such as hematoporphyrins, phthalocyanines, and chlorines. A particularly interesting recent addition to the list of photosensitizers is 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPIX), which represents a promising photosensitizer for new applications of photodynamic diagnosis and therapy because of its rapid pharmacokinetics and topical applicability. ^[4] 5-ALA, a precursor of heme formed by 5-ALA synthase from glycine and succinyl coenzyme A, is the rate limiting step of the heme biosynthesis. Once this step is bypassed by exogenous administration of 5-ALA, PPIX and heme accumulate mainly in malignant tissue. 5-ALA-induced PPIX is cleared from the skin within 24 to 48 hours after topical, systemic, or intradermal administration.^[5] Inconvenience to the patient, such as shielding against exposure to light, is thus minimized.

Photodynamic therapy with topical 5-ALA has already been shown to be effective in the treatment of various neoplastic epithelial lesions, such as basal cell carcinoma of the skin, premalignant lesions of the oral cavity, and high-grade dysplasia of Barrett esophagus,^{[4] [6] [7]} but not in the treatment of cervical intraepithelial neoplasia.^[8] Vulvar dystrophy could be treated successfully with minimal side effects.^[9] Furthermore, the application of 5-ALA has been used clinically for the endoscopic detection, by means of fluorescence imaging, of neoplastic lesions of the bladder, early stage lung cancer, and malignant glioma.^{[10] [12]}

In a model of experimentally induced endometriosis in the rat the intensity of PPIX fluorescence after intravenous or oral delivery of 5-ALA was significantly higher than that in adjacent normal peritoneum.^[13] The aim of this study was to determine the diagnostic potential of porphyrin fluorescence after oral administration of 5-ALA in the assessment of patients referred for endometriosis.

Material and methods

A clinical phase I study was originally designed to include 30 patients. Patients with suspicion of endometriosis were enrolled for the assessment of PPIX fluorescence as a diagnostic tool after oral application of three different concentrations of 5-ALA: 1 mg/kg, 10 mg/kg, and 20 mg/kg body weight. Informed consent was obtained from each patient. Patients with cardiovascular, liver, or chronic diseases were excluded. A negative pregnancy test result was obtained for all women before enrollment in the study. A gynecologic examination that included vaginal ultrasonography was performed. Patients were also eligible for study if they had undergone previous diagnostic or therapeutic procedures for endometriosis. 5-ALA was obtained as a solid (hydrochloride form) from Medac GmbH, Hamburg, Germany. Immediately before use the appropriate amount of 5-ALA was dissolved in mineral water.

Eventually 15 women referred for diagnostic or operative laparoscopy because of suspected endometriosis were included in this study. The mean age was 32.5 years (range, 25-41 years), and all patients were white. Five patients received orally 1 mg/kg body weight 5-ALA, and 10 patients received 10 mg/kg body weight. After an interval of 90 to 280 minutes fluorescence spectral analysis and video inspection were performed. As with any clinical study involving general anesthesia, we could not allocate a precise interval of drug administration to light for each patient. Fluorescence was excited with a filtered short-arc xenon lamp at 380 to 440 nm and a power output of 200 mW (D-Light; Karl Storz GmbH & Co, Tuttlingen, Germany). A modified video laparoscope was attached to a sensitive 1-chip red-green-blue color endoscopic camera with additional features, such as enhancement of the sensitivity in the wavelength >600 nm, automatically and manually adjustable target integration of images in fluorescence mode, separate color balancing for white light and fluorescence, switching of camera modes, and light source from the camera head (Telecam SL PAL; Karl Storz). Rejection of excitation light was accomplished by means of a color glass filter (long-pass OG 515; long-pass lambda = 450 nm) on the eyepiece to select an emitted wavelength range of 470 to 700 nm. Spectral measurements were performed by imaging a 2-mm-diameter tissue area through the endoscope optics by means of a beam splitter onto a 600-mum core quartz fiber connected to a spectrometer (52000; Ocean Optics, Mikropack, Ostfildern, Germany). Fluorescence spectra were collected in the visible region of the electromagnetic spectrum from 350 nm to 750 nm with a resolution of 10 nm. The quantitative analyses of the spectra obtained were performed at a wavelength of 635 ± 5 nm for PPIX. The tissue spectra were then normalized to the peak fluorescence intensity of a calibration standard consisting of an india rubber eraser at the wavelength of 600 ± 50 nm. Differences of the fluorescence spectral intensities were calculated with the nonparametric Mann-Whitney U test. P < .05 was considered significant.

Video sequences under white light and fluorescence were recorded on videotape, digitized, and analyzed later from the tape. Fluorescence imaging considered green autofluorescence and red PPIX fluorescence simultaneously to producing a red-green color contrast of suspected lesions. Fluorescence-directed biopsies were performed endoscopically to take specimens from areas corresponding to the fluorescence and the white-light image. Patients were not exposed to intense light for a period of 24 hours after endoscopy. Routine biochemical examination (sodium, potassium, creatinine, and aspartate aminotransferase levels) and complete blood cell count were performed before and 1 day after oral 5-ALA application. Patients were monitored for local and systemic toxicity 1 and 3 days after endoscopic fluorescence imaging.

Results

A modified laparoscope attached to a sensitive color endoscopic camera with additional features proved to be applicable for endoscopic fluorescence imaging of 5-ALA- induced PPIX in the abdominal cavity. During regular laparoscopy switching of camera and light modes between blue light for fluorescence detection and normal white-light mode was easy to perform and did not hinder the endoscopic procedure. Fiber-based spectral measurements were user friendly and gave reproducible results.

After oral administration of 5-ALA at 1 mg/kg body weight the endoscopic video inspection could not detect any 5-ALA-induced red porphyrin fluorescence within the abdominal cavity. The time interval between oral application and fluorescence assessment varied between 2 and 6 hours (Table I).

Similarly, fluorescence spectral analysis by endoscope did not reveal any PPIX fluorescence of intraperitoneal tissues or skin.

Exposure times of <3 hours after oral administration of 5-ALA at 10 mg/kg body weight resulted in very low PPIX fluorescence, which could only be detected in the mucosa of the tubal fimbriae. Neither the vermillion border nor the mucosa of the vaginal introitus, which are areas known to convert orally applied 5-ALA into PPIX in a nonspecific although time-dependent manner, showed any significant fluorescence. Increased intra-abdominal porphyrin fluorescence intensities were found between 4 and 5 hours after administration. Even after an interval of 6 hours the fluorescence intensities were only slightly less than those after an interval of 4 to 5 hours. Endometriotic lesions that were characterized as white or red peritoneal areas under white light were associated with a specific PPIX fluorescence of pronounced intensity under blue light (Fig 1).

Fig. 1. PPIX fluorescence observed at 4 to 5 hours in 7 active endometriotic lesions (Endo), 10 nodular endometriotic lesions (Nodu), 5 pigmented endometriotic lesions (Pigm), parietal peritoneum (Perit; n = 6), cul-de-sac fluid (Cul; n = 5), fallopian tube (Fall; n = 6), fimbrial mucosa (Fimb; n = 12), and liver (n = 6) from 6 patients (cases 9-14; Table I) after oral administration of 5-ALA at 10 mg/kg. Active endometriosis characterized as white or red peritoneal lesion showed significant enhanced fluorescence intensity compared with peritoneum (P < .01). Nearly no fluorescence was noted in nodular and pigmented endometriotic lesions. Maximal fluorescence was seen in fimbrial mucosa. Bars, Mean; error bars, SD.

However, the fluorescence distribution in these lesions appeared to be heterogeneous. In contrast, no fluorescence was seen in pigmented peritoneal lesions and nodular implants of endometriosis. The difference of the mean fluorescence values between the 7 active endometriotic implants and the adjacent parietal peritoneum measured in patients with a 4- to 5-hour application interval was significant (P < .01 by Mann-Whitney U test; Fig 1). Fluorescence imaging of ovarian endometriomas yielded negative results. Only a small endometriotic implant located on the surface of one ovary and proven by directed biopsy was seen as a distinct fluorescence-positive area. Regular peritoneum yielded negative results for blue light-induced fluorescence, with the exception of few tiny spots that were revealed to be tissue with slight inflammatory reaction or fibrosis on evaluation by site-oriented biopsy.

We observed the highest value of 5-ALA-induced porphyrin fluorescence in the fimbrial mucosa. In addition the tubal mucosa showed pronounced fluorescence, which was visible through the tubal serosa and muscularis. On laparoscopic endoscopy uterus and normal ovaries yielded negative results for fluorescence. A moderate fluorescence intensity was noted at the edge of the liver and to a lesser extent on the surface of the liver. A low 5-ALA-induced fluorescence could be detected in some folds of the omentum and on the surface of the intestinum. The cul-de-sac fluid showed a weak PPIX fluorescence.

The oral administration of 5-ALA at a concentration of either 1 or 10 mg/kg body weight was well tolerated. No systemic effects, such as nausea, vomiting, or elevations of liver enzyme activities, were recorded. None of our patients reported symptoms of cutaneous photosensitization, because exposure to intense white light was avoided for 24 hours after oral administration of 5-ALA. Although higher doses than 10 mg/kg body weight of 5-ALA have been orally administered to human beings without any significant toxic effects,^[7] we did not evaluate the 20-mg/kg dose because a dose of 10 mg/kg proved to be sufficient for fluorescence diagnosis. Furthermore, the possibility cannot be excluded at present that photodiagnosis may lead to a phototoxic damage of the fimbrial mucosa and to a lesser extent of the fallopian tubes because of the strong fluorescence in these tissues, which may be more pronounced with higher doses.

Comment

The hypothesis that fluorescence diagnosis could serve as a diagnostic tool for endometriosis represents an attractive approach. The manifestations of endometriosis are diverse and range from clearly visible nodular implants and cysts to hardly detectable petechial or hemorrhagic areas. These less obvious lesions may be missed easily by laparoscopy, even in skilled hands, and such missed lesions may be responsible for recurrence or persistence of pelvic pain. The potential for selective accumulation of a photosensitizing drug may be useful in the treatment of endometriosis with exposure to photoactivating light. Earlier studies have shown the destruction of endometrial tissue in animal models by photodynamic therapy with topically and systemically applied dihematoporphyrin ether (Photofrin).^{[14] [15]} After intravenous administration of dihematoporphyrin ether, photoactivation by an argon-pumped dye laser resulted in a high degree of destruction of endometrial implants in rabbits, whereas laser damage to implants was minimal in animals that did not receive dihematoporphyrin ether.^[16] Dihematoporphyrin ether has only poor selectivity, however, and consequently generalized exposure of the abdominal cavity to activating light would damage normal intra-abdominal structures. Thus the use of focused light offers no advantage with respect to currently used thermal laser ablation. Furthermore, prolonged skin photosensitization of dihematoporphyrin ether would be unacceptable for clinical practice. These shortcomings have prompted the search for new photosensitizing agents.

Fluorescence of 5-ALA-induced porphyrins was only observed in the endometrium and not in the myometrium of rats after local uterine injection of various doses of 5-ALA. Photoactivation resulted in extensive endometrial damage and was consistent with histologic evidence of complete endometrial ablation.^[17] The endometrial ablation induced by photodynamic therapy with 5-ALA could also significantly reduce the rate of female rat gestation.^[18] Similar results were observed with a rabbit model, in which photodynamic therapy of the endometrium with topical 5-ALA resulted in persistent epithelial destruction. Minimal reepithelialization was noted, however, and may be dependent on variations in optical dosimetry, particularly in the rabbit model.^[19] In human beings intrauterine administration of 5-ALA in vitro and in vivo demonstrated a 9- to 10-fold greater PPIX concentration in the endometrium than in the myometrium, thus reaching a level of photosensitization that should be sufficient for endometrial ablation. However, fluorescence microscopy revealed incomplete endometrial photosensitization after topically applied 5-ALA, which may impair potential therapeutic approaches for photoablation of the endometrium.^[20]

Yang et al^[13] evaluated the 5-ALA-induced fluorescence and photosensitization of experimental endometriosis after systemic 5-ALA administration in rats. Fluorescence intensity of 5-ALA-induced PPIX between 2 and 4 hours after oral and intravenous delivery of 5-ALA was significantly greater in endometriotic lesions than in adjacent normal peritoneum, thus indicating a preferential accumulation of PPIX. Intense fluorescence was seen in skin, bladder, and uterus, whereas peritoneum, bowel mesentery, and eye produced low-intensity fluorescence. Yang et al^[13] concluded that differential fluorescence between active endometriosis and adjacent normal peritoneum may allow the development of this technique for the laparoscopic detection and photodynamic ablation of endometriosis in human beings.

In our study white or red lesions of peritoneal endometriosis achieved a significantly higher level of PPIX fluorescence than did normal peritoneum after oral administration of 10 mg/kg 5-ALA. Usually these lesions are more difficult to detect laparoscopically than are pigmented lesions. Sequential laparoscopic examinations have indicated that nonpigmented endometriotic implants eventually evolve into the typical pigmented lesions.^[21] Nodular and pigmented peritoneal endometriotic lesions and ovarian endometriomas yielded negative fluorescence results and could not be detected by this fluorescence approach. Rarely, tiny false-positive fluorescent spots were visible on video inspection. However, falsepositive results were related to conventional histologic criteria for endometriosis. Occasionally in patients with laparoscopically typical disease biopsy may yield only histologically nondiagnostic tissue.^[22]

Surprisingly, the fimbrial mucosa showed intense fluorescence with oral 5-ALA. This is of some concern, because illumination of porphyrin may cause phototoxic damage. The intensity of 5-ALA-induced porphyrin fluorescence seems to correlate with the extent of the tissue-damaging effect of photodynamic therapy. Divaris et al^[23] demonstrated an increased phototoxic damage to sebaceous glands and hair follicles of mice with an enhanced PPIX fluorescence compared with areas with weak fluorescence. Similar results were reported by Bedwell et al^[24] for the rat colonic tumor model. The pronounced fluorescence of the fimbrial mucosa, and to a lesser extent of the fallopian tubes, on endoscopic imaging suggests the potential of phototoxic damage. Several studies were performed with rat and rabbit models by Wyss et al^{[19] [25]} and Steiner et al^[26] to investigate the impact of photodynamic therapy on the endometrium after topical application of 5-ALA. Histologic studies showed endometrial destruction with atrophy 7 to 10 weeks after treatment. Reproductive performance studies demonstrated significant implantation failure in the treated uterine horns compared with control horns. Because endometrial and tubal glandular epithelia are derived from the mullerian duct and both show a pronounced conversion of 5-ALA to PPIX, tubal epithelium may be at risk. We did not apply such a high light dose for our diagnostic fluorescence assessment as was used in those treatment studies. However, we do know from our photodynamic therapy studies of vulvar lichen sclerosis and vulvar intraepithelial neoplasia after topical 5-ALA application that the diagnostic fluorescence detection may induce localized vulvar pain, which indicates a limited phototoxic effect.^{[9] [27]} From our data it is too early to estimate any effects on tubal morphologic characteristics or function. Patients are being followed up to assess this issue. Because of the possibility of tubal damage and the positive fluorescence of active endometriosis after the 10-mg/kg dosage, however, we did not evaluate higher doses of 5-ALA, such as 20 mg/kg body weight. We therefore cannot rule out that higher doses might lead to the detection of lesions not detected with lower doses.

Theoretically exposure to white light may impair fluorescence assessment as a result of photobleaching. At its maximum setting the white light of the system we used, which leads to excitation of PPIX and thus may cause photobleaching, has a power output in the wavelength range of about a fifth compared to the fluorescence mode. To minimize the photobleaching effect of differential exposures to white light we kept the time interval for white light exploration of the intra-abdominal sites as short as possible and reduced the white light output power. In practice we observed photobleaching only during photodiagnosis; that is, real-time fluorescence imaging and spectral measurements. It was therefore important to limit the time of fluorescence imaging, because the photobleaching effect leads to a reduced fluorescence intensity, thereby influencing the spectral measurements and making interpatient comparison of the fluorescence data difficult.

For optimal fluorescence diagnosis knowledge of concentration of photosensitizer and time course of fluorescence intensity in the examined tissue is essential. In this study the dosage of 1 mg/kg body weight 5-ALA orally was too low for sufficient endoscopic fluorescence detection. Between 3 and 5 hours after oral 5-ALA application at 10 mg/kg body weight high values of 5-ALA-induced porphyrin fluorescence in the abdominal cavity were observed. This interval is consistent with findings in endometrium and endometriotic implants from various studies of animal models. ^{[13] [19] [20]} As opposed to animal studies, the interval of 6 hours between oral 5-ALA administration and endoscopic fluorescence assessment still revealed a high fluorescence, which was sufficient for diagnosis within the abdominal cavity. Intervals >6 hours may yield a sufficient fluorescence intensity; however, we did not assess those longer incubation intervals. From our data we can recommend an application interval of 3 hours. An application interval of <3 hours gave no fluorescence or only weak fluorescence of the fimbrial mucosa, which in our opinion can be used as an internal standard because of its strong porphyrin fluorescence.

At present the clinical implementation of 5-ALA-induced photosensitization for the detection of endometriosis is rather questionable. Young women of reproductive age with problems of infertility are an important subgroup of patients with endometriosis. Because preservation of the tubal and fimbrial mucosa is crucial for fertility, these patients may have to be excluded from 5-ALA-induced porphyrin fluorescence detection for endometriosis until more data are available to assess phototoxic damage to the fallopian tubes.

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