CORRESPONDENCE

Re: Autofluorescence Bronchoscopy in the Detection of Squamous Metaplasia and Dysplasia in Current and Former Smokers

Stephen Lam, Branko Palcic

Affiliations of authors: S. Lam (Department of Respiratory Medicine), B. Palcic (Department of Cancer Imaging), British Columbia Cancer Agency, Vancouver, Canada.

Correspondence to: Stephen Lam, M.D., FRCPC, 601 West 10th Ave., Vancouver, BC, Canada V5Z 1L3 (e-mail: slam{at}bccancer.bc.ca).

Kurie et al. (1) reported in a group of 39 subjects that fluorescence bronchoscopy with the LIFE(TM) (laser-induced fluorescence emission) device did not improve the detection of squamous metaplasia or dysplasia. LIFE was approved by the U.S. Food and Drug Administration for localization of high-grade preinvasive bronchial lesions (moderate/severe dysplasia and carcinoma in situ) that are of prognostic significance. Previous studies (2,3) showed that 10% of subjects with moderate dysplasia and 40%-83% with severe dysplasia would develop invasive cancer. In contrast, metaplasia and mild dysplasia are associated with no increased risk or a very low risk of lung cancer (3). Because of this, LIFE was designed to discriminate between high- and low-grade preneoplastic lesions to minimize false-positive biopsy findings (4,5). Kurie et al. (1) found that only 6.5% of the biopsy specimens classified as normal, hyperplasia, metaplasia, or mild dysplasia exhibited class III abnormal fluorescence. This low false-positive rate compares very favorably with the 20%-30% rate with other imaging tests (computed tomography, magnetic resonance imaging, or positron emission tomography) for lung cancer. In addition, Kurie et al. (1) reported that 15.4% of their subjects had mild dysplasia with LIFE compared with 5.7% of the subjects in a historic control group examined with conventional white-light bronchoscopy. The 2.7-fold improvement is similar to that in other studies for high-grade preinvasive lesions (4-6).

Why then did the study by Kurie et al. (1) fail to find a single high-grade preinvasive lesion? We believe that one key problem may be with the pathologic interpretation. The accompanying editorial (6) also suggested that the pathologic interpretation is a potential problem. An outside pathologist found 18 dysplastic lesions versus the original eight in an independent review of the biopsy specimens.

Another likely possibility is the subjective interpretation of the fluorescence images, similar to that for conventional white-light bronchoscopy. In the multicenter clinical trial (5), an overall 6.3-times improvement in the detection of high-grade preinvasive lesions was observed with the use of LIFE, yet one of the seven participating centers (the one that enrolled the lowest number of subjects) did not detect any of these lesions either.

A third possibility relates to differences in the study populations. In our previous study (4) in 48 current and 19 former smokers without a history of cancer in the upper aerodigestive tract and a much larger study (unpublished results) involving 212 men and 189 women, former smokers differed from current smokers in a lower prevalence of mild dysplasia and metaplasia only. High-grade preinvasive lesions persisted even after smoking cessation for 10 years or more. These findings are in keeping with the finding of numerous genomic abnormalities among former smokers (7). An important observation in our above-mentioned more recent study was the statistically significant finding of a lower prevalence of high-grade lesions among women (13% in women versus 31% in men; odds ratio = 0.36; 95% confidence interval = 0.21-0.60). This sex difference may explain in part the low yield of these lesions in the study by Kurie et al., where 46% of the subjects were women.

In summary, LIFE was not designed or intended to be used for the detection of squamous metaplasia, which can be caused by various nonspecific effects of irritants on the airways (in addition to tobacco smoke) and, thus, may not be related to the carcinogenic effects of tobacco smoking.

NOTES

S. Lam is currently conducting research with Xillix Technologies, Inc., the manufacturer of the LIFE device. B. Palcic is a stockholder of Xillix Technologies, Inc.

REFERENCES

1 Kurie JM, Lee JS, Morice RC, Walsh GL, Khuri FR, Broxson A, et al. Autofluorescence bronchoscopy in the detection of squamous metaplasia and dysplasia in current and former smokers. J Natl Cancer Inst 1998;90:991-5.[Abstract/Free Full Text]

2 Risse EK, Vooijs GP, van't Hof MA. Diagnostic significance of "severe dysplasia" in sputum cytology. Acta Cytol 1988;32:629-34.[Medline]

3 Frost JK, Ball WC Jr, Levin ML, Tockman MS, Erozan YS, Gupta PK, et al. Sputum cytopathology: use and potential in monitoring the workplace environment by screening for biological effects of exposure. J Occup Med 1986;28:692-703.[Medline]

4 Lam S, MacAulay C, LeRiche JC, Ikeda N, Palcic B. Early localization of bronchogenic carcinoma. J Diagn Therap Endoscopy 1994;1:75-8.

5 Lam S, Kennedy T, Unger M, Miller YE, Gelmont D, Rusch V, et al. Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest 1998;113:696-702.[Abstract/Free Full Text]

6 O'Neil KM, Johnson BE. Lights flicker on fluorescence bronchoscopy in patients at risk for lung cancer [editorial]. J Natl Cancer Inst 1998;90:953-5.[Free Full Text]

7 Wistuba II, Lam S, Behrens C, Virmani AK, Fong KM, LeRiche JC, et al. Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst 1997;89:1366-73.[Abstract/Free Full Text]


 
Ben J. Venmans, Egbert F. Smit, Pieter E. Postmus, Thomas G. Sutedja

Affiliation of authors: Department of Pulmonary Diseases, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.

Correspondence to: Thomas G. Sutedja, M.D., Ph.D., Department of Pulmonary Diseases, University Hospital Vrije Universiteit, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands (e-mail: tg.sutedja{at}azvu.nl).

We read with interest the report by Kurie et al. (1). They compared white-light bronchoscopy with fluorescence bronchoscopy using the LIFE(TM) (laser-induced fluorescence emission) system and concluded that the LIFE system did not improve the detection of squamous metaplasia or dysplasia of the proximal airways. As was pointed out by O'Neil and Johnson in their editorial (2), reasons that the LIFE system did not improve detection may have been due to the large interobserver variation between pathologists, the number of biopsy specimens taken, and the low prevalence of premalignant lesions in the population studied. The last reason is supported by the fact that they found only mild dysplasia and no moderate to severe dysplasia or carcinoma in situ. Besides these comments, the conclusion may be questionable because of further mistakes in the design of the study. The first and most important criticism is the use of a historical control group, probably investigated by a number of bronchoscopists, instead of the performance of a randomized study. Second, it is unrealistic to expect that one bronchoscopist would get sufficient experience in interpreting the results of LIFE in such a limited number of patients with so few abnormalities as were found in these patients. This study was performed by two bronchoscopists.

Data obtained in our institution support these comments. From November 1995 through December 1997, we performed white-light bronchoscopy and fluorescence bronchoscopy with the LIFE device in 95 patients with suspected or known lung cancer (n = 64), during follow-up after treatment for lung or head and neck cancer (n = 25), or for other reasons (not cancers, e.g., carcinoma in situ, evidence of malignancy in sputum cytology) (n = 6). There were 16 current smokers, 52 former smokers, and two never smokers. Smoking status was unknown for 25 patients. Of 742 biopsy specimens obtained during 174 bronchoscopies, 681 (92%) were representative. Moderate dysplasia was found in 31 biopsy specimens, severe dysplasia in 39 biopsy specimens, and carcinoma in situ in nine biopsy specimens. A statistically significant increase in the number of premalignant lesions was detected if LIFE was added to white-light bronchoscopy (relative sensitivity = 1.43; 95% confidence interval = 1.16-1.75). In a subgroup of patients, the first bronchoscopy (LIFE or white-light bronchoscopy) was randomly assigned. This random assignment of case subjects did not affect the assessment of premalignant lesions (3). In agreement with Kurie et al. (1), we found a considerable discrepancy between pathologists (kappa = 0.56). Since one bronchoscopist performed all bronchoscopies, we could analyze the effect of experience on the detection rate. In the second half of the group, the results of LIFE during the first bronchoscopy for each patient were better (86% sensitivity in the second half versus 67% sensitivity in the first half). Based on these results, the conclusions of Kurie et al. (1) seem to be premature. It is our opinion that the use of LIFE remains a viable detection method for those individuals who are at high risk for lung cancer.

REFERENCES

1 Kurie JM, Lee JS, Morice RC, Walsh GL, Khuri FR, Broxson A, et al. Autofluorescence bronchoscopy in the detection of squamous metaplasia and dysplasia in current and former smokers. J Natl Cancer Inst 1998;90:991-5.[Abstract/Free Full Text]

2 O'Neil KM, Johnson BE. Lights flicker on fluorescence bronchoscopy in patients at risk for lung cancer [editorial]. J Natl Cancer Inst 1998;90:953-5.[Free Full Text]

3 Venmans BJ, van der Linden JC, van Boxem AJ, Postmus PE, Smit EF, Sutedja G. Early detection of pre-invasive lesions in high risk patients. A comparison of conventional fiberoptic and fluorescence bronchoscopy. J Bronchol 1998;5:280-3.


 

RESPONSE

Jonathan M. Kurie, Jin S. Lee, Rodolfo C. Morice, Waun K. Hong

Affiliation of authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston.

The LIFE(TM) (laser-induced fluorescence emission) bronchoscopy is approved as an adjunct to white-light bronchoscopy; however, we could not confirm its utility in the detection of early premalignant lesions such as squamous metaplasia or dysplasia in current and former smokers without known active or suspected lung cancer (1). Because of this discrepancy, we have analyzed the recent data published on the LIFE system (2,3). We interpret these data quite differently from other investigators. Most notably, there were many more biopsy specimens taken from abnormal-looking sites under LIFE bronchoscopy than under white-light bronchoscopy. Obviously, if more biopsy specimens are taken, there is a greater chance of detecting premalignant lesions. Despite this caveat in the study design, the other investigators reported that LIFE bronchoscopy enhances the sensitivity of detecting premalignant lesions. However, in the series of 700 biopsy specimens reported by Lam et al. (2), it is worthwhile to note that LIFE bronchoscopy enhanced the sensitivity of white-light bronchoscopy more when the invasive carcinomas were excluded from the analysis than when they were included in the analysis (i.e., the ratio of sensitivity of LIFE bronchoscopy over white-light bronchoscopy = 6.3 versus 2.71).

In our opinion, the importance of LIFE bronchoscopy lies in its ability to predict the presence and absence of bronchial premalignancy and invasive carcinomas (i.e., positive and negative predictive values). Based on this standard, the benefit of LIFE bronchoscopy is not impressive. As shown in Table 1,Go positive predictive values of LIFE and white-light bronchoscopy were 33.3% and 39.3%, respectively, for the series reported by Lam et al. (2) and 19.7% and 40.7%, respectively, for the series reported by Venmans et al. (3). Our study demonstrated no benefit derived from LIFE bronchoscopy. At best, the positive predictive value was 6.3%, which is basically identical to the result of 7.8% for the biopsy specimens taken from negative areas by LIFE bronchoscopy. Certainly, differences in study population and interobserver variation in bronchoscopic evaluation of the premalignant lesions and pathology reading might have contributed to this difference, as suggested by us as well as others. However, it should be pointed out that all of the subjects in our study, including those in the white-light bronchoscopy group, had bronchoscopy done by one of two investigators and all pathology slides were interpreted by the same pathologist.


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Table 1. Detection of abnormal pathology findings in the bronchial biopsy samples obtained under LIFE (laser-induced fluorescence emission) bronchoscopy versus white-light bronchoscopy

 
Taken together with the issue of user dependence as pointed out in the corresponding letter, which makes LIFE bronchoscopy impractical for a large-scale community-based trial, it seems legitimate to raise concerns about its utility in a clinical setting of screening and early detection of premalignant lesions for chemoprevention trials (4). Regarding the comment on the genetic alterations, we observed a high prevalence of clonal genetic alterations in these bronchial biopsy samples (5), which is similar to the prevalence reported for the lesions showing dysplasia by the Vancouver group (6). In summary, we believe that the data so far presented do not support the routine use of LIFE bronchoscopy for the detection of premalignant lesions in the bronchial mucosa.

REFERENCES

1 Kurie JM, Lee JS, Morice RC, Walsh GL, Khuri FR, Broxson A, et al. Autofluorescence bronchoscopy in the detection of squamous metaplasia and dysplasia in current and former smokers. J Natl Cancer Inst 1998;90:991-5.[Abstract/Free Full Text]

2 Lam S, Kennedy T, Unger M, Miller YE, Gelmont D, Rusch V, et al. Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest 1998;113:696-702.[Abstract/Free Full Text]

3 Venmans BJ, van der Linden H, van Boxem TJ, Postmus PE, Smit EF, Sutedja TG. Early detection of preinvasive lesions in high-risk patients. J Bronchol 1998;5: 280-3.

4 O'Neil KM, Johnson BE. Lights flicker on fluorescence bronchoscopy in patients at risk for lung cancer [editorial]. J Natl Cancer Inst 1998;90:953-5.[Free Full Text]

5 Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst 1997;89:857-62.[Abstract/Free Full Text]

6 Thiberville L, Payne P, Vielkinds J, LeRich J, Horsman D, Nouvet G, et al. Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus. Cancer Res 1995;55: 5133-9.[Abstract]


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