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Ann Thorac Surg 2001;71:967-970
© 2001 The Society of Thoracic Surgeons

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Original article: general thoracic

Postoperative fluorescence bronchoscopic surveillance in non–small cell lung cancer patients

^a Thoracic Surgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
^b Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
^c Section of Thoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

Address reprint requests to Dr Weigel, Thoracic Surgery Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021
e-mail: weigelt{at}mskcc.org

Presented at the Poster Session of the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Second lung primaries occur at a rate of 1% to 3% per patient-year after complete resections for non–small cell lung carcinoma (NSCLC). Fluorescence bronchoscopy appears to be a sensitive tool for surveillance of the tracheobronchial tree for early neoplasias.

Methods. Patients who were disease-free after complete resection of a NSCLC were entered into a fluorescence bronchoscopy surveillance program. All suspicious lesions were biopsied along with two areas of normal mucosa to serve as negative controls.

Results. A total of 73 fluorescence bronchoscopies were performed after conventional bronchoscopy in 51 patients at a median of 13 months postresection. The majority (46 of 51) of patients had stage I or II NSCLC, whereas 10% (5 of 51) had stage IIIA. Three intraepithelial neoplasias and one invasive carcinoma were identified in 3 of 51 patients (6%), all current or former smokers. Of the four lesions identified, three were in the 20 patients with prior squamous cell carcinomas. No intraepithelial neoplasias were identified by white-light bronchoscopy, whereas two of three were detected by fluorescence examination. The one invasive cancer detected was apparent on both white-light and fluorescence bronchoscopic examinations.

Conclusions. Surveillance with fluorescence bronchoscopy identified lesions in 6% of postoperative NSCLC patients thought to be disease-free. Patients with prior squamous cell carcinomas appear to be a population that may warrant future prospective study of postoperative fluorescence bronchoscopic surveillance.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Standard postoperative surveillance practices vary for patients with non–small cell lung cancer who have undergone complete resections. Clinically significant second primaries are diagnosed in patients with prior NSCLCs at a rate of 1% to 3% per patient per year [1, 2]. Autopsy data suggest that the incidence of carcinoma in situ in the tracheobronchial tree of non–small cell lung cancer (NSCLC) patients may be as high as 15% [3]. The peak incidence of second primaries appears to be in year 3 to 8 postresection [4] and to increase over time [1, 5]. Despite postoperative follow-up, only 50% of second primaries are resectable. At the time of their diagnosis, 19% are locally advanced, 6% are associated with metastatic disease, and 20% occur in patients who are not surgical candidates because of insufficient pulmonary reserve [1]. Currently, the 5-year survival after complete resection of a second lung primary remains only 20% [1].

Routine postoperative chest roentgenograms are neither sensitive nor specific for detection of second lung primaries. Computed tomography can accurately identify and characterize subcentimeter parenchymal nodules [6], but early endobronchial lesions often go undetected. Sputum cytology can detect endobronchial lesions but is not able to localize these lesions. Surveillance using conventional white-light bronchoscopy can identify 69% of microinvasive endobronchial tumors but only 29% of carcinomas in situ [7]. Fluorescence bronchoscopy is nearly six times as sensitive as white-light bronchoscopy in the identification of intraepithelial neoplasias (IENs), including moderate or severe dysplasia and carcinoma in situ [8]. Potentially, postoperative surveillance with fluorescence bronchoscopy could lead to earlier detection of tracheobronchial second primaries that may then be amenable to less invasive, curative endobronchial ablative therapies.

The primary aim of this study was to determine the prevalence of intraepithelial, microinvasive, and occult endobronchial lesions in postresection, non–small cell lung cancer patients who were considered to be disease-free by routine follow-up. Our secondary aims were to determine the utility of fluorescence versus white-light bronchoscopic surveillance in postresection NSCLC patients, as well as the correlation of index tumor histology with the development of second endobronchial NSCLC primaries.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Protocol
Patients treated by the Section of Thoracic Surgery at the University of Pittsburgh who had undergone complete surgical resection for NSCLC and were disease-free by routine follow-up were recruited at the time of their scheduled follow-up clinic visit or from a prospectively collected database. As this was a prevalence study, there was no set interval from time of resection to study entry. Patients were entered into an IRB-approved protocol at the University of Pittsburgh Cancer Institute for fluorescence bronchoscopic surveillance in postresection NSCLC patients and informed consent was obtained.

Bronchoscopic examination
All bronchoscopic examinations were conducted as outpatient procedures using topical anesthesia and conscious sedation, as previously described [9]. All bronchoscopies were done by a single thoracic surgeon trained in fluorescence bronchoscopy. Conventional white-light bronchoscopy was carried out first using an Olympus BF20D (Olympus America Inc, Melville, New York) fiberoptic bronchoscope. After completion of the white light bronchoscopic examination, fluorescence bronchoscopy was performed using the Xillix LIFE-Lung System. This system uses a helium-cadmium laser to generate 12 to 15 mW of noncollimated blue light at the distal end of an Olympus BF20 bronchoscope. The resulting autofluorescence of the tracheobronchial mucosa and submucosa is simultaneously captured in the red (> 630 nm) and green (480–520 nm) spectra and displayed in virtual real time on a color monitor.

Clinical classification
Lesions were classified visually into one of three clinical categories on each bronchoscopic examination according to the classification system used by Lam and colleagues [8] (Table 1). This system classifies endobronchial abnormalities into three categories ranging from visually normal mucosa to bronchial abnormalities that are considered likely to be invasive carcinomas. Classifications assigned to mucosal lesions during white-light bronchoscopy were not modified once the fluorescence bronchoscopic examination was begun. All class II and class III lesions noted on either bronchoscopic examination were biopsied in triplicate, along with a minimum of six biopsies from two separate class I sites, to serve as normal controls (true negatives).

	Results

Top Abstract Introduction Material and methods Results Comment References

The histologies of the 51 primary tumors included: 20 squamous cell carcinoma, 22 adenocarcinoma and 9 other histologies. Resection of the original NSCLC was achieved by a lobectomy in 35 patients, wedge resection in 7, sleeve lobectomy in 2, pneumonectomy in 6 and lingulectomy in one patient. At the time of bronchoscopic surveillance, 10 patients were current smokers, 31 were former smokers, and 8 were nonsmokers. The median number of pack-years for smokers was 60. In former smokers, the median duration of smoking cessation was 3 years. There were no complications attributable to the 73 bronchoscopies (white light and fluorescence) performed over the 17-month study period.

A total of four lesions (three IENs and one invasive carcinoma) were identified in 3 of the 51 (6%) postresection patients who underwent fluorescence surveillance (Fig 1 and 2). Fluorescence bronchoscopy accurately identified three out of four of these lesions as compared to only one of four by white-light bronchoscopy. Two of the three IENs were identified on fluorescence examinations, whereas none were identified with white-light bronchoscopy. A random biopsy of visually-normal mucosa, ie, class I on both conventional and fluorescence bronchoscopy, identified the final IEN. The addition of the fluorescence examination to conventional white-light bronchoscopy increased the overall sensitivity of postoperative surveillance threefold.

View larger version (111K): [in this window] [in a new window]   Fig 1. Arrow points to right upper lobe (class III) carcinoma in situ on conventional white-light bronchoscopy.

View larger version (105K): [in this window] [in a new window]   Fig 2. Class III fluorescence bronchoscopy image corresponding to image in Figure 1. Carcinoma in situ, reddish-brown lesion, is identifiable at 6 o’clock. Bright green areas represent normal mucosa.

The identification of an invasive carcinoma in 1 patient who was not considered to be a surgical candidate led to treatment with chemotherapy and radiation. Another patient found to have two IENs elected observation only; fluorescence bronchoscopy–guided biopsies of both lesions were negative at 6 months of follow-up. The last patient in whom an IEN was diagnosed also elected no therapy, and serial repeat biopsies were negative over 18 months of follow-up. Overall, a new therapeutic intervention (chemotherapy and radiation therapy) was initiated as a direct consequence of bronchoscopic surveillance in 1 of 51 (2%) of the postresection patients in this study.

	Comment

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A recent collective review of 1406 patients with occult or stage I completely resected lung carcinomas reported an 11.4% (range 3% to 30%) incidence of second primary lung cancers [11]. Historically, 20% to 64% of second lung primaries are stage III or IV at the time of diagnosis [12]. Overall, patients who develop second NSCLC primaries have only a 20% 5-year survival and limited surgical treatment options. Nearly 60% of second lung primaries in NSCLC patients are squamous cell carcinomas [4] potentially located proximal enough in the tracheobronchial tree to be detectable with bronchoscopic surveillance.

The histology of the primary (index) tumor appears to correlate with the risk of developing a second primary lung cancer. Levi and colleagues [13] recently reported a cumulative risk of developing a second lung primary after a prior squamous cell lung cancer of 2.8% at 5 years and 6.5% at 10 years, compared to 1.8% and 4.7%, respectively, for all histologies. In the present study, the detection rate of second lung primaries in patients whose index tumors were squamous cell carcinomas was 15% as compared to only 3.2% in patients with prior nonsquamous lung cancers. Postoperative fluorescence bronchoscopic surveillance in patients with prior squamous cell cancers could potentially expand the options for less invasive curative treatment that are available to these patients by identifying lesions at the intraepithelial stage.

The three IENs identified in this study were all absent (and were believed to have regressed) on repeat examination. The fact that one surgeon performed all the examinations and all lesions were rebiopsied after reviewing prior fluorescence bronchoscopic examinations, and that one pulmonary pathologist reviewed all biopsy specimens, diminishes the likelihood of misdirected biopsies or interpathologist variability. Currently it is estimated that 10% of moderately dysplastic and 40% to 83% of severely dysplastic lesions will progress to invasive carcinomas [8]. The true natural history of IENs, however, remains to be defined and is potentially one of the most important roles of fluorescence bronchoscopic surveillance in patients in whom the incidence of IENs is relatively high.

Our study size is small and our data preliminary. However these data, along with reports by others, suggest that larger prospective studies to identify patient populations that might benefit from fluorescence bronchoscopic surveillance are warranted [8, 14]. At present, the cost of fluorescence bronchoscopy prohibits its widespread use as a screening tool. Despite efforts to streamline the procedure, fluorescence bronchoscopy will remain, at least in the near future, a research tool. Periodic surveillance with fluorescence bronchoscopy may help to define better the clinical significance of IENs and to explore the process of tracheobronchial carcinogenesis. The appropriate timing of fluorescence bronchoscopic surveillance and its impact on survival, if any, remain to be determined in future studies.

	References

Top Abstract Introduction Material and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Tracey L. Weigel Valerie W. Rusch Robert J. Ginsberg James D. Luketich Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weigel, T. L. Articles by Luketich, J. D. Search for Related Content PubMed PubMed Citation Articles by Weigel, T. L. Articles by Luketich, J. D. Related Collections Lung - cancer