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PRRLIWIRARX RESULTS FROM SCRRRRIRG PATIRSTS AT EIQR RISK FOR LUNG WCRR TRROUOE DIAGHOSTIC PROTOCOL COWBIWIR~ SPUTUN C YTOLQGIAKD FLUORKSCKRCK BRORCROSCOPI Timothy Kennedy, Susan Proudfoot, Wilbur Franklin. Lung Cancer Institute of Colorado; univ. of Colorado Health Science5 Center, Denver, Colorado, U.S.A.

Introduction: The University of Colorado Cancer Center recently received a lung cancer "Specialized Program of Research Excellence (SPORE)" grant from the National Cancer Institute. Because of the general hypothesis that lung cancer mortality can be reduced if detected earlier in its progression, this program is dominated by prevention and early detection trials. The population of interest for these trials are patient5 with moderate to severe dysplasia and carcinoma in situ. To identify such patients, a regional system for screening patient5 through sputum cytology was established. This paper reviews: (1) the background and significance of the screening system; (2) the cytologic results of enrolled subjects; and (3) the histologic results of selected subject5 who underwent fluorescence bronchoscopy utilizing an experimentalendoecopy, lung imaging system developed by scientists at the British Columbia Cancer Research Centre, Vancouver, British Columbia. (Entitledthe Lung Imaging Fluorescence Endoecope (LIFE), this device was developed to detect dysplasia and neoplasia through tissue autofluorescence.)

Background and Significance: Patient5 eligible for the SPORE sputum screening eystem must have spirometer-confirmed diagnose5 of airflow obstruction and smoking histories of 40 or more pack years. Such patient5 were targeted because studies have shown an association between airflow obstruction, the risk for lung cancer, and smoking status (l-3). When controlling for the effect5 of cigarette smoking, the National Cancer Institute (NCI) Early Detection Trial conducted at John5 Hopkins Medical Inetitutione found that the rate of primary lung cancer occurrence was approximately 11.4/1,000 per year in a population of obstructed cigarette smokers as compared to 3.5/1,000 in non-obstructed smokers (4). In a subsequent report by Euller, it was confirmed that the risk for lung cancer increase5 in proportion to the degree of airflow obstruction and length of smoking (5). The consistency of these results suggests that it may be possible to identify smokers/ex-smokers at high risk for lung cancer by detecting the presence of airway obstruction. An equally important predictor of lung cancer risk is the degree of dysplasia identified through sputum cytology. In a report by Band and Saccomanno, it was found that approximately 75% of patient5 with severe atypia eventually presented with lung carcinoma (6). Similar results were observed by Johnston who conducted a follow-up study of 70 patient5 with atypical metaplaaia; 40% had subsequent tissue confirmation of lung cancer (7). These finding5 support the premise that obstructed, long-term smokers/ex-smokers with abnormal cytology are a group particularly suitable to target for early detection studies.

Methods: In the SPORE sputum screening system, subjects provide sputum specimens through performance of the spontaneous, early morning cough technique at home. specimens are processed and evaluated at: Presbyterian/St. Luke's Medical Center; Denver Veterans Administration Medical Center; and St. Mary’s Hospital and Medical Center in Grand Junction, Colorado.

Patients diagnosed with moderate dysplasia or greater are solicited to undertake an experimental fluorescence bronchoscopy (utilizing the LIFE device). In conformance with the protocol of the LIFE validation trial (Study Chairperson: Stephen Lam, M.D., F.R.C.P.), subjects undergo routine, white-light bronchoscopy first followed by fluorescence examination. Allidentifiedlesions classified as suspicious during both examinations are biopsied; two random biopsies from visually normal area5 in a upper or lower lobe are also procured. In addition, brushings, washings, and lavagee are collected. Bronchial specimen5 are subsequently forwarded to the SPORE Tissue Bank CORE (TBC) laboratory (housed at University of Colorado Health Sciences Center). At the TBC laboratory, bronchial specimen5 are later characterized in term5 of: (1) histologic diagnosis; (2) quality of material submitted; (3) proportion of material consideredviable anddysplastic/neoplastic; and (4) biomarkerexpressionbyindividual cellular populations.

Preliminary Results: Across the past12 months, 204 patient cases have been cytologi- cally diagnosed by the SPORE sputum screening system's panel of pathologists. In Table 1 below, the sputum cytology results of these cases are presented. Of the 26 patient5 with moderate dysplasia or greater, 4 subjects (all moderate dysplastic cases) have

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undergone fluorescence bronchoscopy with the LIFE device to date. Biopsies from two subjects showed evidence of dysplasia; one subject was diagnosed with squamous carcinoma in situ; biopsies from the fourth subject were tentatively diagnosed as normal epithelium. These impressionistic results suggest a correlation between our sputumcytology and fluorescence bronchoscopy results. Statistical analyses conducted on a larger sample are needed to confirm this association and to assess possible diagnostic implications.

Table 1: Breakdownof Cvtolosic Result8 from Patient Cases EvaluatedThrouqhthe SPORE Snutum Screenina System.'

DvsDlasia Grades No. (%) of Cases

1. No significant abnormalities 39 (19) 2. Regular metaplasia 37 (18) 3. Mild dysplasia 69 (34) 4. Moderate dysplasia 24 (12) 5. Severe dysplasia 1 (.05) 6. Carcinoma in situ 0 ( 0) 7. Invasive carcinoma 1 (.05)

'33 (16%) cases were deemed unsatisfactory for interpretation.

DiscusSion: Preliminary studies by Lam and associates have found that the LIFE system can be useful in localizing and detecting early lung cancer (8, 9). Our preliminary data suggest that the LIFE device can be potentially valuable as a research tool because of its ability to detect premalignant lesions. Certainly, the localization, biopsy, and even culture of precancerous colonies enable the study of the genetic alterations, growth factors, and cytologic changes in pre-neoplastic cases.

Fluorescence bronchoscopy devices such as LIFE can also be potentially helpful in validatingnewtechniques for sputumassessmentwhetherthey arebiomarkers, monoclonal antibodies, cytogenetic probes, or robotic microscopes. with such new techniques, serial cytologic examinations may indeed be reconsidered as a viable lung cancer screening strategy. Certainly, the recent findings Bechtel and colleagues support this premise (10).

For the SPORE, we selected subjects with airflow obstruction and abnormal sputum cytology as a target population because of the anticipated higher yield of dysplastic cases and the large, easily identified number of subjects available throughout the local community. Since 13% of our sample population to date have at least moderate dysplasia and in such a group, the yield from white-light bronchoscopy in finding carcinoma can be as high as lo%, we will continue to bronchoscope all willing SPORE subjects utilizing fluorescent light for both clinical and research purposes.

References:

8. 9. 10.

Cohen, BH. Am J Epidemiol 113:274-88, 1980. Davis, AL. JAMA 235:621-2, 1976. Skillrud, DM, et al. AM Intern Med 105:503-7, 1986. To&man, MS, et al. Ann Int Med 106:512-518, 1987. Kuller, LH, et al. Am J Epid 132:265-74, 1990. Band, PR, et al. Cancer Detect Prev 9:157-60, 1986. Johnston, WW. Acta Cytol 26:759-66, 1982. Lam, S, et al. Lasers Surg Med 4:40, 1992. Lam, S, et al. Lung Cancer 7~47, 1991. Bechtel, J, et al. Arch Intern Med (in press).