Histologic evaluation of bronchial squamous lesions: any role in lung cancer risk assessment?

Lung cancer is the leading cause of cancer deaths in the United States and worldwide, and the high mortality of this disease is primarily due to the fact that the majority of the lung cancers are diagnosed at advanced stages (1) when the options for treatment are mostly palliative. Experience with other epithelial tumors, such as uterine cervical, esophageal, and colon carcinomas, has shown that if neoplastic lesions can be detected and treated at their intraepithelial stage the cure rate can be improved significantly. Thus, to reduce the mortality of lung cancer, new techniques and approaches must be developed to diagnose and treat preinvasive lesions. However, lung cancer represents an enormous challenge. From histopathologic and biological perspectives, lung cancer is a highly complex neoplasm (2), probably having multiple preneoplastic pathways (3). Lung cancer consists of several types, including small cell carcinoma (20%) and the non–small cell carcinoma types squamous cell carcinoma (30%), adenocarcinoma (including the noninvasive type of bronchioloalveolar carcinoma; 40%), and large cell carcinoma (10%; ref. 4). Lung cancer may arise from the major bronchi (central tumors) or from the distant airway bronchioles and alveoli (peripheral tumors) of the lung. Squamous cell carcinoma and small cell carcinoma usually arise centrally, whereas adenocarcinoma and large cell carcinoma usually arise peripherally. Because examination of the sputum and bronchoscopy specimens examines the central airways, whereas spiral computed tomography mainly detected peripheral tumors, different approaches are required for the detection of tumors in different compartments of the lung. As with other epithelial malignancies, lung cancers are believed to arise after a series of progressive pathologic changes (preneoplastic lesions; ref. 5). Many of these preneoplastic changes are frequently accompanying lung cancers and may be present in the respiratory mucosa of smokers. Although the sequential preneoplastic changes have been defined for centrally arising squamous carcinomas of the lung, they have been poorly documented for large cell carcinomas, adenocarcinomas, and small cell carcinomas. Mucosal changes in the large airways that may precede or accompany invasive squamous cell carcinoma include hyperplasia (basal cell hyperplasia and goblet cell hyperplasia), squamous metaplasia, different grades (mild, moderate, and severe) of squamous dysplasia, and carcinoma in situ (4). Whereas hyperplasia and squamous metaplasia are considered reactive and reversible changes, dysplasias and carcinoma in situ are the changes most frequently associated with the development of squamous cell lung carcinomas. To improve bronchoscopic detection of the squamous preneoplastic lesions of the bronchial tree, laser-induced fluorescence bronchoscopy has been developed to detect high-grade carcinoma (moderate to severe) and carcinoma in situ by tissue autofluorescence (6, 7). Several studies have shown that the use of fluorescent bronchoscopy improves the detection rate of high-grade squamous preneoplastic changes compared with standard white light bronchoscopy (6, 8). In the last decade, several studies have provided some information regarding the molecular characterization of the premalignant changes involved in the squamous carcinoma pathway (reviewed in ref. 3). The current working model of the sequential molecular abnormalities in the pathogenesis of squamous cell lung carcinoma indicates that (a) genetic abnormalities commence in histologically normal epithelium and increase with increasing severity of histologic changes (9); (b) mutations follow a sequence, with allelic losses at multiple 3p chromosome sites as the earliest detected change (10, 11); (c) molecular changes in the respiratory epithelium are extensive and multifocal throughout the bronchial tree of smokers and lung cancer patients, indicating a field effect (‘‘field cancerization’’) by which much of the respiratory epithelium has been mutagenized, presumably from exposure to tobacco-related carcinogens (12, 13); and (d) multiple clonal and subclonal patches of molecular abnormalities (not much larger in size than the average bronchial biopsy obtained by fluorescent bronchoscopy) can be detected in the normal and slightly abnormal bronchial epithelium of patients with lung cancer (14). Despite all this knowledge, histopathologic evaluation remains as the ‘‘gold standard’’ end point for lung cancer risk assessment, chemoprevention monitoring, and early detection strategies. In the January 15 issue of Clinical Cancer Research , Breuer et al. (15) report a longitudinal study addressing the natural histopathologic course of squamous preneoplastic lesions in bronchial epithelium obtained using white light and fluorescent bronchoscopy examinations. Although similar studies on the natural history of lung squamous preneoplastic lesions have been done in the past using sputum and tissue specimens, the relatively lack of information on this important issue makes Received 10/21/04; accepted 10/27/04. Grant support: NIH Grant 1PO1 CA91844-03. Requests for reprints: Ignacio I. Wistuba, Departments of Pathology and Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Box 85, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-1659; Fax: 713-745-5493; E-mail: [email protected]. D2005 American Association for Cancer Research. Vol. 11, 1358–1360, February 15, 2005 Clinical Cancer Research 1358