Enriching the Molecular Definition of the Airway “Field of Cancerization:” Establishing New Paradigms for the Patient at Risk for Lung Cancer

Field of Cancerization

In seminal studies defining histologic changes in oral malignancies, Slaughter and colleagues first used the term “field cancerization” to describe the histologically normal-appearing tissue adjacent to neoplastic lesions that display molecular abnormalities, some of which are the same as those in the tumors (1). Since that time, investigators have attempted to define the underlying molecular events leading to field cancerization in several different epithelial malignancies, including lung cancer (2, 3). In contrast to other common epithelial malignancies, there is not yet a clinical rationale to evaluate potential premalignant events in the patient at risk for lung cancer. Thus, carefully designed clinical investigations are required to harvest airway specimens that would not otherwise be collected in these individuals. In the absence of a critical mass of such studies, knowledge regarding the molecular changes that occur in the airway epithelium in the setting of lung cancer is only fragmentary. However, it is generally accepted that there are alterations in the airway epithelium that mirror some of the changes seen in the lung cancer itself and that defining these changes could lead to the identification of biomarkers of lung cancer recurrence and provide a pathway for targeted chemoprevention.

The field of cancerization theory has been tested and shown to be present in other epithelial cell malignancies, such as prostate, head and neck, colon, esophageal, and breast cancer (4–6). In fact, the concept of field of cancerization has led to the use of novel technologies to predict the risk of cancer based on testing of cells from the field. Lee and colleagues used aberrant DNA methylation patterns of 4 candidate genes in the normal esophageal mucosa adjacent to squamous carcinoma to develop a risk assessment model that predicted the risk of finding squamous cell carcinoma of the upper aerodigestive tract at endoscopy (7). Damania and colleagues used a novel imaging technique, partial wave spectroscopic microscopy, to risk-stratify patients harboring precancerous lesions of the colon (8). In this study, an optically measured biomarker was obtained from microscopically normal but nanoscopically altered cells that may provide the potential for minimally invasive colorectal cancer risk stratification.

It is hypothesized that lung cancer has a field of cancerization similar to these other epithelial malignancies (2, 9, 10). In lung cancer, mutations in KRAS were described in nonmalignant histologically normal-appearing lung tissue adjacent to lung tumors (2, 11). Moreover, loss of heterozygosity events are frequent in cells obtained from bronchial brushings of normal and abnormal lungs from patients undergoing diagnostic bronchoscopy and were detected in cells from the ipsilateral and contralateral lungs (12). Likewise, mutations in the EGFR oncogene have been reported in normal-appearing tissue adjacent to EGFR-mutant lung adenocarcinoma and also occurred at a higher frequency at sites more proximal to the adenocarcinomas than at more distant regions (13, 14). More recently, global mRNA and microRNA expression profiles have been described in normal-appearing bronchial epithelium of healthy smokers (15, 16), and a cancer-specific gene expression biomarker has been developed in the mainstem bronchus that can distinguish smokers with and without lung cancer (17, 18). In addition, and importantly, modulation of global gene expression in the normal bronchial epithelium in healthy smokers is similar in the large and small airways, and the smoking-induced alterations are mirrored in the epithelia of the mainstem bronchus, buccal, and nasal cavities (10, 19, 20).

Recent molecular findings support the stepwise lung carcinogenesis model in which the development of the field of cancerization with genetically and epigenetically altered cells plays a central role. The hypothesis is that injury (from smoking, for example) leads to aberrant repair by stem/progenitor cells, which undergo self-renewal to form a group of indefinitely self-renewing daughter cells. Additional genetic and epigenetic alterations prevent normal differentiation of these cells and instead result in proliferation and expansion of this field, gradually displacing the normal epithelium. Development of an expanding premalignant field seems to be a critical step in lung carcinogenesis that can persist even after smoking cessation. It is hypothesized that further genetic and/or epigenetic changes result in the stepwise progression of premalignant lesions to full blown malignancy. If this hypothesis regarding the development of lung cancer proves valid, there is potential for targeted chemoprevention in at risk patients based on the biology underlying the field of cancerization and stepwise progression to malignancy.

Studies of the field of cancerization enrich our understanding of the molecular pathogenesis of lung cancer and have potential transformative clinical value. Biomarker signatures within the field could be used for risk assessment, diagnosis, monitoring progression of disease during active surveillance, and predicting the efficacy of adjuvant therapies following surgery. As the field of cancerization for lung cancer may extend to the nose and mouth, these are compelling areas for study of the field, because they represent potential minimally invasive sites for risk assessment and diagnostic testing (10, 18). Studies are now underway evaluating these minimally invasive and potentially cost-effective prescreening strategies using biomarkers obtained from the field of cancerization to identify high risk individuals from the at risk population. In the future, following validation, these biomarkers may be used to stratify the high risk patients to undergo computed tomography scans.

While the studies above have begun to characterize the molecular field of injury among smokers with lung cancer, key questions remain to be addressed. The temporal and spatial pattern of gene expression changes in the airway of smokers with lung cancer has yet to be characterized, and it is unclear what, if any, spatial gradient in the airway transcriptome alterations exist relative to the site of tumor development. Before its use as a screening tool for disease, we must define how far in advance of tumor development this field of cancerization arises within the airway. Importantly, the impact of histologic and molecular subtypes of lung cancer, as well as lung cancer treatment, on airway gene expression profiles remains to be defined, having implications both in terms of the underlying mechanism driving these alterations and their potential to serve as biomarkers of lung cancer recurrence.

Disclosure of Potential Conflicts of Interest

A. Spira has ownership interest (including patents) and is a consultant/advisory board member in Allegro Diagnostics Inc. No potential conflicts of interest were disclosed by the other authors.

Grant Support

The authors' work is supported in part by funding from the National Cancer Institute (#U01CA152751), Department of Defense (#W81XWH-10-1-1006), Veterans Administration (Merit Review #51016X000359), and the UCLA Clinical and Translational Science Institute (#UL1TR000124).