Abstract A55: Mapping the airways: The fate of bronchial epithelium in long term heavy smokers
Authors: Franklin Wilbur A. , Merrick Daniel T. , Matney Kathryn D. , Keith Robert , Ghosh Mormita , Nakachi Ichiro , Miller York E. 
Published: October 2015

Introduction: Although tumors of the bronchi account for a large percentage of the lung cancer burden, little is known about the status of the bronchial epithelium prior to transformation into invasive carcinoma. This report describes in situ cellular changes that occur in the central airways (bronchi and bronchioles) of long term heavy smokers screened by fluorescence bronchoscopy through the Colorado SPORE in Lung Cancer and includes results of recent intensive evaluation of selected sites of high grade lesions.

Methods: Current and former tobacco smokers with a history of more than twenty pack years were asked to undergo fluorescence and white light bronchoscopy. Patients enrolled in clinical trials were offered follow-up bronchoscopy. Over 8900 bronchoscopic biopsies were obtained at abnormal or predetermined bronchial sites from 1373 subjects under IRB approved protocols between Jan-1993 and July-2014. Multiple same site biopsies were obtained from 290 individual. Biopsies from each site were serially sectioned, examined a multiple levels to identify abnormal epithelium throughout the biopsy tissue and graded for dysplasia on the 8 point scale of the WHO atlas, edition IV. Diagnostic H&E images were archived in a digital repository that could be accessed through a digital tool, the Bronchial Map which allows for side by side comparison of digital images from different times and anatomical sites. Changes in histology score were quantified by subtracting later scores from earlier scores at same site. Clonality was assessed by TP53 sequencing in selected cases.

Results: Squamous dysplasia of variable grade was found at 36% of sampled bronchial sites. In contrast to low grade lesions or normal epithelium, higher grade dysplasia often progressed or persisted. Persistent squamous dysplasia was associated with the development of squamous carcinoma (P&lt;0.0001) but invasive carcinoma was rarely observed to develop at specific sites under observation. Four intensively followed cases illustrate the variable and unpredictable outcome of squamous dysplasia: Case 1. Fatal squamous carcinoma developed at a biopsy site that had exhibited grade 5 (moderate) dysplasia 14 years earlier. Case 2. Dysplasia grade improved following irradiation for an adjacent microinvasive squamous carcinoma. Case 3. High grade dysplasia (CIS) with a twice documented TP53 mutation was observed at the left upper lobe and was stable for several years under observation. An invasive squamous carcinoma with a different TP53 mutation subsequently developed on the right and proved fatal. Case 4. A high grade dysplastic lesion has intermittently persisted for several year without progressing to invasive carcinoma.

Conclusions:

1. Squamous dysplasia is frequent and often persistent in the airways of heavy tobacco smokers

2. High grade dysplasia may persist for many years without progression to invasive carcinoma

3. Persistent dysplasia is associated with incident squamous carcinoma but the site of associated invasive tumor is frequently distant and unpredictable

4. Early intervention in progression of squamous lesions may require a combination of local and systemic treatment

Supported by SPORE in Lung Cancer grant NCI CA580187

Citation Format: Wilbur A. Franklin, Daniel T. Merrick, Kathryn D. Matney, Robert Keith, Mormita Ghosh, Ichiro Nakachi, York E. Miller. Mapping the airways: The fate of bronchial epithelium in long term heavy smokers. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A55.