Abstract 1492: Histological and molecular characteristics of 29 cases of carcinoma in situ from a prospective bronchoscopic cohort
Authors: Jonsson Steinn , Miller York E. , Kennedy Tim C. , Varella-Garcia Marileila , Skokan Margaret , Wolf Holly , Feser William , Byers Tim , Haney Jerry , Merrick Dan , Bunn Paul A. , Keith Robert L. , Hirsch Fred R. , Franklin Wilbur A. 
Published: February 2011

Introduction: The identification of carcinoma in situ (CIS) in a bronchial biopsy may indicate 1.) an adjacent invasive Lung Cancer (LC) 2.) a premalignant lesion that will progress to invasive LC or 3.) a lesion that can regress to a lower histologic grade or normal mucosa. The study of markers that identify lesions at high risk for invasive LC is of critical importance for early detection and treatment.

Methods: Over a sixteen year period more than one thousand smokers underwent autofluorsecence bronchoscopy and biopsy. Biopsies were serially sectioned and graded for level of dysplasia according to standard WHO histological criteria. The distribution of the CIS lesions was assessed with the aid of a web-based bronchial mapping tool. Immunohistochemical stains for for Ki-67 (Ki-67 growth fraction) and p53 and FISH tests for seven DNA markers including centromere 6, EGFR, 5p15.2, MYC, NKX21, TP63 and KRAS were performed on subsets of biopsies. Finally, areas of mucosa in a subset of biopsies with features of CIS were marked and microdissected for mutational analysis of TP53 (exons 5-8). Histologic slides and immunohistochemical stains for all biopsies from the date of CIS diagnosis and follow up studies were reviewed, imaged and entered on a web-based bronchial map to visually track histological and molecular changes in the airways.

Results: CIS was identified 29 subjects from the more than 1000 who were bronchoscopically examined. Fifty-eight bronchoscopies were conducted on these individuals and 435 biopsies examined. Maximum follow-up time averaged 13 mos. with a maximum of 94 mos. Among the twenty nine 65% had an associated invasive LC at the time of biopsy or during a short period of follow up whereas CIS lesions in 35% did not progress to invasive carcinoma during the follow-up period. All CIS had high Ki-67 growth fraction; p53 staining was variable. FISH analysis showed higher degrees of aneusomy in CIS lesions than lower histological grades and multiple chromosomal gains in CIS lesions shared among subjects and within a given lesion. In one patient, a CIS lesion with a TP53 mutation (G245V, GGC-GTC) spread intramucosally from the site of origin in the right lung to the contralateral lung over a period of 2 years. In another patient, nearly diffuse CIS with extremely high Ki-67 growth fraction was absent on rebiopsy of several bronchial sites three years later.

Conclusions: These data indicate that a clonal subset of cells with histologic features of CIS may spread across bronchial mucosal surfaces and be detected by fluorescence bronchoscopy and available histological and molecular studies. CIS lesions with TP53 mutation and multiple genomic gains by FISH analysis are associated with an invasive LC at the time of diagnosis or during follow up. Molecular testing of CIS may assist in determining which lesions will progress.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1492.