Banerjee, A.K.; (2012) The detection, outcome and molecular biology of pre-invasive lesions of the bronchus. Doctoral thesis , UCL (University College London).

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Abstract

Introduction: It is proposed that squamous cell carcinoma of the bronchus develops from carcinogen-exposed epithelium through a series of pre-invasive lesions of increasing histological and cytological abnormality. This has not been reliably demonstrated, and it is not known whether pre-invasive lesion development follows a predictable time-course and pattern or whether all pre-invasive lesions are committed to the development of malignancy. Pre-invasive lesions manifest genetic changes similar in pattern to that of squamous cell carcinoma. The accumulation of genetic damage, as a consequence of prolonged carcinogen exposure, may drive the progression of an individual pre-invasive lesion to malignancy, and the ultimate pattern of genetic changes may determine the outcome of that lesion. Methods: In the present work patients with pre-invasive lesions underwent serial bronchoscopy and biopsy to determine the natural history of pre-invasive lesions. Serial biopsies from lesions under follow-up were studied histologically and using loss of heterozygosity analysis at chromosomal loci thought to be involved in the pathogenesis of squamous cell carcinoma. Results: The natural history of pre-invasive lesions is variable. Some lesions progress, some regress and some remain unchanged histologically. Different lesions in a single patient may have different natural histories and different outcomes. Short-term follow-up may misrepresent the long-term evolution of an individual lesion or bronchoscopic location. Molecular studies showed that different lesions in individual patients appeared to have originated from a single progenitor cell, but acquired significant genetic differences during lesion development. Progression of pre-invasive lesions to carcinoma was associated with loss of heterozygosity along the majority of 3p with loss at 9p and the acquisition of 4p16 loss at the transition from carcinoma-in-situ to invasive disease. Regression to normal epithelium was associated with the failure to acquire these changes at the same time.

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