*From the Molecular Oncology Group (Drs. Banerjee and Rabbitts), Department of Oncology, University of Cambridge, Cambridge, UK; and the Department of Thoracic Medicine (Dr. George), University College London Hospitals National Health Service Trust, London, UK.
Correspondence to: P. Jeremy George, Consultant Physician, Department of Thoracic Medicine, University College London Hospitals NHS Trust, Mortimer St, London W1T 3AA, UK; e-mail email@example.com
Preinvasive lesions are prevalent in the bronchial epithelium of smokers and are believed to be precursors of squamous cell carcinoma.1These lesions are not easily detected with standard white light bronchoscopy, and so their natural history remains incompletely understood. However, their detection has been enhanced significantly over the past decade with the development of fluorescence bronchoscopy.2We are undertaking a detailed longitudinal study of patients with preinvasive bronchial epithelial lesions in order to define their natural history. In contrast to the practice of most other centers,3 we have elected to keep lesions of all grades of severity under surveillance, including carcinoma in situ, but to intervene at the earliest signs of progression to invasive disease.
Patients who are at high risk for lung cancer presenting to the University College London Hospitals Early Lung Cancer Detection Programme are evaluated using an autofluorescence bronchoscope (Karl Storz Gmbh; Tuttlingen, Germany). Those with preinvasive lesions but no clinical or radiologic evidence of invasive carcinoma are entered into the study. Patients with carcinoma who receive curative treatment but have preinvasive lesions at remote sites are also eligible for the study. Autofluorescence bronchoscopies are performed at intervals ranging from 4 to 12 months, depending on the histologic grade of the most severe lesion. Sequential bronchial biopsies are obtained from all sites appearing to be abnormal and from those areas previously noted to be abnormal. In addition to biopsy specimens obtained for diagnostic histopathology, further specimens are frozen and stored in our tissue archive for subsequent molecular analyses.
Twenty-two patients (19 men) with a median age of 62 years (range, 49 to 75 years) were recruited into the study and have been observed for a mean duration of 22 months (range, 4 to 65 months). Twelve patients were current smokers, and 10 patients were former smokers (ie, they had stopped a mean duration of 9.9 years prior to study entry). The mean smoking consumption for the whole group of patients was 26.7 cigarettes per day (SD, 12.7 cigarettes per day) for an average duration of 46.2 years (SD, 10.8 years).
At study entry, 16 patients were found to have one or more high-grade lesions, with a total of 22 high-grade lesions and 2 low-grade lesions being found in this group. Five patients were found to have seven low-grade lesions. One patient was found to have squamous metaplasia only but was kept under surveillance because his sputum cytology was suspicious for squamous cell carcinoma.
Five lesions in five patients have progressed to squamous cell carcinoma over a period of 2 to 19 months. One of these patients developed a remote high-grade lesion after receiving curative treatment for his initial carcinoma, which progressed rapidly to an invasive squamous cell carcinoma while under surveillance. Three incidental carcinomas have developed at remote sites in a further three patients during 2 to 16 months of follow-up. Two patients, both of whom received curative treatment, were found to have remote carcinomas at entry into the study, and one of those patients remains under surveillance. Two lesions have regressed spontaneously. A further three lesions that were identified before study entry had regressed to a lower histologic grade or to normal at the time of the first study bronchoscopy. During the course of the study, seven new high-grade lesions and two new low-grade lesions have developed. One of these new high-grade lesions progressed rapidly to an invasive carcinoma.
No lesions have progressed to invasive carcinoma, although one high-grade lesion has developed at the site of a low-grade lesion. Five lesions have regressed, but four new low-grade lesions have developed during surveillance.
gives examples of three patterns of lesion progression. Figure 1, top, A, shows a patient with lesion progression to invasive carcinoma; Figure 1, middle, B, shows a patient with regression of a high-grade lesion to normal; and Figure 1, bottom, C, shows a patient with a high-grade lesion that progressed to invasive carcinoma and developed a synchronous remote second carcinoma.
This study illustrates the unpredictable nature of preinvasive bronchial epithelial lesions. These lesions have the capacity to progress to invasive carcinoma, to regress toward normal, or to remain indolent for substantial periods of time, and their behavior appears to be independent of their histologic grade at the time of initial detection.
This study also illustrates the multifocal distribution of preinvasive lesions in keeping with the “field cancerization” effect of cigarette smoke. Moreover, patients with preinvasive lesions appear to be at a substantial risk of developing incidental carcinomas at remote sites. We believe that these findings justify our conservative approach to management as it ensures that treatment is targeted to the most appropriate site within the airway. Ultimately, systemic therapies that prevent lesion progression within the entire tracheobronchial tree may be more appropriate than local ablative treatments in this group of patients.
The establishment of our tissue archive provides an important resource with which to study preinvasive lesions of the bronchus. It is now possible to compare histologically indistinguishable but anatomically distinct lesions from within the same patient that exhibit a different malignancy potential on follow-up. We believe that this approach, unencumbered by interpatient variability, will facilitate the identification of molecular markers that predict the behavior of these lesions, while also providing unique insights into the biology of the process of invasion.
Support was provided by The Ellermann Foundation and University College London Hospitals Charitable Foundation; Karl Storz Gmbh, Tuttlingen, Germany, provided the loan of the fluorescence bronchoscope. However, no input into the study design, conduct, or results was made by the company, and the investigators remained completely independent.
The authors thank Karl Storz Gmbh for the loan of the D-light autofluorescence bronchoscope.
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