Our study supports the hypothesis that most of the high‐grade preinvasive lesions do not progress to invasive carcinoma, but patients bearing these lesions are at extremely high risk of developing lung cancer (fig 4). Our findings also show the potential of surveillance with fluorescence bronchoscopy and computed tomography of the chest to detect lung cancers in such high‐risk patients at early stages when treatment with curative intent is feasible.
Previous studies on preinvasive lesions have treated severe dysplasia and CIS because of concerns that a large proportion would progress to invasive carcinoma.7,8,9,10,15
In our study, treatment was withheld until there was histological or radiological evidence of progression to invasive carcinoma in order to evaluate their malignant potential as precisely as possible. Although the outcome of high‐grade lesions was variable, only a minority progressed to invasive carcinoma in the first 2 years (fig 3). A similar proportion of high‐grade lesions regressed to normal, whereas the remainder persisted with unchanged histology for long periods of time (fig 3). In addition, new lesions appeared during the course of surveillance, and it has not been possible to predict which lesion is destined to progress to invasive carcinoma from the initial histology.
These findings differ from those of Venmans et al
and Breuer et al7,10
who reported that all CIS lesions progressed to squamous cell carcinoma. However, comparison between studies may be complicated by the classification of preinvasive lesions. We have found that sequential biopsy specimens from the same site may be scored as severe dysplasia or CIS (unpublished observations). In addition to intraobservational and interobservational variation, there may also be morphological heterogeneity within lesions. Further, we found no difference in the outcomes of lesions classified as severe dysplasia or CIS at initial presentation.16
We therefore find it appropriate to group these two grades together.
In our study, no low‐grade lesions progressed to carcinoma (fig 3) or to a higher grade (results not shown) unlike those observed in the study by Breuer et al10
who described a 9% (6/64) progression rate for mild–moderate dysplasia followed up for a median of 21 months. The reasons for these discrepancies are unknown but could be elucidated in a large multicentre study with a longer follow‐up.
Our study has two important limitations. Firstly, it has been assumed that preinvasive lesions in patients with previous histories of lung cancer behave similarly to those in patients with no such histories. Although there is no apparent difference between these two groups (fig 2), a larger study with a longer follow‐up is needed to establish whether this assumption is correct. Secondly, it is assumed that biopsy specimens taken from preinvasive lesions do not influence the outcome of that lesion. However, it has been suggested that bronchial biopsies may completely remove some lesions.7
Although this possibility cannot be discounted, this is unlikely as most lesions appeared considerably larger than the area sampled by biopsy. This could be considered in a future study by using non‐invasive techniques, such as endobronchial ultrasound and optical coherence tomography. It is likely, however, that treatment given to invasive carcinomas will have affected the behaviour of preinvasive lesions adjacent to these carcinomas. Follow‐up data from these lesions were therefore censored at the time of treatment (table 3). Although a large proportion of data were discarded, our assessments of the behaviour of preinvasive lesions are consistent with the conclusions made by Auerbach et al
Despite this relatively low rate of malignant progression of individual lesions (fig 3), we found that patients with high‐grade lesions are at extremely high risk of developing invasive carcinoma (fig 4). This high risk is because of the multifocal distribution of lesions and the development of incidental cancers at remote sites within the lung. These findings are consistent with the “field cancerisation” concept, in which the entire bronchial epithelium is exposed to the carcinogenic effects of tobacco smoke and is therefore at risk of progressing to invasive carcinoma.17
The observation of multifocal disease and the large proportion of patients developing incidental cancers at remote sites within their lungs raises important questions as to how high‐grade lesions and patients should be managed clinically. Treatment options presently include surgery and a variety of endobronchial treatments. Surgery undoubtedly provides the most effective method of eradicating lesions, but is associated with considerable morbidity and mortality, which is difficult to justify for a condition that may not necessarily progress to malignancy. Further, there is a risk that it may render the patient unfit for curative treatment if an invasive carcinoma subsequently develops within the remaining lung.
Endobronchial treatments have the advantage of conserving lung tissue and are used more widely. However, their efficacy is difficult to evaluate, given the unpredictable nature of high‐grade lesions and the observation that patients with these lesions are just as likely to develop incidental cancers at remote sites within their lungs. Ultimately, systemic treatments aimed at preventing the progression to invasive carcinoma may be more appropriate for such a field‐change disease.
Maintaining combined surveillance with computed tomography and bronchoscopy ensures that definitive treatment has been directed to the most appropriate site within the patient's airway and that incidental lung cancers have been diagnosed and treated early. Nevertheless, four of the eight patients developed metastatic disease despite receiving treatment with curative intent. Three cancers progressed from known preinvasive lesions (table 2), and it could be argued that preemptive treatment would have prevented this. However, three studies have reported high rates of tumour progression, ranging from 17% to 67%, despite endobronchial treatment,7,9,15
and underline the importance of conducting randomised controlled clinical trials to evaluate different treatment strategies.
The evidence of variable outcomes in preinvasive lesions also highlights the need to identify reliable markers of tumour progression. We have established an archive of blood, sputum and bronchoscopic specimens so that it is now possible to conduct molecular biological studies on histologically identical lesions with different clinical outcomes.18
In addition to identifying markers of disease progression, this study also provides new insights into the biology of the invasion process.
Although our main aim was to study the natural history of preinvasive lesions, the finding of such a high risk of lung cancer in patients with severe dysplasia and CIS suggests that the lesions have potential as disease biomarkers. The clinical value of fluorescence bronchoscopy may therefore lie in its ability to identify patients at especially high risk of developing lung cancer by detecting these lesions. Although bronchoscopy is too invasive and time consuming to be developed as a screening tool, evidence suggests that patients with preinvasive lesions may be identified non‐invasively with sputum cytometry.19
Screening with sputum cytometry, combined with surveillance, may therefore facilitate the diagnosis of lung cancers at earlier stages when curative treatment is feasible in high‐risk groups.