Abstract
Autofluorescence bronchoscopy can detect proximal preneoplastic lesions. Intensive surveillance with this modality, however, may not alter health outcomes. https://bit.ly/3s98vN1
Lung cancer biology has changed, with a histological shift from the previously dominant central squamous cell carcinoma to peripheral lung adenocarcinomas. Changes in cigarette characteristics and smoking practice are commonly attributed; however, other carcinogens such as air pollution and diesel fumes may also play an as yet unidentified role in lung cancers in never-smokers [1]. This shift and advances in cross sectional imaging have resulted in increasing adoption of low dose computed tomography (CT)-based lung cancer screening, when earlier attempts with chest radiography and sputum cytology failed [2].
Nonetheless, due to global case numbers (>2 million), there is an ongoing clinical need to address this challenging subset of central cancers and effectively prevent and/or manage potentially pre-neoplastic changes and cellular atypia, ranging from hyperplasia, metaplasia, grades of dysplasia and carcinoma in situ, to avoid invasive cancer.
Bronchoscopic inspection and longitudinal surveillance is the basis of the clinical approach to pre-invasive airway lesions [3–5], and has also enabled research which posits a stepwise evolution of ever more disordered pre-invasive lesions, ranging from mild and moderate dysplasia (low-grade lesions) to severe dysplasia and carcinoma in situ underpinned by accumulating molecular aberrations [6]. Moreover, the observation that bronchial airway gene expression alterations may predict risk of lung cancer development is consistent with field cancerisation [7], emphasises the link between morphology and biology and has led to efforts to translate a candidate airway epithelial biomarker [8, 9].
While higher grade lesions more often progress to invasiveness, this is not invariable [10–13], with progression rates using different endpoints reported between 43% and 87% [14], making generalisation to surveillance algorithms difficult.
White light bronchoscopy has been boosted by technological advances, adding on autofluorescence bronchoscopy (AFB) and/or narrow band imaging [15–19], with both in combination potentially more sensitive than each technique, but of course resulting in a more costly strategy [20]. Other technologies, such as optical coherence tomography, confocal endomicroscopy and laser Raman spectroscopy, are in active development [21].
In this issue of the European Respiratory Journal, Guisier et al. [22] describe a large, prospective, French multicentre randomised study comparing surveillance strategies for patients with heavy smoking (60% active smokers) including the 20% with histologically confirmed low grade preinvasive lesions at initial bronchoscopy. Participants were randomised to routine follow-up (clinical review and 6-monthly chest radiograph), or an added intensive AFB bronchoscopic surveillance at 6- or 12-month intervals; all underwent bronchoscopy and CT scan at 36 months with long-term follow-up. They report that mild or moderate dysplasia at baseline bronchoscopy was a significant lung cancer risk factor both at 3 years (OR 6.9, 95% CI 2.5–18.9) and at maximum follow-up (OR 5.9, 95% CI 2.9–12.0). While intensive bronchoscopy surveillance did not improve patient outcomes, smoking cessation was significantly associated with clearance of bronchial dysplasia at follow-up (OR 0.12, 95% CI 0.01–0.66; p=0.005) and with a reduced risk of lung cancer at 5 years (OR 0.15, 95% CI 0.003–0.99; p=0.04), reminding us that smoking cessation continues to be front and centre to counter this cancer.
We congratulate the authors on their significant achievements in a challenging disease to research; a cohesive collaboration maintaining focus for a high quality randomised controlled trial across multiple centres to achieve adequate follow-up and minimising dropouts, central pathology review and convincing statistical handling. No study is perfect however, with some uncertainty resulting from: potential biases from recruitment of the group with occupational exposure compared to those with previous curatively treated smoking-related cancers and those with just a heavy smoking history as their lung cancer risks would almost certainly differ; the fact that the central panel review did not include every biopsy undertaken with some histopathological discordance; and the possibility that these tiny lesions may be completed removed at biopsy (a concept advanced by the legendary pathologist, Adi Gazdar, pre-eminent pioneer of lung preneoplasia research).
The authors conclude that while intensive bronchoscopy surveillance does not improve patient outcome, the identification of bronchial dysplasia during initial bronchoscopy may be useful for risk stratification strategies in lung cancer screening programmes, as a substantial proportion of lung cancers that developed during the surveillance programme were peripheral lung adenocarcinomas. This concept has been tested in trials, in various combinations with sputum cytology and low dose CT screening [23–26] but not yet proven ready for prime time.
Perhaps more fruitful will be innovative research exploiting “omics” to molecularly characterise pre-malignant lung lesions in the proximal airways, with emerging new knowledge [8, 27] and anticipated from the multicentre multiomic Lung PreCancer Atlas effort [28, 29]. A better understanding of preneoplasia evolution will not only help us design better screening strategies, but also help address the void in secondary prevention [30] for central cancers as well as peripheral cancers.
Lung cancer is evolving and in the late 20th century, pulmonary adenocarcinoma became predominant, overtaking squamous cell carcinoma. This is presumed to be a consequence of changes in tobacco agriculture, curing and manufacturing processes, including the use of ventilated filters, leading to higher levels of free-base nicotine, more addictive products, deeper inhalation of cooler and less harsh smoke, and increased tobacco-specific nitrosamine concentrations [31]. In this regard, it is notable that evidence is mounting that electronic cigarettes can also exert marked adverse biological effects on the airways [32], and that vape liquids contain known carcinogens [33–35].
To conclude, this helpful study adds considerably to our relatively limited knowledge of lung preneoplasia, strongly reinforces smoking cessation benefits, speaks against low value medical interventions that do not improve health outcomes and spurs research efforts [36] in order to harness modern “omics” and advanced bronchoscopy to enable more effective screening, detection and secondary prevention strategies for this terrible disease. Much more is needed than meets the eye.
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Footnotes
Conflict of interest: K.M. Fong reports grants from MRFF EPCDR (Improving Diagnosis in Cancers Low Survival Rates), NHMRC (Ideas grant: Early lung cancer biomarkers), MRFF Next Generation Clinical Researchers Program (Practitioner Fellowship), NHMRC Project (Novel biomarkers for lung cancer), NHMRC (low dose computed tomography to diagnose lung cancer); royalties from UpToDate and Cochrane Clinical Answers; unpaid leadership role at Asia Pacific Society of Respirology (former President); support with a loan bronchoscope for 12 months for the purpose of a research trial study (no financial funding) from Olympus; software licensing for computer aided diagnosis research in the International Lung Screen Trial (ILST) from Mevis Veolity; outside the submitted work. G.N. Olive and R.V. Bowman report receipt of loan bronchoscopes from Olympus Australia; outside the submitted work. H. Marshall reports grants from NHMRC and MRFF; lecture honoraria from AstraZeneca and Boehringer Ingelheim; travel and accommodation expenses from Boehringer Ingelheim; special interest group convenor (tobacco control) for Thoracic Society ANZ (unpaid); expert advisory member (lung cancer advocacy) for Lung Foundation Australia (unpaid); education committee member for Asian Pacific Society of Respirology (unpaid); outside the submitted work. I.A. Yang has nothing to disclose.
Support statement: This work was supported by NHMRC, MRFF and TPCH Foundation.
- Received April 20, 2022.
- Accepted April 27, 2022.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org