Preinvasive Bronchial Lesions Research Articles

Endoscopic follow-up of low-grade precancerous bronchial lesions in high-risk patients: long-term results of the SELEPREBB randomised multicentre trial.

3-9% of low-grade preinvasive bronchial lesions progress to cancer. This study assessed the usefulness of an intensive bronchoscopy surveillance strategy in patients with bronchial lesions up to moderate squamous dysplasia. SELEPREBB (ClinicalTrials.gov NCT00213603) was a randomised study conducted in 17 French centres. After baseline lung computed tomography (CT) and autofluorescence bronchoscopy (AFB) to exclude lung cancer and bronchial severe squamous dysplasia or carcinoma in situ (CIS), patients were assigned to standard surveillance (arm A) with CT and AFB at 36 months or to intensive surveillance (arm B) with AFB every 6 months. Further long-term data were obtained with a median follow-up of 4.7 years. 364 patients were randomised (A: 180, B: 184). 27 patients developed invasive lung cancer and two developed persistent CIS during the study, with no difference between arms (OR 0.63, 95% CI 0.20-1.96, p=0.42). Mild or moderate dysplasia at baseline bronchoscopy was a significant lung cancer risk factor both at 3 years (8 of 74 patients, OR 6.9, 95% CI 2.5-18.9, p<0.001) and at maximum follow-up (16 of 74 patients, OR 5.9, 95% CI 2.9-12.0, p<0.001). Smoking cessation was significantly associated with clearance of bronchial dysplasia on 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). Patients with mild or moderate dysplasia are at very high risk for lung cancer at 5 years, with smoking cessation significantly reducing the risk. Whereas intensive bronchoscopy surveillance does not improve patient outcomes, the identification of bronchial dysplasia using initial bronchoscopy maybe useful for risk stratification strategies in lung cancer screening programmes.

Application of Quantitative Autofluorescence Bronchoscopy Image Analysis Method in Identifying Bronchopulmonary Cancer.

Autofluorescence bronchoscopy shows good sensitivity and poor specificity in detecting dysplasia and cancer of the bronchus. Through quantitative analysis on the target area of autofluorescence bronchoscopy image, determine the optimal identification index and reference value for identifying different types of diseases and explore the value of autofluorescence bronchoscopy in diagnosis of lung cancer. Patients with 1 or more preinvasive bronchial lesions were enrolled and followed up by white-light bronchoscope and autofluorescence bronchoscopy. Color space quantitative image analysis was conducted on the lesion shown in the autofluorescence image using MATLAB image measurement software. A retrospective analysis was conducted on 218 cases with 1208 biopsies. One hundred seventy-three cases were diagnosed as positive, which included 151 true-positive cases and 22 false-positive cases. White-light bronchoscope associated with autofluorescence bronchoscopy was able to differentiate between benign and malignant lesion with a high sensitivity, specificity, positive predictive value, and negative predictive value (92.1%, 59.3%, 87.3%, and 71.1%, respectively). Taking 1.485 as the cutoff value of receiver operating characteristic of red-to-green value to differentiate benign and malignant diseases, the diagnostic sensitivity reached 82.3% and the specificity reached 80.5%. U values could differentiate invasive carcinoma and other groups well. Quantitative image analysis method of autofluorescence bronchoscopy provided effective scientific basis for the diagnosis of lung cancer and precancerous lesions.

Abstract 1419: Characterization of the evolution of immune response in lung squamous carcinogenesis

Abstract Molecular profiling of from pre-invasive bronchial lesions, and particularly the evolution of immune response, may identify promising new biomarkers for early detection and targets for chemoprevention/treatment of lung cancer. mRNA expression was analyzed (Agilent microarrays) from fresh frozen human bronchial biopsies (N = 122, 77 patients) at successive morphological stages of lung squamous carcinogenesis. Modules of co-expressed genes were identified among the stage associated genes, selected using a linear mixed-effects model adjusting for smoking status, gender, and history of cancer as fixed effects and patient as a random effect. Cell type specific signatures were applied to the genes co-expressed in these modules in order to identify the immune response signal through the stages of lung carcinogenesis. Genes expression alterations were grouped into 4 successive molecular steps. Based on their behavior across the 4 steps, 8 modules of genes with different patterns were observed: gene modules primarily up-regulated among the early or late steps, up-regulated in a linearly across the 4 steps, as well as down- then up-regulated (biphasic). Genes signing the presence of activating CD8 and CD4 T cells, as well as some memory B cells were progressively and linearly up-regulated from metaplasia through all stages of carcinogenesis. At the later stages, the transition to high-grade dysplasia, the most significant gene expression changes included immune/inflammatory response genes. At this stage a very strong adaptive immune response is noted involving T cells - mainly Th1 and T regulators - and dendritic cells. In addition, immunosuppressive signals, corresponding to negative co-inhibitory molecules, also significantly appears at the high-grade dysplasia stage. The adaptive CD4/CD8 related immune response starts from the earlier stages (metaplasia) of lung carcinogenesis. The significant modification of inflammatory/immune response genes in association with high-grade lesions suggests, at this critical stage of carcinogenesis, a major role of the surrounding microenvironment with an adaptive immune response, driven by Th1 and Treg cells, and but also, before tumor invasion across the basal membrane, a tumor versus host immunosuppressive response. Citation Format: Celine Mascaux, Mihaela Angelova, Jennifer Beane, Kahkeshan Hijazi, Geraldine Antoine, Karen Willard Gallo, Vincent Ninane, Arsène Burny, Jean-Paul Sculier, Avrum Spira, Jérôme Galon. Characterization of the evolution of immune response in lung squamous carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1419.

Abstract 212: Infrared spectral diagnosis for predictive cancer medicine: application to the early diagnosis and prognosis of preinvasive bronchial intraepithelial lesions

Abstract This study concerns the development of a new imaging diagnostic tool for bronchial cancer. This malignancy is a wide-spread cancer in the world, with an increasing incidence. Our objective is to assess the potential of infrared (IR) spectroscopy in the early diagnosis of the bronchial cancer. Our approach is divided into two steps: the first issue aims at highlighting specific spectroscopic markers of the bronchial cancer permitting to detect unambiguously the presence of cancer cells. The second step relies on establishing a chemometric model able to estimate the tumor invasivity of these malignant cells For our approach, we used 4 different bronchial cellular lines displaying different in vitro invasive properties assessed by a modified Boyden chamber assay : the non invasive cell line 16HBE used as a control, the moderate invasive cell line Beas2B and the two highly invasive cell lines BZR and BZRT33. Four samples of each cell line were cultured and embedded in paraffin wax. Slices of 10 μm were prepared on CaF2 windows suitable for IR measurements. The infrared acquisitions were performed with an imager (Bruker, Germany) equipped with a Focal Plane Array detector allowing to image large tissue areas with a spatial resolution of a few micrometers. The IR spectra were processed using chemometric and statistical multivariate treatments. A first stage permitted to correct spectral interferences originated from the paraffin and optical effects. Then, supervised models were established by means of PLS-DA (Partial Least Square Discriminant Analysis) method. A first model, based on sparse-PLS method, was optimized to highlight spectroscopic markers specific of the normal and cancerous states; this model has proved effective in terms of sensibility (96%) and specificity (90%). Based on these promising results, the study will be pursued by the analysis of tissue samples from biopsies and tumor samples. Subsequently, the next investigation will rely on the construction of a second model to model and quantify the aggressiveness level of the cell lines. Citation Format: Vincent D. Gaydou, Myriame Polette, Cyril Gobinet, Claire Kileztky, Michel Manfait, Philippe Birembaut, Olivier Piot. Infrared spectral diagnosis for predictive cancer medicine: application to the early diagnosis and prognosis of preinvasive bronchial intraepithelial lesions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 212. doi:10.1158/1538-7445.AM2015-212

Synchronous invasive or preinvasive bronchial lesions detected by autofluorescence bronchoscopy in patients with lung cancer

ObjectivesIn support with field cancerization theory, some patients with lung cancer (LC) will also have synchronous invasive or pre-invasive bronchial lesions. In this cross sectional – analytic study autofluorescence bronchoscopy (AFB) was used to assess the prevalence of synchronous lesions in patients with LC. Materials and methodsAll patients with abnormal sputum cytology underwent white light and AFB. From 335 patients with abnormal sputum cytology referred for AFB, lung cancer was detected in 91 patients (89 male and 2 female) of age (mean±SD), 67±8years. 77 had squamous cell carcinoma (SqCC), 13 had adenocarcinoma and one patient with small cell lung cancer (SCLC). ResultsSynchronous lesions detected in 26 (29%) patients, 25 (33%) of patients with SqCC, one with adenocarcinoma, no synchronous lesion detected in one patient with SCLC. The most severe detected synchronous lesion was adenocarcinoma in one patient, Carcinoma insitu (CIS) in 4 patients, severe dysplasia in 3 patients, moderate dysplasia in 10 patients, and mild dysplasia in 8 patients. Synchronous lesions were more frequently detected in current smokers (35%), than in ex-smokers (20%) and non-smokers (15%). ConclusionSynchronous preinvasive lesions are frequent in patients with LC and AFB should be included in pre-operative evaluation of these patients.

Loss of polymeric immunoglobulin receptor expression is associated with lung tumourigenesis

Polymeric immunoglobulin receptor (pIgR) expression is downregulated in lung cancer, but its implications in lung tumourigenesis remain unknown. We hypothesised that loss of pIgR expression occurs early, and is associated with cell proliferation and poor prognosis. pIgR expression was evaluated by immunohistochemistry in airways of patients with normal mucosa, pre-invasive lesions and invasive lesions, and correlated with clinical outcomes. 16-HBE and A549 cells stably transfected with pIgR were tested for proliferation, apoptosis and cell cycle progression. Immunostaining was strong in normal epithelium, but severely reduced in pre-invasive lesions and most lung cancers. Persistent expression was associated with younger age and adenocarcinoma subtype but not survival. pIgR overexpression significantly reduced A549 and 16-HBE proliferation. Growth inhibition was not due to cell cycle arrest, increased apoptosis or endoplasmic reticulum stress, but we observed altered expression of genes encoding for membrane proteins, including NOTCH3. Interestingly, NOTCH3 expression was inversely correlated with pIgR expression in cell lines and tissues. pIgR expression was lost in most lung cancers and pre-invasive bronchial lesions, suggesting that pIgR downregulation is an early event in lung tumourigenesis. pIgR overexpression in A549 and 16-HBE cells inhibited proliferation. Future investigations are required to determine the mechanisms by which pIgR contributes to cell proliferation.

Risk of lung cancer in patients with preinvasive bronchial lesions followed by autofluorescence bronchoscopy and chest computed tomography

ObjectivesTo assess risk of lung cancer (LC) in patients with preinvasive bronchial lesions and to identify factors associated with higher risk. Methods124 patients with one or more preinvasive bronchial lesions and normal chest computed tomography (CT) (mean age 66.7 years, 121 males and 3 females), followed-up by white light and autofluorescence bronchoscopy (AFB) every 4–6mo and chest CT every 6–12mo, end points were development of carcinoma in situ (CIS) or LC. ResultsAmong 124 patients with 240 preinvasive bronchial lesions, 20 CIS or LC lesions were detected during follow-up in 20 (16%) patients, 7 were detected as new endobronchial lesions, 10 as new peripheral lesions and 3 as local progression from severe dysplasia to CIS. Median time to progression from the same site or development of CIS/LC elsewhere was 24 months (range: 6–54mo). The Cumulative risk of development of CIS/LC was 7% at one year, 20% at three years and 44% at 5 years. Among detected lung cancers, 80% were stage 0 or stage I and underwent treatment with curative intent. Diagnosis of new SD during follow-up (p=0.0001), chronic obstructive pulmonary disease (COPD) (p=0.001) or smoking index >52 pack-year (p=0.042) was associated with higher risk. Even after controlling for other risk factors, COPD was associated with risk for lung cancer. Baseline lesion grade was not predictive of patient outcome (p=0.146). ConclusionPatients with preinvasive bronchial lesions, especially those with new SD during follow-up, COPD or smoking >52 pack-year are at high risk of LC, AFB and CT follow-up facilitated early detection and treatment with curative intent.

Natural history of bronchial preinvasive lesions

Preinvasive bronchial lesions defined as dysplasia and carcinoma in situ (CIS) have been considered as precursors of squamous cell carcinoma of the lung. The risk and rate of progression of preinvasive lesions to invasive squamous cell carcinoma as well as the mechanism of progression or regression are incompletely understood. While the evidence for the multistage, stepwise progression model is weak with relatively few documented lesions that progress through various grades of dysplasia to CIS and then to invasive carcinoma, the concept of field carcinogenesis is strongly supported. The presence of high-grade dysplasia or CIS is a risk marker for lung cancer both in the central airways and peripheral lung. Genetic alterations such as loss of heterozygosity in chromosome 3p or chromosomal aneusomy as well as host factors such as the inflammatory load and levels of anti-inflammatory proteins in the lung influence the progression or regression of preinvasive lesions. CIS is different than severe dysplasia at the molecular level and has different clinical outcome. Molecular analysis of dysplastic lesions that progress to CIS or invasive cancer and rare lesions that progress rapidly from hyperplasia or metaplasia to CIS or invasive cancer will shed light on the key molecular determinants driving development to an invasive phenotype versus those associated with tobacco smoke damage.

The pathogenesis of pre-invasive lesion development

<h3>Educational aims</h3> To describe the progression of pre-invasive bronchial lesions. To highlight malignant transformation causes and risks. To explain somatic and epigenetic abnormalities contributing to lesions. <h3>Summary</h3> The progression of pre-invasive bronchial lesions is a multifocal and multistep process. Morphological malignant transformation is driven by the accumulation of multiple genetic and epigenetic abnormalities, the rate and number of which determines the risk and rate of progression toward cancer. The field effect of mutagenesis in airways is characterised by the multifocality of the lesions. To date, no evidence has been presented for genetic alterations accumulating in a known sequence. No individual alteration is sufficient to predict the occurrence of invasive cancer in the bronchial tree.

Diagnostic précoce du cancer bronchique : apport de la bronchoscopie en autofluorescence

Less than 15% of all patients survive five years after a diagnosis of lung cancer. This poor prognosis is attributed to a lack of early detection. Among the methods of early diagnosis of bronchial cancer, autofluorescence bronchoscopy allows for the early identification of preinvasive bronchial lesions. The goal of this prospective study is to evaluate the contribution of the autofluorescence bronchoscopy, on a hospital site, over a period of one year. All patients with an indication of autofluorescence bronchoscopy were included in the study. The following parameters were collected: age, sex, smoking status, FEV1, FVC, biopsy sites, histology, duration of examination. Two hundred and seventy-four patients were included. The average age was 63.8 years (+/-12), the smoking status was 35 packs/year (+/-19). A fluorescence abnormality was detected in 131 patients and 165 sites were biopsied. An histological abnormality was found in 76% of the samples, with 34 hyperplasia (28%), 56 squamous metaplasia (46%), three mild dysplasia (3%), two moderate dysplasia (2%), one severe dysplasia (1%), two carcinomas in situ (2%) and 21 invasive carcinomas (18%). Autofluorescence bronchoscopy is an effective examination for the detection of the preinvasive neoplasic lesions and may be proposed when lung cancer is suspected.

Angiogenic squamous dysplasia-like phenomenon in oral epithelial precursor lesions

Statement of the problemDysplasia, the morphological yardstick of epithelial precursor lesions, is the collective term for a variety of architectural and cytological changes within the altered oral epithelium. Angiogenic squamous dysplasia (ASD), a distinct morphological characteristic in pre-invasive bronchial lesions, describes the presence of capillary tufts that are closely juxtaposed to and projecting into the dysplastic bronchial epithelium.ObjectiveTo determine whether ASD-like phenomenon occurs in oral epithelial precursor lesions, and to speculate on its relevance.MethodsTwenty cases each of mild, moderate and severe oral dysplasia (inclusive of carcinoma-in-situ), and 10 normal oral mucosa (normal controls) were serial sectioned for H and E staining, and for microvessel density (MVD) scoring with CD31, CD34 and CD105. Microcapillary pattern images were digitally captured for 3-D reconstruction.ResultsOral ASD foci consisting of CD31-and CD34-positive capillary loops abutting onto the overlying dysplastic oral epithelium (and causing it to assume an irregular or papillary surface configuration) were identified in moderate (3/20; 15%) and severe dysplasia (13/20; 65%), but not in normal oral mucosa and mild dysplasia. MVD score demonstrated increasing vascularity as epithelium progressed from normal to severe dysplasia (p < 0.05). CD105 demonstrated increase neovascularization in all dysplasia grades (p < 0.05).ConclusionsThese preliminary findings taken together suggest that: 1. ASD-like phenomenon may be an important intermediary biomarker in oral precursor lesions; and 2. architectural alterations of the entire disturbed mucosa may be a more useful pre-malignancy index.

Narrow Band Imaging in the Airway: Where Do We Stand?

Narrow Band Imaging in the Airway: Where Do We Stand?

Cytological findings of pre-invasive bronchial lesions detected by light-induced fluorescence endoscopy in a lung cancer screening system

Lung cancer is a global epidemic and the number one cause of death among all cancers, with a very high morbidity. A new strategy for the treatment of lung cancer is the detection and eradication of pre-invasive bronchial lesions before they become invasive carcinomas. We conducted a detailed investigation into the use of fluorescence bronchoscopy in the detection of pre-invasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy. We also studied the distinctive cytological findings in the sputum specimens corresponding to the pre-invasive bronchial lesions. Sputum examinations were performed by mass screening a high-risk group of participants. From 1997 to 1999, 61 participants with sputum cytology suspicious or positive for malignancy were referred to our institute, and were examined with both white-light and fluorescence bronchoscopy. For the cytological findings, the collection of sputum was performed in the early morning. Conventional white-light examinations were first performed, and areas with abnormal findings were recorded for subsequent biopsy. Fluorescence bronchoscopy examinations were then carried out. Biopsy specimens for a pathological examination were taken from all the suspicious or abnormal areas discovered by the white-light bronchoscopy, or fluorescence bronchoscopy examination, or both. The laser-induced fluorescence bronchoscopic examination showed a high sensitivity for invasive carcinoma, carcinoma in situ, as well as severe, moderate, and mild dysplasia. In the sputum cytological findings, a thickened cytoplasm and slight hyperchromasia were frequently observed in the mild dysplasias compared with the squamous cells without atypia. Hyperchromasia and an Orange G (OG)-philic cytoplasm of squamous cells were frequently observed in the moderate compared with the mild dysplasias. A thickened cytoplasm, a nuclear pleomorphism, a thickened nuclear rim, a coarse chromatin, an uneven chromatin distribution, and an OG-philic cytoplasm were frequently observed in the carcinomas in situ and severe dysplasias compared with the moderate dysplasias. We found that the use of fluorescence bronchoscopy in addition to conventional white-light examination can enhance the detection and localization of pre-invasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy. Sputum cytology is therefore a potential approach to diagnosing pre-invasive bronchial lesions.

Clinical Experience with Autofluorescence Imaging System in Patients with Lung Cancers and Precancerous Lesions

Background: It is important to detect preinvasive bronchial lesions before they become invasive cancer, because detection of early cancer is expected to lead to a cure. Autofluorescence bronchoscopy is a useful device in the detection of preinvasive and cancerous lesions. Recently, a new autofluorescence bronchoscopic system, autofluorescence imaging (AFI) system, has been developed. Objectives: We evaluated the efficacy of AFI in the diagnosis of precancerous and cancerous lesions. Methods: A total of 31 patients underwent both conventional white-light bronchoscopy (WLB) and AFI from January 2002 to September 2004. We evaluated autofluorescence findings using a four-point scale: AFI-I, II, III, and B. The findings in WLB were evaluated on a three-point scale: WLB-I, II, and III. Abnormal areas by WLB and AFI were biopsied for histopathological examinations. Results: A total of 64 lesions were evaluated. When the AFI-III finding was regarded as positive in AFI and WLB-III as positive in WLB, sensitivity for severe dysplasia or worse was 94.7% with AFI and 73.7% with WLB, respectively. Conclusions: AFI is an effective system for the detection of precancerous and cancerous lesions.

Clinical Prognostic Indicators of High-Grade Pre-invasive Bronchial Lesions

Clinical Prognostic Indicators of High-Grade Pre-invasive Bronchial Lesions

Proteomic patterns of preinvasive bronchial lesions.

A proteomics approach is warranted to further elucidate the molecular steps involved in lung tumor development. We asked whether we could classify preinvasive lesions of airway epithelium according to their proteomic profile. We obtained matrix-assisted laser desorption/ionization time-of-flight mass spectrometry profiles from 10-microm sections of fresh-frozen tissue samples: 25 normal lung, 29 normal bronchial epithelium, and 20 preinvasive and 36 invasive lung tumor tissue samples from 53 patients. Proteomic profiles were calibrated, binned, and normalized before analysis. We performed class comparison, class prediction, and supervised hierarchic cluster analysis. We tested a set of discriminatory features obtained in a previously published dataset to classify this independent set of normal, preinvasive, and invasive lung tissues. We found a specific proteomic profile that allows an overall predictive accuracy of over 90% of normal, preinvasive, and invasive lung tissues. The proteomic profiles of these tissues were distinct from each other within a disease continuum. We trained our prediction model in a previously published dataset and tested it in a new blinded test set to reach an overall 74% accuracy in classifying tumors from normal tissues. We found specific patterns of protein expression of the airway epithelium that accurately classify bronchial and alveolar tissue with normal histology from preinvasive bronchial lesions and from invasive lung cancer. Although further study is needed to validate this approach and to identify biomarkers of tumor development, this is a first step toward a new proteomic characterization of the human model of lung cancer tumorigenesis.

Somatic genetic changes accompanying lung tumor development

Carcinomas are believed to develop by incremental steps of increasingly abnormal morphology driven by accumulating somatic genetic changes. This process is often difficult to study, as the early stages are undetectable. We used fluorescence bronchoscopy, which enhances detection of preinvasive bronchial lesions, and have obtained sequential biopsies of carcinoma in situ (CIS) from a patient with no detectable tumor and from a squamous cell carcinoma that developed 19 months after presentation at the site of one of the previous CIS lesions. Biopsies of preinvasive CIS, which follow-up showed had different pathologic outcomes, and tumor were microdissected to obtain enriched cell populations and DNA prepared from them. Molecular characteristics of these biopsies were compared by loss of heterozygosity analysis, TP53 mutation analysis, and comparative genomic hybridization. Although all lesions examined had the same TP53 mutation and almost identical allelotypes, differences were observed. Loss in 5q21 and amplification of 3q25-26 were associated with the lesion that progressed and the subsequent carcinoma. Allele loss at 4p16 was detected in the tumor but not in any of the CIS lesions, suggesting it was a late event associated with tumor invasion. Amplification at 4q12 was specifically observed in the tumor and in the CIS at the site of eventual tumor formation. Although these findings may be unique to this one patient, the successful demonstration of sequential genetic changes raises the possibility that this approach, unencumbered by interpatient variability between lesions, will greatly facilitate the identification of molecular events driving the invasive process

Effective detection of bronchial preinvasive lesions by a new autofluorescence imaging bronchovideoscope system

Autofluorescence bronchoscopy is an important tool for the early detection of preinvasive bronchial lesions. However, autofluorescence bronchoscopy has difficulty distinguishing between preinvasive lesions and other benign epithelial changes. A new autofluorescence imaging bronchovideoscope system (AFI) comprises three signals, including an autofluorescence (460-690 nm) on excitation blue light (395-445 nm) and two different bands of reflected light: G' (550 nm) and R' (610 nm). We hypothesized that color analyses of these three wave lengths would improve our ability to differentiate between inflammation and preinvasive lesions. In order to prove this hypothesis and to evaluate the efficacy of AFI for detecting preinvasive lesions, we conducted a prospective study. A total of 32 patients with suspected or known lung cancer were entered into this study. Conventional white light bronchovideoscopy (WLB) and light induced fluorescence endoscopy (LIFE) were performed prior to using AFI. WLB and LIFE detected 62 lesions, including lung cancers (n=2), squamous dysplasias (n=30), and bronchitis (n=30). By utilizing AFI, 24 dysplasias and 2 cancer lesions were magenta in color, while 25 bronchitis lesions were blue. The sensitivities of detecting dysplasia by LIFE and AFI were 96.7% and 80%, respectively. The specificity of AFI (83.3%) was significantly higher than that of LIFE (36.6%) (p=0.0005). We conclude that AFI appears to represent a significant advance in distinguishing preinvasive and malignant lesions from bronchitis or hyperplasia under circumstances where LIFE would identify these all as abnormal lesions.

S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas.

S100A2 gene products were shown to be frequently and dramatically over-represented in non-small cell lung cancer (NSCLC) lesions over normal tissue by microarray analysis. We have now analysed an independent series of NSCLC tumours and multiple matched normal bronchial epithelial sites by RT–PCR and immunohistochemistry to investigate: whether this expression pattern can be confirmed and whether elevated expression is associated with tumour histology, clinical outcome or preneoplasia. In this second series, S100A2 was strongly expressed in 76% (35 out of 46) of tumours, more frequently in squamous cell than adenocarcinomas (P<0.002). This strong expression was not related to high-level gene amplification, but was associated in one of five informative cases with an allele-specific imbalance in transcript levels. Most tumours strongly expressed the ΔNp63 transcript, the product of which is a putative regulator of S100A2 transcription and while all but one of the tumours positive for ΔNp63 expressed S100A2, others negative for this regulator also expressed the gene. Contrary to the hypothesis that S100A2 is a tumour suppressor, no somatic mutations were identified in the coding sequence in 44 tumours. Furthermore, an examination of multiple tumour-free epithelial sites from 20 patients showed that strong expression was often associated with increasing levels of disorder in preinvasive bronchial lesions (P<0.0001).

Clinical prognostic indicators of high-grade pre-invasive bronchial lesions

Lung cancer arises from multistep genetic damage of bronchial epithelium, driving multifocal progressive dysplastic lesions. However, the risk of progression of high-grade pre-invasive bronchial lesions to cancer is poorly assessed. The purpose of this study was to better define the parameters that predict the outcome of these lesions. The current authors prospectively studied 27 patients with 31 histologically proven severe dysplasia (SD) and carcinoma in situ (CIS), with repeated bronchoscopy and endobronchial treatment. The influence of respiratory-cancer history, histopathological classification, tobacco consumption, and number of biopsies on the progression rate into cancer was studied. The actuarial progression rate to cancer was 17% at 1 yr and 63% at 3 yrs. A total of 11 cases of CIS progressed to invasive cancer, 17 were stable or regressed during the study, two with SD regressed and one progressed to invasive cancer. Progression of CIS appeared more frequent in lesions diagnosed as "questionable CIS". Persistence of smoking did not influence high-grade lesion outcome. The existence of synchronous lung cancer did not seem to impact on progression. The number of biopsies did not influence the outcome. In conclusion, the current study suggests that the outcome of high-grade pre-invasive lesions is not modified by the number of biopsies performed on these lesions. Careful pathological examination of these lesions and pathological revision seem necessary, since questionable cases have the worse progression rate.