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Screening and Early Detection of Lung Cancer

van't Westeinde, Susan C. MD; van Klaveren, Rob J. MD, PhD

doi: 10.1097/PPO.0b013e3182099319
Special Issue on Treatment of Early-Stage Lung Cancer

Lung cancer with an estimated 342,000 deaths in 2008 (20% of total) is the most common cause of death from cancer, followed by colorectal cancer (12%), breast cancer (8%), and stomach cancer (7%) in Europe. In former smokers, the absolute lung cancer risk remains higher than in never-smokers; these data therefore call for effective secondary preventive measures for lung cancer in addition to smoking cessation programs. This review presents and discusses the most recent advances in the early detection and screening of lung cancer.

An overview of randomized controlled computerized tomography-screening trials is given, and the role of bronchoscopy and new techniques is discussed. Finally, the approach of (noninvasive) biomarker testing in the blood, exhaled breath, sputum, and bronchoscopic specimen is reviewed.

From the Department of Pulmonology, Erasmus MC Rotterdam, Rotterdam, the Netherlands.

Reprints: Susan C. van't Westeinde, MD, Department of Pulmonology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands. E-mail:

Lung cancer with an estimated 342,000 deaths in 2008 (19.9% of total) is the most common cause of death from cancer, followed by colorectal cancer (12.3%), breast cancer (7.5%), and stomach cancer (6.8%) in Europe.1 More than 1 billion people around the world currently smoke tobacco. The use of tobacco kills more than 5 million people yearly. If this trend continues, it is expected that more than 8 million people will die of tobacco-related diseases yearly by 2030. The chance that a lifelong smoker will die prematurely of a tobacco-related disease is about 50%, and smokers who continued smoking died on average 10 years younger compared with lifelong nonsmokers. In contrast to other cancers, there has been almost no improvement in the 5-year survival rates of lung cancer in the past 30 years, primarily because lung cancer is detected in most cases in an advanced stage. Even with successful smoking cessation, the absolute risk of developing lung cancer remains high. As a result, 80% of all lung cancer cases occur in former smokers today. These data call for effective secondary preventive measures for lung cancer in addition to smoking cessation programs. This review presents and discusses the most recent advances in the early detection and screening of lung cancer.

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The introduction of low-dose multidetector helical computerized tomography (CT) has led to a major advance in cross-sectional imaging due to advance scan speed, improved spatial resolution, and the capacity to reconstruct multiple series from a single data acquisition. The low-dose technique results in an effective radiation dose2 of approximately 0.65 mSv, as apposed to 3.5 to 7.0 mSv for diagnostic CTs.3 In addition, no intravenous contrast is used.

A large number of review studies have been published on lung cancer low-dose CT (LDCT) screening in recent years.4-15 They all conclude that CT screening will detect lung cancer more often in an early stage, with rates varying between 38%16 and 66%.17 Whether this will translate into a lung cancer mortality reduction was until very recently unknown.4-15 Therefore, the American College of Chest Physicians guideline does not recommend CT screening unless as part of a well-designed clinical trial.18 Lung cancer and overall mortality data from the randomized controlled lung cancer CT screening trials NELSON, the Danish randomized CT screening trial, ITALUNG CT, and LUSI have to be awaited (Table 1). So far, only the DANTE trial investigators reported on the all-cause and lung cancer mortality and stage distribution in both study arms.24 After a median follow up of 3 years, there was no significant difference between the LDCT group and the control group with respect to the lung cancer-specific mortality. However, in a recent press release by the National Cancer Institute Data and Safety Monitoring Board of the National Lung Screening Trial, a 20% lung cancer mortality reduction and a 7% overall mortality reduction was reported after 7 years of follow up.27 Publication of the results is to be awaited.



One of the concerns around lung cancer screening was the high rate of test-positive results and the associated high number of workups. Investigators from the NELSON study, a population-based randomized lung cancer screening trial, demonstrated, however, that this problem could be overcome by using a semiautomated volumetry software (LungCare; Siemens Medical Solutions, Forchheim, Germany).17 Subjects received a positive test result and were referred to a pulmonologist based on the size and volume doubling time (VDT) of the noncalcified nodules detected. A nodule was classified as noncalcified if it did not meet previously specified criteria for a benign lesion. For solid pleural-based and nonsolid pulmonary nodules, the diameter was manually determined, and the VDT calculated as described before.28 For pleural-based nodules, the diameter perpendicular to the costal pleura was taken. For partially solid lesions, only the volume of the solid region was used. Diameter was defined as the average of maximum nodule length and width. Growth was defined as a change in volume between the first and the second scan of 25% or greater. The 25% threshold was based on 3 zero-change data sets in which volume variation of individual nodules was assessed between 2 LDCT scans. In these studies, the volume measurement error varied between 20% and 25%.12,14,15 Growing nodules were classified into 3 growth categories according to their VDT (<400, 400-600, and >600 days).

A baseline scan was considered positive if any noncalcified nodule had a solid component of greater than 500 mm3 (>9.8 mm in diameter) or indeterminate if the volume of the largest solid nodule or the solid component of a partially solid nodule was 50 to 500 mm3 (4.6-9.8 mm in diameter) or greater than 8 mm in diameter for nonsolid nodules. Subjects with an indeterminate result had a follow-up scan 3 months later to assess growth. If at that time the lesion had a VDT o less than 400 days, the final result was declared positive, otherwise negative. Subjects with positive screening tests were referred to a chest physician for workup and diagnosis. If lung cancer was diagnosed, the participant was treated for the disease and went off screening; if no lung cancer was found, the regular second-round CT scan was scheduled 12 months after the baseline scan. For participants with 1 or more new nodules on the second round scan, the result (positive or negative) was based on size of the nodule, as for round 1; a follow-up scan for an indeterminate result was performed 6 weeks later. For participants with previously detected nodules, the second round result was based on the VDT. If there was no growth or if the VDT was greater than 600 days, the screen was negative. If the VDT was less than 400 days, or if a new solid component had emerged in a previously nonsolid nodule, the scan was considered to be positive. When the VDT was 400 to 600 days, the test was indeterminate, and a follow-up scan was done 1 year after the second round. With a VDT less than 400 days, the final result was considered to be positive, otherwise negative. If both new and existing nodules were present, the nodule with the largest volume or fastest growth determined the test result.

As a result of this NELSON nodule management strategy, the rate of test-positive results during baseline and second-round screening dropped from 8.3% to 30.3%16,25 and 18% to 25.8%20,24 to 2.6% and 1.8%, respectively.17 The NELSON strategy did not compromise the sensitivity (94.6%; 95% confidence interval [95% CI], 86.5%-98.0%), and the negative predictive value (NPV) increased to 99.9% (95% CI, 99.9%-100.0%). Despite a major reduction in the number of test-positive results, the rate of surgical resections for benign disease (false-positives) remained too high with 27% at baseline and 19% at second-round screening, even though this was within the range reported by others (6%-38%).16 Novel biomarkers (see below) might help to reduce this high rate of false-positive test results in the future.

Furthermore, it is yet unknown what proportion of the cancer cases detected are overdiagnosed cases.29,30 As no long-term follow-up data are available for lung cancer, this question cannot yet be answered.

Recently, new data have been published on the effect of CT screening on informed decision making, quality of life, and smoking behavior. The best way to transfer information about lung cancer screening to eligible subjects still needs to be determined as about only half of the participants showed adequate knowledge on lung cancer screening.31 Nevertheless, the health-related quality of life in subjects with and without adequate knowledge on the subject was similar.32 Factors that influence quality of life in participants of a CT screening program are related to the CT test result33 and their affective lung cancer risk perception.34 In addition, waiting for the test result was reported to be discomforting.35 Lung cancer screening studies reported that the test result in subjects with negative screening CT did not influence the duration of long-term smoking abstinence.36,37 Subjects with a positive test result were reported to have a higher likelihood of point abstinence,37 and in subjects with an indeterminate test, a higher number of quit attempts was seen.36 Lung cancer screening may thus be regarded as a teachable moment to improve smoking behavior.38

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As discussed before, multidetector CT technology enables us to detect lung cancer in a high proportion at an early stage, and they are predominantly adenocarcinomas. Multidetector CT technology is unable to detect preinvasive lesions and less suited to detect early-stage lung cancer in the central airways. Epithelial changes, such as high-grade dysplasia and carcinoma in situ in the central airways, are early-stage squamous cell carcinomas.39 The most widely used and investigated technique for the detection of this kind of premalignant endobronchial lesions is the light-induced fluorescence endoscopy (LIFE), a technique recommended by the American College of Chest Physicians.40 Limitation of the LIFE system is that it is sensitive to the total mucosal blood volume. As a result, it is difficult to discriminate between bronchitis and inflammation on one hand, and premalignant bronchial lesions on the other hand. As a result, two thirds of the LIFE-detected suggestive lesions are false positive after correlation with pathology.41 Because of this, low-specificity LIFE cannot be used as a screening tool. The modified autofluorescence technique relies on the same technique as LIFE, but by using additional filters, a red-green ratio is generated, which is sensitive to the microvascular pattern instead of the total mucosal blood volume. By using this narrow-band bronchoscopic technique, a higher specificity can be achieved up to 80% without significantly compromising the sensitivity.39 A novel technique currently under investigation is the optical coherence tomography.42,43 By this high-resolution point imaging technique, cross-sectional images of the mucosa can be made up to 3 mm in depth. Inflammation can be differentiated from premalignant lesions by measurement of the epithelial thickness. The advantage of this technique is that it is based on real-time imaging; the disadvantages are the complex interpretation of the images and the high costs. Another novel diagnostic approach is the fibered confocal fluorescence microscopy.44 The technique is based on the same principle as confocal microscopy. By using a fiberoptic miniprobe (1 mm in diameter), 0- to 50-μm deep real-time cross sectional images of the bronchial epithelium can be obtained. It also increases the specificity as compared with LIFE, but the interpretation is complex, and the scopist must know the characteristics of premalignant lesions. Maldonado and Jett45 reviewed the use of molecular biological techniques applied to bronchoscopically obtained biopsies. Although not yet implemented in daily practice, the authors expect a role for early diagnosis and clinical guidance for inoperable lung cancer cases with regard to prognosis and expected response to therapy.

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Circulating DNA, Epigenetics, and Transcriptomics

Circulating Tumor DNA

Stroun et al46 were the first to report that cancer patients with malignant disease had extractable amounts of DNA in their plasma. Several case-control studies on circulating DNA have been conducted ever since with cutoff values varying between 2 and 25 ng/mL. Paci et al47 found a positive predictive value of 75% and an NPV of 64%. Despite the excellent NPV, varying between 65% and 95% depending on cutoff value for circulating DNA, reported by Sozzi et al,48 baseline assessment of plasma DNA levels did not improve the accuracy of lung cancer screening by spiral CT.49 When combining circulating tumor DNA with COX-2 mRNA expression in peripheral blood, an excellent diagnostic performance could be achieved, with a specificity of 92% and a sensitivity of 91%.50 Yoon et al51 reported that the odds ratio for lung cancer detection with circulating DNA levels greater than 20 ng/mL was 50 as compared with healthy controls. In conclusion, cutoff values for circulating DNA value greatly in different studies, and larger studies are necessary to determine an adequate cutoff value for circulating DNA in the blood.

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Promoter Hypermethylation

Epigenetics refer to modification of genes that are not coded in the DNA sequence itself but by posttranslational modifications in DNA. In cancer cells, hypermethylation of certain areas is seen, which is associated with silencing of promoter regions of growth-controlling genes.52 In subjects with lung cancer, elevated levels of methylated genes in plasma have been found such as RASSFIA, p16 (cell cycle), APC (adhesion), FIHT, RARbeta, MGMT, DAPK (apoptosis), CDH13, tissue inhibitors of metalloproteinase 3 (TIMP-3), GSTP1, and SOCS1 and SOCS3 (cytokine signaling).53,54

In several case-control studies, the accuracy of promoter hypermethylation as an early detection marker has been investigated. These studies showed highly variable sensitivities and specificities.54-57 Ostrow et al54 used a panel of 4 different genes and found a specificity of 71% in subjects with benign nodules on their CT scan, and in 22%, the test was false positive. Therefore, promoter hypermethylation cannot yet be used as a lung cancer early detection biomarker in daily practice.

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Transcriptomics: Messenger and Micro-RNA

Messenger RNA has been used for the detection of circulating tumor cells. Xi et al58 demonstrated that a panel including CK7, EGFR, SCCA, and SFTPB identified all of the 22 lung cancers. Micro-RNAs (miRNAs) are a class of small noncoding RNA gene products thought to regulate other genes' expressions. Circulating tumor-derived exosome levels and miRNA patterns appeared to be significantly different in lung cancer patients as compared with controls.59 Micro-RNA expression profiles in lung cancer tissues have been used for risk stratification and outcome prediction studies.60,61 Downside of serum miRNA profiles in solid cancer is that this approach often fails to identify miRNAs commonly found in lung cancer tissue and that the miRNA profiles found by the different groups are almost nonoverlapping, as is the case with gene expression profiling. A possible explanation may be the different techniques and experimental platforms used.62

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As a result of genomic mutations and subsequent translational changes, protein products could be used as potential biomarkers of neoplasia.63 Examples are CEA (carcinoembryonic antigen), NSE (neuron-specific enolase), chromogranin, CA125 (carbohydrate antigen 125), and CA19-9.64 The following individual biomarkers have been investigated in case-control studies: Cyfra 21-1 (cytokeratin 19 fragment),65 C-reactive protein,66 SAA (serum amyloid α),67 adomet,68 MIF (macrophage migration inhibitory factor),69 suPAR (soluble urokinase plasminogen activator receptor),70 soluble E-selectin,71 NNMT (nicotinamide N-methyltransferase),72 cAMP (cyclic adenosine 3′,5′ monophosphate) protein kinase,73 connective tissue-activating peptide III,74 and TIMP-1 and TIMP-2 (serum TIMP-1 and TIMP-2).75 None of these biomarkers are ideal early detection markers because of their low specificity and/or sensitivity.

In a matched case-control study including 49 lung cancer patients by Patz et al,76 a panel of 4 serum proteins was tested (CEA, retinol-binding protein, α1-antitrypsin, and squamous cell carcinoma antigen); a sensitivity of 78% and specificity of 75% were seen. Xiao et al77 found that a combination of 4 biomarkers had a higher sensitivity and specificity than any single marker, but even then, the specificity remained low (53%) at a sensitivity of 86%.

Because lung cancer is a heterogeneous disease, it is unlikely that 1 single marker will be uniformly elevated. Comparative protein profiling is generally acknowledged as a promising way for the detection of specific and predictive protein expression patterns reflecting certain stages of cancer. The advances of new analyzing mass spectrometry techniques as surface-enhanced laser desorption/ionization time-of-flight (TOF) mass spectrometry and conventional matrix-assisted laser desorption ionization (MALDI) TOF mass spectrometry make it possible to detect multiple protein changes simultaneously.65

With MALDI-TOF profiling, a sensitivity of 34% for adenocarcinomas, 52% for squamous cell carcinomas, at a specificity of 90% was reached.78 By surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, the sensitivity of the marker pattern ranged between 87% and 93%, and the specificity was 80% to 97%.79 Ueda et al80 focused on glycoprotein patterns and found a sensitivity 19% and a specificity of 100%. Lin et al81 used a novel magnetic bead-based MALDI-TOF-MS technique and found a sensitivity of 80% and specificity of 93%.

Limitation of all the studies presented is that independent validation is missing. Despite the discovery of new biomarkers, identification of biomarkers that are superior to those currently used has been proven to be difficult, and very few, if any, newly discovered biomarkers have entered the clinic in the past 10 years.82

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From breast and also from lung cancer studies, we know that autoantibodies against cancer-associated antigens can be measured up to 5 years before symptomatic disease.83 Autoantibodies to tumor antigens represent a humoral response and are not the product of mutated genes. Different studies have shown that cancer growth and progression are associated with cancer immunosurveillance and inflammation. Not only in autoimmune diseases such as multiple sclerosis but also in cancer, immunoglobulins are released at high levels into the blood. The molecular signatures of such immunoglobulins could potentially be used as diagnostic or prognostic biomarkers. Screening for disease-related immune responses is generally performed by testing patients' sera against libraries of known antigens. Although successful, techniques such as serological expression cloning (SEREX) are aimed at detecting the targeted antigens, rather than the reactive immunoglobulins. An alternative strategy is a direct comparison of the amino acid sequences of immunoglobulin molecules between cases and controls using high-resolution Orbitrap (LTQ Orbitrap XL, Thermo Fisher Scientific, Bremen, Germany) mass spectrometry.84

Several authors have studied the value of individual autoantibodies as early detection markers for lung cancer. Brichory et al85 investigated the protein gene product 9.5 (PGP 9.5); in 14% of the subjects with lung cancer, autoantibodies against PGP 9.5 were detected. In another study, they found serum anti-annexins I and II autoantibodies in 30% and 33%, respectively, of subjects with lung cancer, and for adenocarcinomas, a slightly better performance was seen.86

Chapman et al83 tested 7 autoantibodies, and for a panel based on all 7 autoantibodies with positivity defined as a raised level of at least 1 autoantibody, the best diagnostic values were seen as compared with individual autoantibody testing or a panel of only 4 autoantibodies. The 7-autoantibody-based panel showed a sensitivity of 76% for all types of lung cancer, with a specificity of 92%.83 Boyle et al87 investigated the diagnostic performance of the Early CDT-Lung (Early CDT-Lung test, Oncimmune, Kansas), a panel of 6 lung cancer-associated antigens. In a pilot study consisting of 842 lung cancer patients, the positivity rate varied between 0% and 51%, depending on the lung cancer stage and histology; no diagnostic values could be calculated because no controls were included. In another study with 85 cases and 85 matched controls, a panel of 3 antigens (annexin I, LAMR1, and 14-3-3 theta) had a sensitivity to detect lung cancer of 51% and a specificity of 82%.88 Zhong et al89 tested a panel of 5 tumor-associated antibodies as markers in a subset of participants of 102 subjects of the Mayo clinic CT screening trial, including 46 cancer cases; they found a sensitivity of 91% and specificity of 91%. Farlow et al90 used a panel of 6 autoantibodies, which showed only a 7% misclassification rate and an excellent sensitivity and specificity of 95% and 91%, respectively. For diagnosing squamous cell lung cancer and healthy controls, a panel of 20 antibodies was established, which showed both a sensitivity and specificity of 93%.91 For distinguishing between nontumor lung pathologic findings and squamous cell lung cancer, the panel with the best diagnostic performance was based on 69 antigens, resulting in a sensitivity and specificity of 75% and 94%, respectively.91 Leidinger et al92 achieved, with a library of 1827 peptide clones with reactivity against serum antibodies, an accuracy of 98% in discriminating lung cancer from healthy controls and an 89% accuracy to discriminate lung cancer patients from patients with nontumor lung pathologic findings.

Individual autoantibodies lack sensitivity; autoantibody signatures are more promising; in studies on antibody profiling, they provide better diagnostic performance as compared with individual autoantibodies. The identified signatures need replication and independent clinical validation before they can be used in clinical practice. Furthermore, extracting lung cancer cases from nontumor lung pathologic findings based on serological assays may even be more challenging; future studies therefore should also focus on this matter.

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Breath Test

Exhaled breath analysis is a novel approach to identify inflammatory and oxidative stress markers involved in the pathogenesis of various respiratory conditions. A frequently used technique is based on exhaled breath condensate (EBC). Drawback of EBC is that the values obtained from different devices may not be directly comparable, that the markers may reflect each part of the ororespiratory tract,93 and that independent validation is missing. Therefore, the EBC approach is still in its experimental phase and cannot be used in clinic practice yet.

The following markers have been studied in EBC: 3-p microsatellite signature,94 DNA methylation,95 endothelin,96 COX-2, and survivin,97 and angiogenic markers.98 The aforementioned studies found significant differences in biomarkers between controls and lung cancer cases, but no diagnostic values were provided. Di Natale et al99 used an electronic nose; the analyses of patterns of chromatography were correct in 100% of lung cancer patients, and controls were misdiagnosed in 6% of cases. A model based on 16 volatile organic compounds (VOCs) had a sensitivity of 85% and specificity of 80%,100 and a model based on 13 VOCs showed a sensitivity of 72% and a specificity of 94%.101 Song et al102 found for the VOCs 3-hydroxy-2-butanone and 1-butanol a sensitivity of 95% and a specificity of 93%, and a sensitivity of 85% and specificity of 93%, respectively.

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Exfoliative Materials


The role of genomic-based markers in bronchoalveolar lavage (BAL) samples to distinguish lung cancer from noncancer cases has been studied by several authors. For promoter hypermethylation of p16, a sensitivity of 64% and specificity of 75% were found.103 Liloglou et al104 investigated genomic instability using 4 microsatellite markers and found a sensitivity of 74% and a specificity of 77%. In a study by Kim et al,105 promoter hypermethylation of at least 1 of the 4 tested genes was seen in 68% of the lavage samples. However, in cancer-free subjects, hypermethylation of 1 of the 4 genes was seen in 3% to 28%. A test based on 14 genes from bronchial epithelial cells related to DNA repair, antioxidant activity, and DNA transcription showed areas under the curve of 0.82 and 0.87 in 2 small case-control sets including 25 and 18 cases, respectively, described by Blomquist et al.106

In the next paragraph, studies on the role of biomarkers in both sputum and BAL are discussed. Telomerase activity in sputum had a sensitivity of 82% and a specificity of 100%, whereas for bronchial washings, these values were only 68% and 100%, respectively; the authors explain this finding by the high number of inflammatory cells found in bronchial washings.107 Mecklenburg et al108 found expression of at least 1 MAGE gene in 33% (5/15) of the sputum specimens from patients with lung cancer, whereas in BAL fluid MAGE expression was observed in 78% (18/23) of the patients with confirmed lung cancer. In the lung cancer screening study of McWilliams et al,109 18% (4/22) of the lung cancers detected were radio-occult and were detected by light-induced fluoroscope endoscope (LIFE) bronchoscopy only. Of the subjects with lung cancer, 95% (21/22) had sputum atypia on quantitative sputum cytometry using an automatic image analysis of a number of (abnormal) nuclear features.109 However, a large proportion, 75% (423/561) of the screened subjects, had sputum atypia, as apposed to only 14 subjects with screening-detected lung cancers. Spira et al110 found an excellent sensitivity and specificity of both 95% when they combined cytopathology with an 80-probeYbased genetic biomarker on bronchoscopically obtained large airway epithelial cells.

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To improve the diagnostic accuracy of sputum cytology, the diagnostic value of promoter hypermethylation, fluorescence in situ hybridization (FISH) and genetic mutations has been investigated. Although it is unlikely that early-stage lung cancers less than 1 cm in diameter will exfoliate detectable cancer cells in sputum, it is hypothesized that, because of the process of field cancerization, genetic or epigenetic changes in exfoliated cells may reflect increased lung cancer risk.111

Honorio et al112 reported that the methylation status of a single gene (RASSF1A) had a sensitivity of 28% and a specificity of 76%. Authors studying methylation status with panels of 3 to 6 genes found sensitivities varying between 56% and 64% and specificities between 64% and 100%.113-115 Destro et al116 reported that 48% of the lung cancer cases had either a K-ras mutation or p16 hypermethylation, which were almost mutually exclusive seen. Combining the molecular and cytologic results increased the sensitivity to 60% and the specificity to 95%. Adding FISH to conventional sputum cytology (HYAL2 or FHT deletions) increased the sensitivity to 76% and specificity to 92%.117

Automated sputum cytometry can be based on aneuploidity (abnormal number of chromosomes), nuclear abnormalities, and/or malignancy-associated changes of cells. Using this technique, Kemp et al118 found improved sensitivity of sputum cytology from 16% to 40% at a specificity of 91%. Using a comparable technique, Li et al119 found a sensitivity of 75% at a specificity of 50%. A FISH-based panel consisting of 4 DNA targets (epidermal growth factor, MYC, 5p15, and CEP 6) had a sensitivity of 76% to detect lung cancer 18 months before diagnosis.120

With conventional sputum cytology for all 444 participants with lung cancer, sensitivities of 38% and 20%, respectively, were found for detecting premalignant and cancer cells; of all lung cancer patients with adequate specimens in 75%, the sputum was positive for cancer cells.121 These results are higher than in daily practice; this is due to the labor-intensive study protocol, with 3 cytopathologists reviewing 2 sputum specimens per participant (including 1 induced sputum). The authors suggest a role for automated sputum processing and magnetic-assisted cell sorting to improve efficiency and sensitivity when sputum cytology is to be implemented in a screening setting; in addition, the presence of premalignant cells may identify high-risk patients and guide follow up and imaging intervals.121 Besides standardization of sputum collection and additional (new) processing techniques of the cytologic specimen, the addition of biomarkers may improve diagnostic values. Again, larger studies are necessary to confirm these results.

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The results of ongoing randomized lung cancer CT screening trials have to be awaited before final conclusions can be drawn with regard to the effectiveness and cost-effectiveness of CT screening, although preliminary data from the National Lung Screening Trial are very promising. The final role of lung cancer biomarkers for early detection, risk stratification, or as an adjunct to CT screening to reduce the rate of false-positive test results is yet unknown. Although some studies report high sensitivities and/or specificities, most of them lack reproducibility, and none of them have been validated in independent large-scale clinical trials.

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    Cancer screening; lung neoplasms; biomarkers; exhaled breath; multidetector CT scan

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