Detection and size quantification of pulmonary nodules in ultralow-dose versus regular-dose CT: a comparative study in COPD patients.

OBJECTIVE: To evaluate detectability and semi-automatic diameter and volume measurements of pulmonary nodules in ultralow-dose CT (ULDCT) vs regular-dose CT (RDCT). METHODS: Fifty patients with chronic obstructive pulmonary disease (COPD) underwent RDCT on 64-multidetector CT (120 kV, filtered back projection), and ULDCT on third-generation dual source CT (100 kV with tin filter, advanced modeled iterative reconstruction). One radiologist evaluated the presence of nodules on both scans in random order, with discrepancies judged by two independent radiologists and consensus reading. Sensitivity of nodule detection on RDCT and ULDCT was compared to reader consensus. Systematic error in semi-automatically derived diameter and volume, and 95% limits of agreement (LoA) were evaluated. Nodule classification was compared by κ statistics. RESULTS: ULDCT resulted in 83.1% (95% CI: 81.0-85.2) dose reduction compared to RDCT (p < 0.001). 45 nodules were present, with diameter range 4.0-25.3 mm and volume range 16.0-4483.0 mm3. Detection sensitivity was non-significant (p = 0.503) between RDCT 88.8% (95% CI: 76.0-96.3) and ULDCT 95.5% (95% CI: 84.9-99.5). No systematic bias in diameter measurements (median difference: -0.2 mm) or volumetry (median difference: -6 mm3) was found for ULDCT compared to RDCT. The 95% LoA for diameter and volume measurements were ±3.0 mm and ±33.5%, respectively. κ value for nodule classification was 0.852 for diameter measurements and 0.930 for volumetry. CONCLUSION: ULDCT based on Sn100 kV enables comparable detectability of solid pulmonary nodules in COPD patients, at 83% reduced radiation dose compared to RDCT, without relevant difference in nodule measurement and size classification. ADVANCES IN KNOWLEDGE: Pulmonary nodule detectability and measurements in ULDCT are comparable to RDCT.

Lung cancer prediction by Deep Learning to identify benign lung nodules.

INTRODUCTION: Deep Learning has been proposed as promising tool to classify malignant nodules. Our aim was to retrospectively validate our Lung Cancer Prediction Convolutional Neural Network (LCP-CNN), which was trained on US screening data, on an independent dataset of indeterminate nodules in an European multicentre trial, to rule out benign nodules maintaining a high lung cancer sensitivity. METHODS: The LCP-CNN has been trained to generate a malignancy score for each nodule using CT data from the U.S. National Lung Screening Trial (NLST), and validated on CT scans containing 2106 nodules (205 lung cancers) detected in patients from from the Early Lung Cancer Diagnosis Using Artificial Intelligence and Big Data (LUCINDA) study, recruited from three tertiary referral centers in the UK, Germany and Netherlands. We pre-defined a benign nodule rule-out test, to identify benign nodules whilst maintaining a high sensitivity, by calculating thresholds on the malignancy score that achieve at least 99 % sensitivity on the NLST data. Overall performance per validation site was evaluated using Area-Under-the-ROC-Curve analysis (AUC). RESULTS: The overall AUC across the European centers was 94.5 % (95 %CI 92.6-96.1). With a high sensitivity of 99.0 %, malignancy could be ruled out in 22.1 % of the nodules, enabling 18.5 % of the patients to avoid follow-up scans. The two false-negative results both represented small typical carcinoids. CONCLUSION: The LCP-CNN, trained on participants with lung nodules from the US NLST dataset, showed excellent performance on identification of benign lung nodules in a multi-center external dataset, ruling out malignancy with high accuracy in about one fifth of the patients with 5-15 mm nodules.

Evaluation of a novel deep learning-based classifier for perifissural nodules.

OBJECTIVES: To evaluate the performance of a novel convolutional neural network (CNN) for the classification of typical perifissural nodules (PFN). METHODS: Chest CT data from two centers in the UK and The Netherlands (1668 unique nodules, 1260 individuals) were collected. Pulmonary nodules were classified into subtypes, including "typical PFNs" on-site, and were reviewed by a central clinician. The dataset was divided into a training/cross-validation set of 1557 nodules (1103 individuals) and a test set of 196 nodules (158 individuals). For the test set, three radiologically trained readers classified the nodules into three nodule categories: typical PFN, atypical PFN, and non-PFN. The consensus of the three readers was used as reference to evaluate the performance of the PFN-CNN. Typical PFNs were considered as positive results, and atypical PFNs and non-PFNs were grouped as negative results. PFN-CNN performance was evaluated using the ROC curve, confusion matrix, and Cohen's kappa. RESULTS: Internal validation yielded a mean AUC of 91.9% (95% CI 90.6-92.9) with 78.7% sensitivity and 90.4% specificity. For the test set, the reader consensus rated 45/196 (23%) of nodules as typical PFN. The classifier-reader agreement (k = 0.62-0.75) was similar to the inter-reader agreement (k = 0.64-0.79). Area under the ROC curve was 95.8% (95% CI 93.3-98.4), with a sensitivity of 95.6% (95% CI 84.9-99.5), and specificity of 88.1% (95% CI 81.8-92.8). CONCLUSION: The PFN-CNN showed excellent performance in classifying typical PFNs. Its agreement with radiologically trained readers is within the range of inter-reader agreement. Thus, the CNN-based system has potential in clinical and screening settings to rule out perifissural nodules and increase reader efficiency. KEY POINTS: • Agreement between the PFN-CNN and radiologically trained readers is within the range of inter-reader agreement. • The CNN model for the classification of typical PFNs achieved an AUC of 95.8% (95% CI 93.3-98.4) with 95.6% (95% CI 84.9-99.5) sensitivity and 88.1% (95% CI 81.8-92.8) specificity compared to the consensus of three readers.

Optimization of CT windowing for diagnosing invasiveness of adenocarcinoma presenting as sub-solid nodules.

PURPOSE: To evaluate the optimal window setting to diagnose the invasiveness of lung adenocarcinoma in sub-solid nodules (SSNs). METHODS: We retrospectively included 437 SSNs and randomly divided them 3:1 into a training group (327) and a testing group (110). The presence of a solid component was regarded as indicator of invasiveness. At fixed window level (WL) of 35 Hounsfield Units (HU), two readers adjusted the window width (WW) in the training group and recorded once a solid component appeared or disappeared on CT images acquired at 120 kVp. The optimal WW cut-off value to differentiate between invasive and pre-invasive lesions, based on the receiver operating characteristic (ROC) curve, was defined as "core" WW. The diagnostic performances of the mediastinal window setting (WW/WL, 350/35 HU) and core window setting were then compared in the testing group. RESULTS: Of the 437 SSNs, 88 were pre-invasive [17 atypical adenomatous hyperplasia (AAH) and 71 adenocarcinoma in situ (AIS)], 349 were invasive [233 minimally invasive adenocarcinoma (MIA), 116 invasive adenocarcinoma (IA)]. In training group, the core WW of 1175 HU was the optimal cut-off to detect solid components of SSNs (AUC:0.79). In testing group, the sensitivity, specificity, positive, negative predictive value, and diagnostic accuracy for SSN invasiveness were 49.4%, 90.5%, 95.7%, 29.7%, and 57.3% for mediastinal window setting, and 87.6%, 76.2%, 91.6%, 76.2%, and 85.5% for core window setting. CONCLUSION: At 120 kVp, core window setting (WW/WL, 1175/35 HU) outperformed the traditional mediastinal window setting to diagnose the invasiveness of SSNs.

A Subsolid Nodules Imaging Reporting System (SSN-IRS) for Classifying 3 Subtypes of Pulmonary Adenocarcinoma.

OBJECTIVES: To develop an imaging reporting system for the classification of 3 adenocarcinoma subtypes of computed tomography (CT)-detected subsolid pulmonary nodules (SSNs) in clinical patients. METHODS: Between November 2011 and October 2017, 437 pathologically confirmed SSNs were retrospectively identified. SSNs were randomly divided 2:1 into a training group (291 cases) and a testing group (146 cases). CT-imaging characteristics were analyzed using multinomial univariable and multivariable logistic regression analysis to identify discriminating factors for the 3 adenocarcinoma subtypes (pre-invasive lesions, minimally invasive adenocarcinoma, and invasive adenocarcinoma). These factors were used to develop a classification and regression tree model. Finally, an SSN Imaging Reporting System (SSN-IRS) was constructed based on the optimized classification model. For validation, the classification performance was evaluated in the testing group. RESULTS: Of the CT-derived characteristics of SSNs, qualitative density (nonsolid or part-solid), core (non-core or core), semantic features (pleural indentation, vacuole sign, vascular invasion), and diameter of solid component (≤6 mm or >6 mm), were the most important factors for the SSN-IRS. The total sensitivity, specificity, and diagnostic accuracy of the SSN-IRS was 89.0% (95% confidence interval [CI], 84.8%-92.4%), 74.6% (95% CI, 70.8%-78.1%), and 79.4% (95% CI, 76.5%-82.0%) in the training group and 84.9% (95% CI, 78.1%-90.3%), 68.5% (95% CI, 62.8%-73.8%), and 74.0% (95% CI, 69.6%-78.0%) in the testing group, respectively. CONCLUSIONS: The SSN-IRS can classify 3 adenocarcinoma subtypes using CT-based characteristics of subsolid pulmonary nodules. This classification tool can help clinicians to make follow-up recommendations or decisions for surgery in clinical patients with SSNs.

Clinical characteristics and work-up of small to intermediate-sized pulmonary nodules in a Chinese dedicated cancer hospital.

Objectives: To evaluate the characteristics and work-up of small to intermediate-sized pulmonary nodules in a Chinese dedicated cancer hospital. Methods: Patients with pulmonary nodules 4-25 mm in diameter detected via computed tomography (CT) in 2013 were consecutively included. The analysis was restricted to patients with a histological nodule diagnosis or a 2-year follow-up period without nodule growth confirming benign disease. Patient information was collected from hospital records. Results: Among the 314 nodules examined in 299 patients, 212 (67.5%) nodules in 206 (68.9%) patients were malignant. Compared to benign nodules, malignant nodules were larger (18.0 mm vs. 12.5 mm, P < 0.001), more often partly solid (16.0% vs. 4.7%, P < 0.001) and more often spiculated (72.2% vs. 41.2%, P < 0.001), with higher density in contrast-enhanced CT (67.0 HU vs. 57.5 HU, P = 0.015). Final diagnosis was based on surgery in 232 out of 314 (73.9%) nodules, 166 of which were identified as malignant [30 (18.1%) stage III or IV] and 66 as benign. In 36 nodules (11.5%), diagnosis was confirmed by biopsy and the remainder verified based on stability of nodule size at follow-up imaging (n = 46, 14.6%). Among 65 nodules subjected to gene (EGFR) mutation analyses, 28 (43.1%) cases (EGFR19 n = 13; EGFR21 n = 15) were identified as EGFR mutant and 37 (56.9%) as EGFR wild-type. Prior to surgery, the majority of patients [n = 194 (83.6%)] received a contrast-enhanced CT scan for staging of both malignant [n = 140 (84.3%)] and benign [n = 54 (81.8%)] nodules. Usage of positron emission tomography (PET)-CT was relatively uncommon [n = 38 (16.4%)]. Conclusions: CT-derived nodule assessment assists in diagnosis of small to intermediate- sized malignant pulmonary nodules. Currently, contrast-enhanced CT is commonly used as the sole diagnostic confirmation technique for pre-surgical staging, often resulting in surgery for late-stage disease and unnecessary surgery in cases of benign nodules.

New Fissure-Attached Nodules in Lung Cancer Screening: A Brief Report From The NELSON Study.

INTRODUCTION: In incidence lung cancer screening rounds, new pulmonary nodules are regular findings. They have a higher lung cancer probability than baseline nodules. Previous studies have shown that baseline perifissural nodules (PFNs) represent benign lesions. Whether this is also the case for incident PFNs is unknown. This study evaluated newly detected nodules in the Dutch-Belgian randomized-controlled NELSON study with respect to incidence of fissure-attached nodules, their classification, and lung cancer probability. METHODS: Within the NELSON trial, 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new nodules detected after baseline were included. Nodules were classified based on location and attachment. Fissure-attached nodules were re-evaluated to be classified as typical, atypical, or non-PFN by two radiologists without knowledge of participant lung cancer status. RESULTS: One thousand four hundred eighty-four new nodules were detected in 949 participants (77.4% male, median age 59 years [interquartile range: 55-63 years]) in the second, third, and final NELSON screening round. Based on 2-year follow-up or pathology, 1393 nodules (93.8%) were benign. In total, 97 (6.5%) were fissure-attached, including 10 malignant nodules. None of the new fissure-attached malignant nodules was classified as typical or atypical PFN. CONCLUSIONS: In the NELSON study, 6.5% of incident lung nodules were fissure-attached. None of the lung cancers that originated from a new fissure-attached nodule in the incidence lung cancer screening rounds was classified as a typical or atypical PFN. Our results suggest that also in the case of a new PFN, it is highly unlikely that these PFNs will be diagnosed as lung cancer.

Comparison of Veterans Affairs, Mayo, Brock classification models and radiologist diagnosis for classifying the malignancy of pulmonary nodules in Chinese clinical population.

BACKGROUND: Several classification models based on Western population have been developed to help clinicians to classify the malignancy probability of pulmonary nodules. However, the diagnostic performance of these Western models in Chinese population is unknown. This paper aimed to compare the diagnostic performance of radiologist evaluation of malignancy probability and three classification models (Mayo Clinic, Veterans Affairs, and Brock University) in Chinese clinical pulmonology patients. METHODS: This single-center retrospective study included clinical patients from Tianjin Medical University Cancer Institute and Hospital with new, CT-detected pulmonary nodules in 2013. Patients with a nodule with diameter of 4-25 mm, and histological diagnosis or 2-year follow-up were included. Analysis of area under the receiver operating characteristic curve (AUC), decision curve analysis (DCA) and threshold of decision analysis was used to evaluate the diagnostic performance of radiologist diagnosis and the three classification models, with histological diagnosis or 2-year follow-up as the reference. RESULTS: In total, 277 patients (286 nodules) were included. Two hundred and seven of 286 nodules (72.4%) in 203 patients were malignant. AUC of the Mayo model (0.77; 95% CI: 0.72-0.82) and Brock model (0.77; 95% CI: 0.72-0.82) were similar to radiologist diagnosis (0.78; 95% CI: 0.73-0.83; P=0.68, P=0.71, respectively). The diagnostic performance of the VA model (AUC: 0.66) was significantly lower than that of radiologist diagnosis (P=0.003). A three-class classifying threshold analysis and DCA showed that the radiologist evaluation had higher discriminatory power for malignancy than the three classification models. CONCLUSIONS: In a cohort of Chinese clinical pulmonology patients, radiologist evaluation of lung nodule malignancy probability demonstrated higher diagnostic performance than Mayo, Brock, and VA classification models. To optimize nodule diagnosis and management, a new model with more radiological characteristics could be valuable.

An Update on the European Lung Cancer Screening Trials and Comparison of Lung Cancer Screening Recommendations in Europe.

While lung cancer screening has been implemented in the United States, it is still under consideration in Europe. So far, lung cancer screening trials in Europe were not able to replicate the results of the National Lung Screening Trial, but they do show a stage shift in the lung cancers that were detected. While eagerly awaiting the final result of the only lung cancer screening trial with sufficient statistical power, the NELSON trial, a number of European countries and medical societies have published recommendations for lung cancer screening using computed tomography. However, there is still a debate with regard to the design of future lung cancer screening programs in Europe. This review summarizes the latest evidence of European lung cancer screening trials and gives an overview of the essence of recommendations from the different European medical societies and countries.

Influence of lung nodule margin on volume- and diameter-based reader variability in CT lung cancer screening.

OBJECTIVE:: To evaluate the influence of nodule margin on inter- and intrareader variability in manual diameter measurements and semi-automatic volume measurements of solid nodules detected in low-dose CT lung cancer screening. METHODS:: 25 nodules of each morphological category (smooth, lobulated, spiculated and irregular) were randomly selected from 93 participants of the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON). Semi-automatic volume measurements were performed using Syngo LungCARE® software (Version Somaris/5 VB10A-W, Siemens, Forchheim, Germany). Three radiologists independently measured mean diameters manually. Impact of nodule margin on interreader variability was evaluated based on systematic error and 95% limits of agreement. Interreader variability was compared with the nodule growth cut-off as used in Lung CT Screening Reporting and Data System (LungRADS; +1.5-mm diameter) and the Dutch-Belgian Randomized Lung Cancer Screening Trial(acronym: NELSON) /British Thoracic Society (+25% volume). RESULTS:: For manual diameter measurements, a significant systematic error (up to 1.2 mm) between readers was found in all morphological categories. For semi-automatic volume measurements, no statistically significant systematic error was found. The interreader variability in mean diameter measurements exceeded the 1.5-mm cut-off for nodule growth for all morphological categories [smooth: ±1.9 mm (+27%), lobulated: ±2.0 mm (+33%), spiculated: ±3.5 mm (+133%), irregular: ±4.5 mm (+200%)]. The 25% vol growth cut-off was exceeded slightly for spiculated [28% (+12%)] and irregular [27% (+8%)] nodules. CONCLUSION:: Lung nodule sizing based on manual diameter measurement is affected by nodule margin. Interreader variability increases especially for nodules with spiculated and irregular margins, and causes substantial misclassification of nodule growth. This effect is almost neglectable for semi-automated volume measurements. Semi-automatic volume measurements are superior for both size and growth determination of pulmonary nodules. ADVANCES IN KNOWLEDGE:: Nodule assessment based on manual diameter measurements is susceptible to nodule margin. This effect is almost neglectable for semi-automated volume measurements. The larger interreader variability for manual diameter measurement results in inaccurate lung nodule growth detection and size classification.

Volume versus diameter assessment of small pulmonary nodules in CT lung cancer screening.

Currently, lung cancer screening by low-dose chest CT is implemented in the United States for high-risk persons. A disadvantage of lung cancer screening is the large number of small-to-intermediate sized lung nodules, detected in around 50% of all participants, the large majority being benign. Accurate estimation of nodule size and growth is essential in the classification of lung nodules. Currently, manual diameter measurements are the standard for lung cancer screening programs and routine clinical care. However, European screening studies using semi-automated volume measurements have shown higher accuracy and reproducibility compared to diameter measurements. In addition to this, with the optimization of CT scan techniques and reconstruction parameters, as well as advances in segmentation software, the accuracy of nodule volume measurement can be improved even further. The positive results of previous studies on volume and diameter measurements of lung nodules suggest that manual measurements of nodule diameter may be replaced by semi-automated volume measurements in the (near) future.