Enhancing the prediction of the invasiveness of pulmonary adenocarcinomas presenting as pure ground-glass nodules: Integrating intratumor heterogeneity score with clinical-radiological features via machine learning in a multicenter study.

Objective: The invasiveness of lung adenocarcinoma significantly impacts clinical decision-making. However, assessing this invasiveness preoperatively, especially when it manifests as pure ground-glass nodules (pGGN) on CT scans, poses challenges. This study aims to quantify intratumor heterogeneity (ITH) and determine whether the ITH score can enhance the accuracy of invasiveness predictions. Methods: A total of 524 patients with lung adenocarcinomas presenting as pGGN were enrolled in the study, with 177 (33.78%) receiving a pathologic diagnosis of invasiveness. Four diagnostic approaches were developed to predict the invasiveness of lung adenocarcinoma presenting as pGGN: (1) conventional lesion size, (2) ITH score, (3) clinical-radiological features (ClinRad), and (4) integration of the ITH score with ClinRad. ClinRad alone or in combination with the ITH score served as the input for 11 machine learning approaches. The trained models were evaluated in an independent validation cohort, and the area under the curve (AUC) was calculated to assess classification performance. Results: The conventional lesion size showed the lowest performance, with an AUC of 0.826 (95% confidence interval [CI]: 0.758-0.894), while the ITH score outperformed it with an AUC of 0.846 (95% CI: 0.787-0.905). The CatBoost model performed best when the ITH score and ClinRad were both used as input features, leading to the development of an ITH-ClinRad-guided CatBoost classifier. CatBoost also excelled with ClinRad alone, resulting in a ClinRad-guided CatBoost classifier with an AUC of 0.830 (95% CI: 0.764-0.896), surpassed by the ITH-ClinRad-guided CatBoost classifier with an AUC of 0.871 (95% CI: 0.818-0.924). Conclusion: The ITH-ClinRad-guided CatBoost classifier emerges as a promising tool with significant potential to revolutionize the management of lung adenocarcinomas presenting as pGGNs.

The growth of screening-detected pure ground-glass nodules after 10 years of stability.

BACKGROUND: It remains uncertain how long pure ground-glass nodules (pGGNs) detected on low dose computed tomography (LDCT) should be followed. Further studies with longer follow-up periods are needed to determine the optimal follow-up duration for pGGNs. RESEARCH QUESTION: What is the percentage of enlarging nodules among pGGNs that have remained stable for 10 years? STUDY DESIGN AND METHODS: This was a retrospective cohort study originating from subjects with pGGNs detected on LDCT scans between 1997 and 2006, whose natural courses were reported in 2013. We re-analyzed all the follow-up data until July 2022. The study subjects were followed by our institutional guidelines until they were no longer a candidate for definitive treatment. The growth of the pGGNs was defined as an increase in the diameter of the entire nodule by 2 mm or more or the appearance of new solid portions within the nodules. RESULTS: A total of 89 patients with 135 pGGNs were followed for a median of 193 months. Of 135 pGGNs, 23 (17.0%) increased in size, and the median time to the first detection of a size change was 71 months. Of the 23 growing pGGNs, 122 were detected on the first LDCT, and 13 were newly detected on the follow-up CT scan. An increase in size was observed within 5 years in 8 nodules (34.8%), between 5 and 10 years in 12 nodules (52.2%) and after 10 years in 3 nodules (13.0%). Fifteen nodules were histologically confirmed as adenocarcinoma by surgery. Among the 76 pGGNs stable for 10 years, 3 (3.9%) increased in size. INTERPRETATION: Among pGGNs that remained stable for 10 years, 3.9% eventually grew, indicating that some pGGNs can grow even after a long period of stability. We suggest that pGGNs may need to be followed for more than 10 years to confirm growth.

Evaluation of the invasiveness of pure ground-glass nodules based on dual-head ResNet technique.

OBJECTIVE: To intelligently evaluate the invasiveness of pure ground-glass nodules with multiple classifications using deep learning. METHODS: pGGNs in 1136 patients were pathologically confirmed as lung precursor lesions [atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS)], minimally invasive adenocarcinoma (MIA), or invasive adenocarcinoma (IAC). Four different models [EfficientNet-b0 2D, dual-head ResNet_3D, a 3D model combining three features (3D_3F), and a 3D model combining 19 features (3D_19F)] were constructed to evaluate the invasiveness of pGGNs using the EfficientNet and ResNet networks. The Obuchowski index was used to evaluate the differences in diagnostic efficiency among the four models. RESULTS: The patients with pGGNs (360 men, 776 women; mean age, 54.63 ± 12.36 years) included 235 cases of AAH + AIS, 332 cases of MIA, and 569 cases of IAC. In the validation group, the areas under the curve in detecting the invasiveness of pGGNs as a three-category classification (AAH + AIS, MIA, IAC) were 0.8008, 0.8090, 0.8165, and 0.8158 for EfficientNet-b0 2D, dual-head ResNet_3D, 3D_3F, and 3D_19F, respectively, whereas the accuracies were 0.6422, 0.6158, 0.651, and 0.6364, respectively. The Obuchowski index revealed no significant differences in the diagnostic performance of the four models. CONCLUSIONS: The dual-head ResNet_3D_3F model had the highest diagnostic efficiency for evaluating the invasiveness of pGGNs in the four models.

The Value of Radiomics Features Based on HRCT in Predicting whether the Lung Sub-Centimeter Pure Ground Glass Nodule is Benign or Malignant.

OBJECTIVE: In this study, a radiomics model was created based on High-Resolution Computed Tomography (HRCT) images to noninvasively predict whether the sub-centimeter pure Ground Glass Nodule (pGGN) is benign or malignant. METHODS: A total of 235 patients (251 sub-centimeter pGGNs) who underwent preoperative HRCT scans and had postoperative pathology results were retrospectively evaluated. The nodules were randomized in a 7:3 ratio to the training (n=175) and the validation cohort (n=76). The volume of interest was delineated in the thin-slice lung window, from which 1316 radiomics features were extracted. The Least Absolute Shrinkage and Selection Operator (LASSO) was used to select the radiomics features. Univariate and multivariable logistic regression were used to evaluate the independent risk variables. The performance was assessed by obtaining Receiver Operating Characteristic (ROC) curves for the clinical, radiomics, and combined models, and then the Decision Curve Analysis (DCA) assessed the clinical applicability of each model. RESULTS: Sex, volume, shape, and intensity mean were chosen by univariate analysis to establish the clinical model. Two radiomics features were retained by LASSO regression to build the radiomics model. In the training cohort, the Area Under the Curve (AUC) of the radiomics (AUC=0.844) and combined model (AUC=0.871) was higher than the clinical model (AUC=0.773). In evaluating whether or not the sub-centimeter pGGN is benign, the DCA demonstrated that the radiomics and combined model had a greater overall net benefit than the clinical model. CONCLUSION: The radiomics model may be useful in predicting the benign and malignant sub-centimeter pGGN before surgery.

Construction and validation of a risk score system for diagnosing invasive adenocarcinoma presenting as pulmonary pure ground-glass nodules: a multi-center cohort study in China.

Background: Anxiety-driven clinical interventions have been queried due to the nondeterminacy of pure ground-glass nodules (pGGNs). Although radiomics and radiogenomics aid diagnosis, standardization and reproducibility challenges persist. We aimed to assess a risk score system for invasive adenocarcinoma in pGGNs. Methods: In a retrospective, multi-center study, 772 pGGNs from 707 individuals in The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital were grouped into training (509 patients with 558 observations) and validation (198 patients with 214 observations) sets consecutively from January 2017 to November 2021. An additional test set of 143 observations in Hainan Cancer Hospital was analyzed in the same period. Computed tomography (CT) signs and clinical features were manually collected, and the quantitative parameters were achieved by artificial intelligence (AI). The positive cutoff score was ≥3. Risk scores system 3 combined carcinoma history, chronic obstructive pulmonary disease (COPD), maximum diameters, nodule volume, mean CT values, type II or III vascular supply signs, and other radiographic characteristics. The evaluation included the area under the curves (AUCs), accuracy, sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) for both the risk score systems 1, 2, 3 and the AI model. Results: The risk score system 3 [AUC, 0.840; 95% confidence interval (CI): 0.789-0.890] outperformed the AI model (AUC, 0.553; 95% CI: 0.487-0.619), risk score system 1 (AUC, 0.802; 95% CI: 0.754-0.851), and risk score system 2 (AUC, 0.816; 95% CI: 0.766-0.867), with 88.0% (0.850-0.904) accuracy, 95.6% (0.932-0.972) PPV, 0.620 (0.535-0.702) NPV, 89.6% (0.864-0.920) sensitivity, and 80.6% (0.717-0.872) specificity in the training sets. In the validation and test sets, risk score system 3 performed best with AUCs of 0.769 (0.678-0.860) and 0.801 (0.669-0.933). Conclusions: An AI-based risk scoring system using quantitative image parameters, clinical features, and radiographic characteristics effectively predicts invasive adenocarcinoma in pulmonary pGGNs.

Clinical Outcomes of Resected Pure Ground-Glass, Heterogeneous Ground-Glass, and Part-Solid Pulmonary Nodules.

BACKGROUND. Increased (but not definitively solid) attenuation within pure ground-glass nodules (pGGNs) may indicate invasive adenocarcinoma and the need for resection rather than surveillance. OBJECTIVE. The purpose of this study was to compare the clinical outcomes among resected pGGNs, heterogeneous ground-glass nodules (GGNs), and part-solid nodules (PSNs). METHODS. This retrospective study included 469 patients (335 female patients and 134 male patients; median age, 68 years [IQR, 62.5-73.5 years]) who, between January 2012 and December 2020, underwent resection of lung adenocarcinoma that appeared as a subsolid nodule on CT. Two radiologists, using lung windows, independently classified each nodule as a pGGN, a heterogeneous GGN, or a PSN, resolving discrepancies through discussion. A heterogeneous GGN was defined as a GGN with internal increased attenuation not quite as dense as that of pulmonary vessels, and a PSN was defined as having an internal solid component with the same attenuation as that of the pulmonary vessels. Outcomes included pathologic diagnosis of invasive adenocarcinoma, 5-year recurrence rates (locoregional or distant), and recurrence-free survival (RFS) and overall survival (OS) over 7 years, as analyzed by Kaplan-Meier and Cox proportional hazards regression analyses, with censoring of patients with incomplete follow-up. RESULTS. Interobserver agreement for nodule type, expressed as a kappa coefficient, was 0.69. Using consensus assessments, 59 nodules were pGGNs, 109 were heterogeneous GGNs, and 301 were PSNs. The frequency of invasive adenocarcinoma was 39.0% in pGGNs, 67.9% in heterogeneous GGNs, and 75.7% in PSNs (for pGGNs vs heterogeneous GGNs, p < .001; for pGGNs vs PSNs, p < .001; and for heterogeneous GGNs vs PSNs, p = .28). The 5-year recurrence rate was 0.0% in patients with pGGNs, 6.3% in those with heterogeneous GGNs, and 10.8% in those with PSNs (for pGGNs vs heterogeneous GGNs, p = .06; for pGGNs vs PSNs, p = .02; and for heterogeneous GGNs vs PSNs, p = .18). At 7 years, RFS was 97.7% in patients with pGGNs, 82.0% in those with heterogeneous GGNs, and 79.4% in those with PSNs (for pGGNs vs heterogeneous GGNs, p = .02; for pGGNs vs PSNs, p = .006; and for heterogeneous GGNs vs PSNs, p = .40); OS was 98.0% in patients with pGGNs, 84.6% in those with heterogeneous GGNs, and 82.9% in those with PSNs (for pGGNs vs heterogeneous GGNs, p = .04; for pGGNs vs PSNs, p = .01; and for heterogeneous GGNs vs PSNs, p = .50). CONCLUSION. Resected pGGNs had excellent clinical outcomes. Heterogeneous GGNs had relatively worse outcomes, more closely resembling outcomes for PSNs. CLINICAL IMPACT. The findings support surveillance for truly homogeneous pGGNs versus resection for GGNs showing internal increased attenuation even if not having a true solid component.

Predicting the Invasiveness of Pulmonary Adenocarcinomas in Pure Ground-Glass Nodules Using the Nodule Diameter: A Systematic Review, Meta-Analysis, and Validation in an Independent Cohort.

The nodule diameter was commonly used to predict the invasiveness of pulmonary adenocarcinomas in pure ground-glass nodules (pGGNs). However, the diagnostic performance and optimal cut-off values were inconsistent. We conducted a meta-analysis to evaluate the diagnostic performance of the nodule diameter for predicting the invasiveness of pulmonary adenocarcinomas in pGGNs and validated the cut-off value of the diameter in an independent cohort. Relevant studies were searched through PubMed, MEDLINE, Embase, and the Cochrane Library, from inception until December 2022. The inclusion criteria comprised studies that evaluated the diagnostic accuracy of the nodule diameter to differentiate invasive adenocarcinomas (IAs) from non-invasive adenocarcinomas (non-IAs) in pGGNs. A bivariate mixed-effects regression model was used to obtain the diagnostic performance. Meta-regression analysis was performed to explore the heterogeneity. An independent sample of 220 pGGNs (82 IAs and 128 non-IAs) was enrolled as the validation cohort to evaluate the performance of the cut-off values. This meta-analysis finally included 16 studies and 2564 pGGNs (761 IAs and 1803 non-IAs). The pooled area under the curve, the sensitivity, and the specificity were 0.85 (95% confidence interval (CI), 0.82-0.88), 0.82 (95% CI, 0.78-0.86), and 0.73 (95% CI, 0.67-0.78). The diagnostic performance was affected by the measure of the diameter, the reconstruction matrix, and patient selection bias. Using the prespecified cut-off value of 10.4 mm for the mean diameter and 13.2 mm for the maximal diameter, the mean diameter showed higher sensitivity than the maximal diameter in the validation cohort (0.85 vs. 0.72, p < 0.01), while there was no significant difference in specificity (0.83 vs. 0.86, p = 0.13). The nodule diameter had adequate diagnostic performance in differentiating IAs from non-IAs in pGGNs and could be replicated in a validation cohort. The mean diameter with a cut-off value of 10.4 mm was recommended.

Lung-PNet: An Automated Deep Learning Model for the Diagnosis of Invasive Adenocarcinoma in Pure Ground-Glass Nodules on Chest CT.

BACKGROUND. Pure ground-glass nodules (pGGNs) on chest CT representing invasive adenocarcinoma (IAC) warrant lobectomy with lymph node resection. For pGGNs representing other entities, close follow-up or sublobar resection without node dissection may be appropriate. OBJECTIVE. The purpose of this study was to develop and validate an automated deep learning model for differentiation of pGGNs on chest CT representing IAC from those representing atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA). METHODS. This retrospective study included 402 patients (283 women, 119 men; mean age, 53.2 years) with a total of 448 pGGNs on noncontrast chest CT that were resected from January 2019 to June 2022 and were histologically diagnosed as AAH (n = 29), AIS (n = 83), MIA (n = 235), or IAC (n = 101). Lung-PNet, a 3D deep learning model, was developed for automatic segmentation and classification (probability of IAC vs other entities) of pGGNs on CT. Nodules resected from January 2019 to December 2021 were randomly allocated to training (n = 327) and internal test (n = 82) sets. Nodules resected from January 2022 to June 2022 formed a holdout test set (n = 39). Segmentation performance was assessed with Dice coefficients with radiologists' manual segmentations as reference. Classification performance was assessed by ROC AUC and precision-recall AUC (PR AUC) and compared with that of four readers (three radiologists, one surgeon). The code used is publicly available (https://github.com/XiaodongZhang-PKUFH/Lung-PNet.git). RESULTS. In the holdout test set, Dice coefficients for segmentation of IACs and of other lesions were 0.860 and 0.838, and ROC AUC and PR AUC for classification as IAC were 0.911 and 0.842. At threshold probability of 50.0% or greater for prediction of IAC, Lung-PNet had sensitivity, specificity, accuracy, and F1 score of 50.0%, 92.0%, 76.9%, and 60.9% in the holdout test set. In the holdout test set, accuracy and F1 score (p values vs Lung-PNet) for individual readers were as follows: reader 1, 51.3% (p = .02) and 48.6% (p = .008); reader 2, 79.5% (p = .75) and 75.0% (p = .10); reader 3, 66.7% (p = .35) and 68.3% (p < .001); reader 4, 71.8% (p = .48) and 42.1% (p = .18). CONCLUSION. Lung-PNet had robust performance for segmenting and classifying (IAC vs other entities) pGGNs on chest CT. CLINICAL IMPACT. This automated deep learning tool may help guide selection of surgical strategies for pGGN management.

A nomogram for predicting invasiveness of lung adenocarcinoma manifesting as pure ground-glass nodules: incorporating subjective CT signs and histogram parameters based on artificial intelligence.

PURPOSE: To construct a nomogram based on subjective CT signs and artificial intelligence (AI) histogram parameters to identify invasiveness of lung adenocarcinoma presenting as pure ground-glass nodules (pGGNs) and to evaluate its diagnostic performance. METHODS: 187 patients with 228 pGGNs confirmed by postoperative pathology were collected retrospectively and divided into pre-invasive group [atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS)] and invasive group [minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC)]. All pGGNs were randomly assigned to training cohort (n = 160) and validation cohort (n = 68). Nomogram was developed using subjective CT signs and AI-based histogram parameters by logistic regression analysis. The diagnostic performance was evaluated by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) curve. RESULTS: The nomogram was constructed with nodule shape, 3D mean diameter, maximum CT value, and skewness. It showed better discriminative power in differentiating invasive lesions from pre-invasive lesions with area under curve (AUC) of 0.849 (95% CI 0.790-0.909) in the training cohort and 0.831 (95% CI 0.729-0.934) in the validation cohort, which performed better than nodule shape (AUC 0.675, 95% CI 0.609-0.741), 3D mean diameter (AUC 0.762, 95% CI 0.688-0.835), maximum CT value (AUC 0.794, 95% CI 0.727-0.862), or skewness (AUC 0.594, 95% CI 0.506-0.682) alone in training cohort (for all, P < 0.05). CONCLUSION: For pulmonary pGGNs, the nomogram based on subjective CT signs and AI histogram parameters had a good predictive ability to discriminate invasive lung adenocarcinoma from pre-invasive lung adenocarcinoma, and it has the potential to improve diagnostic efficiency and to help the patient management.

CT-based three-dimensional invasiveness analysis of adenocarcinoma presenting as pure ground-glass nodules.

Background: We invest computed tomography (CT) image differences between non-invasive adenocarcinomas (NIAs) and invasive adenocarcinomas (IAs) presenting as pure ground glass nodules (GGNs). Methods: From 2013 to 2019, 48 pure GGNs were surgically resected in 45 patients. Of these, 40 were pathologically diagnosed as non-small cell lung cancers (NSCLCs). We assessed them using the Synapse Vincent (Fujifilm Co., Ltd., Tokyo, Japan) three-dimensional (3D) analysis system; we drew histograms of the CT densities. We calculated the maximum, minimum, means, and standard deviations of the densities. The proportions of GGNs of high CT density were compared between the two groups. The diagnostic performance was investigated via receiver operating curve (ROC) analysis. Results: Of the 40 pure GGNs, 20 were NIAs (4 adenocarcinomas in situ and 16 minimally IAs) and 20 IAs. Significant correlations were evident between histological invasiveness and the maximum and mean CT densities and the standard deviation. Neither the nodule volume nor the minimum CT density significantly predicted invasiveness. A CT volume density proportion >-300 Hounsfield units optimally predicted the invasiveness of pure GGNs; the cutoff was 5.41% with a sensitivity of 85% and a specificity of 95%. Conclusions: CT density reflected the invasiveness of pure GGNs. A CT volume proportion density >-300 Hounsfield units may significantly predict histological invasiveness.

Software-based quantitative CT analysis to predict the growth trend of persistent nonsolid pulmonary nodules: a retrospective study.

PURPOSE: Persistent nonsolid nodules (NSNs) usually exhibit an indolent course and may remain stable for several years; however, some NSNs grow quickly and require surgical excision. Therefore, identifying quantitative features capable of early discrimination between growing and nongrowing NSNs is becoming a crucial aspect of radiological analysis. The main purpose of this study was to evaluate the performance of an open-source software (ImageJ) to predict the future growth of NSNs detected in a Caucasian (Italian) population. MATERIAL AND METHODS: We retrospectively selected 60 NSNs with an axial diameter of 6-30 mm scanned with the same acquisition-reconstruction parameters and the same computed tomography (CT) scanner. Software-based analysis was performed on thin-section CT images using ImageJ. For each NSNs, several quantitative features were extracted from the baseline CT images. The relationships of NSN growth with quantitative CT features and other categorical variables were analyzed using univariate and multivariable logistic regression analyses. RESULTS: In multivariable analysis, only the skewness and linear mass density (LMD) were significantly associated with NSN growth, and the skewness was the strongest predictor of growth. In receiver operating characteristic curve analyses, the optimal cutoff values of skewness and LMD were 0.90 and 19.16 mg/mm, respectively. The two predictive models that included the skewness, with or without LMD, exhibited an excellent power for predicting NSN growth. CONCLUSION: According to our results, NSNs with a skewness value > 0.90, specifically those with a LMD > 19.16 mg/mm, should require closer follow-up due to their higher growth potential, and higher risk of becoming an active cancer.

A narrative review of the clinical approach to subsolid pulmonary nodules.

Background and Objective: The widespread use of chest computed tomography (CT) for lung cancer screening has led to increased detection of subsolid pulmonary nodules. The management of subsolid nodules (SSNs) is challenging since they are likely to grow slowly and a long-term follow-up is needed. In this review, we discuss the characteristics, natural history, genetic features, surveillance, and management of SSNs. Methods: PubMed and Google Scholar were searched to identify relevant articles published in English between January 1998 and December 2022 using the following keywords: "subsolid nodule", "ground-glass nodule (GGN)", and "part-solid nodule (PSN)". Key Content and Findings: The differential diagnosis of SSNs includes transient inflammatory lesions, focal fibrosis, and premalignant or malignant lesions. Long-term CT surveillance follow-up is needed to manage SSNs that persist for >3 months. Although most SSNs have an indolent clinical course, PSNs may have a more aggressive clinical course than pure GGNs. The proportion of growth and the time to grow is higher and shorter in PSN than pure GGN. In lung adenocarcinoma manifesting as SSNs, EGFR mutations were the major driver mutations. Guidelines are available for the management of incidentally detected and screening-detected SSNs. The size, solidity, location, and number of SSNs are important factors in determining the need for surveillance and surgical resection, as well as the interval of follow-up. Positron emission tomography/CT and brain magnetic resonance imaging (MRI) are not recommended for the diagnosis of SSNs, especially for pure GGNs. Periodic CT surveillance and lung-sparing surgery are the main strategies for the management of persistent SSNs. Nonsurgical treatment options for persistent SSNs include stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA). For multifocal SSNs, the timing of repeated CT scans and the need for surgical treatment are decided based on the most dominant SSN(s). Conclusions: The SSN is a heterogeneous disease and a personalized medicine approach is required in the future. Future studies of SSNs should focus on their natural history, optimal follow-up duration, genetic features, and surgical and nonsurgical treatments to improve the corresponding clinical management. All these efforts will lead to the personalized medicine approach for the SSNs.

Natural progression of persistent pure ground-glass nodules 10 mm or smaller: long-term observation and risk factor assessment.

PURPOSE: Semi-automatic segmentation was used to investigate the natural progression of pure ground-glass nodules (pGGNs) of 5-10 mm in long-term follow-up and to analyze independent risk factors for subsequent growth. MATERIALS AND METHODS: A total of 154 pGGNs of 5-10 mm from 132 patients with 698 follow-up CT scans were retrospectively identified. Subsequently, enrolled pGGNs were semiautomatically segmented on initial and follow-up CT to obtain diameter, density and volume, thus calculating mass, volume doubling time (VDT), and mass doubling time (MDT). Kaplan‒Meier analysis and multivariate Cox proportional risk regression were performed to explore independent predictors of pGGN growth. We analyzed growth differences among different pathological results of pGGNs confirmed by surgery. The prognosis was analyzed using the total diameter or solid size of the nodules on the last preoperative CT. RESULTS: Among the 85 (55.2%) pGGNs with growth, 5.9%, 51.8%, and 80.0% showed growth within 1, 3, and 5 years, respectively. The median VDT and MDT were 1206.4 (range 349.8-5134.4) days and 1161.3 (range 339.4-6630.4) days, respectively. The multivariate Cox risk regression analysis showed that mean CT attenuation (m-CTA) [hazard ratio (HR) = 2.098, p = 0.010] and roundness index (HR = 1.892, p = 0.021) were independent risk factors for pGGN growth. In total, 67.6% of surgically resected and growing pGGNs were invasive non-mucinous adenocarcinoma (IA), including 2 cases of endpoint events, showing a PSN with solid components of 5.6 mm and a solid nodule with a diameter of 19.9 mm. CONCLUSIONS: pGGNs of 5-10 mm showed an indolent clinical course. Follow-up CT imaging of pGGNs in the latter half of the first two years should be a rational management strategy. Small pGGNs with a larger overall m-CTA and roundness index on baseline CT are more likely to grow.

Tertiary lymphoid structures in lung adenocarcinoma: characteristics and related factors.

OBJECTIVE: Tertiary lymphoid structures (TLSs) are found in a variety of malignancies and affect the growth of tumors, but few studies have addressed their role in lung adenocarcinoma (LAC). We aimed to evaluate clinical features associated with TLSs in patients with LAC. METHODS AND MATERIALS: A collection of resected pulmonary nodules in patients with LAC was retrospectively analyzed. TLSs were quantified by their number per square millimeter tumor area (density) and by the degree of lymphocyte aggregation (maturity) in each case. The correlation between TLS density and maturity and clinical features was calculated. RESULTS: A total of 243 patients were selected, of whom 219 exhibited TLSs. The occurrence of TLSs was correlated with computed tomography (CT) features as follows: pure ground-glass nodules (pGGNs) (n = 43) was associated with a lower occurrence rate than part-solid nodules (PSNs) (n = 112) and solid nodules (SNs) were (n = 88) (p = 0.037). TLS density was correlated with age and CT features. Poisson regression showed higher TLS density in PSNs and SNs than in pGGNs (incidence rate ratio [IRR]: 3.137; 95% confidence interval [CI]: 1.35-7.27; p = 0.008 and IRR: 2.44; 95% CI: 1.02-5.85; p = 0.046, respectively). In addition, TLS density was higher in patients aged under 60 years than in those aged over 60 years (IRR: 0.605; 95% CI: 0.4-0.92; p = 0.018). The maturity of TLSs was higher in patients with higher tumor stages (p = 0.026). CONCLUSIONS: We demonstrated distinct profiles of TLSs in early LAC and their correlations with CT features, age, and tumor stages, which could help understand tumor progression and management.

A Multi-Classification Model for Predicting the Invasiveness of Lung Adenocarcinoma Presenting as Pure Ground-Glass Nodules.

Objectives: To establish a multi-classification model for precisely predicting the invasiveness (pre-invasive adenocarcinoma, PIA; minimally invasive adenocarcinoma, MIA; invasive adenocarcinoma, IAC) of lung adenocarcinoma manifesting as pure ground-glass nodules (pGGNs). Methods: By the inclusion and exclusion criteria, this retrospective study enrolled 346 patients (female, 297, and male, 49; age, 55.79 ± 10.53 (24-83)) presenting as pGGNs from 1292 consecutive patients with pathologically confirmed lung adenocarcinoma. A total of 27 clinical were collected and 1409 radiomics features were extracted by PyRadiomics package on python. After feature selection with L2,1-norm minimization, logistic regression (LR), extra w(ET) and gradient boosting decision tree (GBDT) were used to construct the three-classification model. Then, an ensemble model of the three algorithms based on model ensemble strategy was established to further improve the classification performance. Results: After feature selection, a hybrid of 166 features consisting of 1 clinical (short-axis diameter, ranked 27th) and 165 radiomics (4 shape, 71 intensity and 90 texture) features were selected. The three most important features are wavelet-HLL_firstorder_Minimum, wavelet-HLL_ngtdm_Busyness and square_firstorder_Kurtosis. The hybrid-ensemble model based on hybrid clinical-radiomics features and the ensemble strategy showed more accurate predictive performance than other models (hybrid-LR, hybrid-ET, hybrid-GBDT, clinical-ensemble and radiomics-ensemble). On the training set and test set, the model can obtain the accuracy values of 0.918 ± 0.022 and 0.841, and its F1-scores respectively were 0.917 ± 0.024 and 0.824. Conclusion: The multi-classification of invasive pGGNs can be precisely predicted by our proposed hybrid-ensemble model to assist patients in the early diagnosis of lung adenocarcinoma and prognosis.

Development and validation of qualitative and quantitative models to predict invasiveness of lung adenocarcinomas manifesting as pure ground-glass nodules based on low-dose computed tomography during lung cancer screening.

Background: Due to different management strategy and prognosis of different subtypes of lung adenocarcinomas appearing as pure ground-glass nodules (pGGNs), it is important to differentiate invasive adenocarcinoma (IA) from adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA) during lung cancer screening. The aim of this study was to develop and validate the qualitative and quantitative models to predict the invasiveness of lung adenocarcinoma appearing as pGGNs based on low-dose computed tomography (LDCT) and compare their diagnostic performance with that of intraoperative frozen section (FS). Methods: A total of 223 consecutive pathologically confirmed pGGNs from March 2018 to December 2020 were divided into a primary cohort (96 IAs and 64 AIS/MIAs) and validation cohort (39 IAs and 24 AIS/MIAs) according to scans (Brilliance iCT and Somatom Definition Flash) performed at Sichuan Cancer Hospital and Institute. The following LDCT features of pGGNs were analyzed: the qualitative features included nodule location, shape, margin, nodule-lung interface, lobulation, spiculation, pleural indentation, air bronchogram, vacuole, and vessel type, and the quantitative features included the diameter, volume, and mean attenuation. Multivariate logistic regression analysis was used to build a qualitative model, quantitative model, and combined qualitative and quantitative model. The diagnostic performance was assessed according to the following factors: the area under curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity, and accuracy. Results: The AUCs of the qualitative model, quantitative model, combined qualitative and quantitative model, and the FS diagnosis were 0.854, 0.803, 0.873, and 0.870, respectively, in the primary cohort and 0.884, 0.855, 0.875, and 0.946, respectively, in the validation cohort. No significant difference of the AUCs was found among the radiological models and the FS diagnosis in the primary or validation cohort (all corrected P>0.05). Among the radiological models, the combined qualitative and quantitative model consisting of vessel type and volume showed the highest accuracy in both the primary and validation cohorts (0.831 and 0.889, respectively). Conclusions: The diagnostic performances of the qualitative and quantitative models based on LDCT to differentiate IA from AIS/MIA in pGGNs are equivalent to that of intraoperative FS diagnosis. The vessel type and volume can be preoperative and non-invasive biomarkers to assess the invasive risk of pGGNs in lung cancer screening.

Computed tomography radiomics-based distinction of invasive adenocarcinoma from minimally invasive adenocarcinoma manifesting as pure ground-glass nodules with bubble-like signs.

BACKGROUND: To explore an effective model based on radiomics features extracted from nonenhanced computed tomography (CT) images to distinguish invasive adenocarcinoma (IAC) from minimally invasive adenocarcinoma (MIA) presenting as pure ground-glass nodules (pGGNs) with bubble-like (B-pGGNs) signs. PATIENTS AND METHODS: We retrospectively reviewed 511 nodules (MIA, n = 288; IAC, n = 223) between November 2012 and June 2018 from almost all pGGNs pathologically confirmed MIA or IAC. Eventually, a total of 109 B-pGGNs (MIA, n = 55; IAC, n = 54) from 109 patients fulfilling the criteria were randomly assigned to the training and test cluster at a ratio of 7:3. The gradient boosting decision tree (GBDT) method and logistic regression (LR) analysis were applied to feature selection (radiomics, semantic, and conventional CT features). LR was performed to construct three models (the conventional, radiomics and combined model). The performance of the predictive models was evaluated using the area under the curve (AUC). RESULTS: The radiomics model had good AUCs of 0.947 in the training cluster and of 0.945 in the test cluster. The combined model produced an AUC of 0.953 in the training cluster and of 0.945 in the test cluster. The combined model yielded no performance improvement (vs. the radiomics model). The rad_score was the only independent predictor of invasiveness. CONCLUSION: The radiomics model showed excellent predictive performance in discriminating IAC from MIA presenting as B-pGGNs and may provide a necessary reference for extending clinical practice.

Discriminating invasive adenocarcinoma among lung pure ground-glass nodules: a multi-parameter prediction model.

BACKGROUND: Patients with consistent lung pure ground-glass nodules (pGGNs) have a high incidence of lung adenocarcinoma that can be classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), or invasive adenocarcinoma (IAC). Regular follow-up is recommended for AIS and MIA, while surgical resection should be considered for IAC. This study sought to develop a multi-parameter prediction model to increase the diagnostic accuracy in discriminating between IAC and AIS or MIA. METHODS: The training data set comprised consecutive patients with lung pGGNs who underwent resection from January to December 2017 at the Zhongshan Hospital. Of the 370 resected pGGNs, 344 were pathologically confirmed to be AIS, MIA, or IAC and were included in the study. The 26 benign pGGNs were excluded. We compared differences in the clinical features (e.g., age and gender), the content of serum tumor biomarkers, the computed tomography (CT) parameters (e.g., nodule size and the maximal CT value), and the morphologic characteristics of nodules (e.g., lobulation, spiculation, pleura indentation, vacuole sign, and normal vessel penetration or abnormal vessel) between the pathological subtypes of AIS, MIA, and IAC. An abnormal vessel was defined as "vessel curve" or "vessel enlargement". Statistical analyses were performed using the chi-square test, analysis of variance (ANOVA), and rank test. The IAC prediction model was constructed via a multivariate logistical regression. Our prediction model for lung pGGNs was further validated in a data set comprising consecutive patients from multiple medical centers in China from July to December 2018. In total, 345 resected pGGNs were pathologically diagnosed as lung adenocarcinoma in the validation data set. RESULTS: In the training data set, patients with pGGNs ≥10 mm in size had a high incidence (74.5%) of IAC. The maximal CT value of IAC [-416.1±121.2 Hounsfield unit (HU)] was much higher than that of MIA (-507.7±138.0 HU) and AIS (-602.6±93.3 HU) (P<0.001). IAC was more common in pGGNs that displayed any of the following CT manifestations: lobulation, spiculation, pleura indentation, vacuole sign, and vessel abnormality. The IAC prediction model was constructed using the parameters that were assessed as risk factors (i.e., the nodule size, maximal CT value, and CT signs). The receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of this model for diagnosing IAC was 0.910, which was higher than that of the AUC for nodule size alone (0.891) or the AUC for the maximal CT value alone (0.807) (P<0.05, respectively). A multicenter validation data set was used to validate the performance of our prediction model in diagnosing IAC, and our model was found to have an AUC of 0.883, which was higher than that of the AUC of 0.827 for the module size alone model or the AUC of 0.791 for the maximal CT value alone model (P<0.05, respectively). CONCLUSIONS: Our multi-parameter prediction model was more accurate at diagnosing IAC than models that used only nodule size or the maximal CT value alone. Thus, it is an efficient tool for identifying the IAC of malignant pGGNs and deciding if surgery is needed.

CT Characteristics for Predicting Invasiveness in Pulmonary Pure Ground-Glass Nodules.

OBJECTIVE. The objective of our study was to investigate the differences in the CT features of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA) manifesting as a pure ground-glass nodule (pGGN) with the aim of determining parameters predictive of invasiveness. MATERIALS AND METHODS. A total of 161 patients with 172 pGGNs (14 AAHs, 59 AISs, 68 MIAs, and 31 IAs) were retrospectively enrolled. The following CT features of each histopathologic subtype of nodule were analyzed and compared: lesion location, diameter, area, shape, attenuation, uniformity of density, margin, nodule-lung interface, and internal and surrounding changes. RESULTS. ROC curves revealed that nodule diameter and area (cutoff value, 10.5 mm and 86.5 mm2; sensitivity, 87.1% and 87.1%; specificity, 70.9% and 65.2%) were significantly larger in IAs than in AAHs, AISs, and MIAs (p < 0.001), whereas the latter three were similar in size (p > 0.050). CT attenuation higher than -632 HU in pGGNs indicated invasiveness (sensitivity, 78.8%; specificity, 59.8%). As opposed to noninvasive pGGNs (AAHs and AISs), invasive pGGNs (MIAs and IAs) usually had heterogeneous density, irregular shape, coarse margin, lobulation, spiculation, pleural indentation, and dilated or distorted vessels (each, p < 0.050). Multivariate analysis showed that mean CT attenuation and presence of lobulation were predictors for invasive pGGNs (p ≤ 0.001). CONCLUSION. The likelihood of invasiveness is greater in pGGNs with larger size (> 10.5 mm or > 86.5 mm2), higher attenuation (> -632 HU), heterogeneous density, irregular shape, coarse margin, spiculation, lobulation, pleural indentation, and dilated or distorted vessels.

Quantitative features can predict further growth of persistent pure ground-glass nodule.

BACKGROUND: To evaluate whether quantitative features of persistent pure ground-glass nodules (PGGN) on the initial computed tomography (CT) scans can predict further nodule growth. METHODS: This retrospective study included 59 patients with 101 PGGNs from 2011 to 2012, who received regular CT follow-up for lung nodule surveillance. Nineteen quantitative image features consisting of 8 volumetric and 11 histogram parameters were calculated to detect lung nodule growth. For the extraction of the quantitative features, semi-automatic GrowCut segmentation was implemented on chest CT images in 3D slicer platform. Univariate and multivariate analyses were performed to identify risk factors for nodule growth. RESULTS: With a median follow-up of 52 months, nodule growth was detected in 10 nodules by radiological assessment and in 16 nodules by quantitative features. In univariate analysis, 3D maximum diameter (MD), volume, mass, surface area, 90% percentile, and standard deviation value (SD) of PGGN on the initial CT scan were significantly different between stable nodules and nodules with further growth. In multivariate analysis, MD [hazard ratio (HR), 3.75; 95% confidence interval (CI), 2.14-6.55] and SD (HR, 2.06; 95% CI, 1.35-3.14) were independent predictors of further nodule growth. Also, the area under the curve was 0.896 (95% CI: 0.820-0.948) and 0.813 (95% CI: 0.723-0.883) for MD with a cut-off value of 10.2mm and SD of 50.0 Hounsfield Unit (HU). Besides, the growth rate was 55.6% (n=15) of PGGNs with MD >10.2 mm and SD >50.0 HU. CONCLUSIONS: Based on the initial CT scan, the quantitative features can predict PGGN growth more precisely. PGGN with MD >10.2 mm and SD >50.0 HU may require close follow-up or surgical intervention for the high incidence of growth.