Atypical Adenomatous Hyperplasia Research Articles

Experience Sharing in Pathological Diagnosis of Early Adenocarcinoma of the Lung.

Background: In daily work, there are still many pathologists who have difficulty handling the diagnosis of atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma, and the boundaries are not clear enough. Sometimes, the diagnosis is difficult, and there is sometimes poor reproducibility between different pathologists. Accurate diagnosis and differential diagnosis require a certain amount of experience. Methods: During the COVID-19 pandemic, we collected a large number (n = 381) of specimens of early lung adenocarcinoma, most of which (n = 356) were solitary lesions and 25 were multifocal lesions. There were 78 nodules in multifocal lesions, total 434 nodules. We summarized very careful microscopic observation and comparative analysis on all frozen and paraffin sections collected from many early lung adenocarcinoma specimens, continuously summarizing our experience. Results: Based on the World Health Organization's 2021 classification and diagnostic criteria for lung adenocarcinoma, new perspectives have been proposed on how to distinguish between atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma. In particular, new perspectives have been proposed on how to identify invasive aspects, and there are also some new perspectives on early lung mucinous lesions. Conclusion: Atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma all have corresponding morphological diagnostic criteria, but the morphological boundaries are sometimes not easy to determine and require some experience accumulation. The intraoperative frozen pathological diagnosis of early adenocarcinoma of the lung needs to be closely combined with imaging examination, and has very rich morphological experience.

Clinical Multi-features Analysis of Cystic Lung Adenocarcinoma and Construction of Invasive Risk Prediction Model

Cystic lung cancer, a special type of lung cancer, has been paid more and more attention. The most common pathological type of cystic lung cancer is adenocarcinoma. The invasiveness of cystic lung adenocarcinoma is vital for the selection of clinical treatment and prognosis. The aim of this study is to analyze the multiple clinical features of cystic lung adenocarcinoma, explore the independent risk factors of its invasiveness, and establish a risk prediction model. A total of 129 cases of cystic lung adenocarcinoma admitted to the Department of Thoracic Surgery of the First Affiliated Hospital of Nanjing Medical University from January 2021 to July 2022 were retrospectively analyzed and divided into pre-invasive group [atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA)] and invasive group [invasive adenocarcinoma (IAC)] according to pathological findings. There were 47 cases in the pre-invasive group, including 19 males and 28 females, with an average age of (51.23±14.96) years. There were 82 cases in the invasive group, including 60 males and 22 females, with an average age of (61.27±11.74) years. Multiple clinical features of the two groups were collected, including baseline data, imaging data and tumor markers. Univariate analysis, LASSO regression and multivariate Logistic regression analysis were used to screen out the independent risk factors of the invasiveness of cystic lung adenocarcinoma, and the risk prediction model was established. In univariate analysis, age, gender, smoking history, history of emphysema, neuron-specific enolase (NSE), number of cystic airspaces, lesion diameter, cystic cavity diameter, nodule diameter, solid components diameter, cyst wall nodule, smoothness of cyst wall, shape of cystic airspace, lobulation, short burr sign, pleural retraction, vascular penetration and bronchial penetration were statistically different between the pre-invasive group and invasive groups (P<0.05). The above variables were processed by LASSO regression dimensionality reduction and screened as follows: age, gender, smoking history, NSE, number of cystic airspaces, lesion diameter, cystic cavity diameter, cyst wall nodule, smoothness of cyst wall and lobulation. Then the above variables were included in multivariate Logistic regression analysis. Cyst wall nodule (P=0.035) and lobulation (P=0.001) were found to be independent risk factors for the invasiveness of cystic lung adenocarcinoma (P<0.05). The prediction model was established as follows: P=e^x/(1+e^x), x=-7.927+1.476* cyst wall nodule+2.407* lobulation, and area under the curve (AUC) was 0.950. Cyst wall nodule and lobulation are independent risk factors for the invasiveness of cystic lung adenocarcinoma, which have certain guiding significance for the prediction of the invasiveness of cystic lung adenocarcinoma.

Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma.

Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblastactivation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normallung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.

Abstract LB359: Lung epithelial specific IL-1R promotes K-ras mutant lung cancer by inducing angiogenesis that might be medicated via myeloid tumor microenvironment

Abstract As the leading cause of cancer-related deaths worldwide, the development of targeted therapeutics and immunotherapies as a means for treating lung cancer remains crucial. Non-small cell lung cancer (NSCLC), the most common histological subtype accounting for 85%, predominantly arises from lung adenocarcinoma with driver mutations in the K-ras oncogene (KM-LUAD). Studies have shown that KM-LUAD progression partly occurs through activation of the NF-κB pathway initiating an inflammatory response and creating a pro-tumor microenvironment. Notably, the pro-inflammatory cytokine IL-1β a potent activator and product of the NF-κB pathway is elevated in the lungs and sera of KM-LUAD patients. Our preliminary studies have shown that IL-1β blockade reprograms the lung immune microenvironment to that of an anti-tumor immune phenotype in a mouse model of KM-LUAD driven by lung epithelial cell-specific expression of KRASG12D (CCSPCre/LSL-KRASG12D, CC-LR mouse), suggesting that indeed this cytokine mediates tumor-promoting inflammation in KM-LUAD pathogenesis. Yet, cell-specific mechanisms that underlie tumor-promoting roles of IL-1β signaling are still poorly understood. Thus, we sought to elucidate the role of IL-1β signaling via its ability to bind to its receptor, IL-1R, in the context of KM-LUAD by conditionally knocking out the IL-1R in KRAS-mutant lung epithelial cells in CC-LR mice. Tumor development as well as immune microenvironment in 14 and 18-week-old CC-LR mice with epithelial specific conditional knockout of IL-1R (LR/IL-1RΔ/Δ) in comparison to age- and sex-matched control CC-LR littermates were studied. Notably reduced tumor burden in LR/IL-1RΔ/Δ mice with an interesting shift toward atypical adenomatous hyperplasia (AHH) lesion formation was evident when compared to their CC-LR counterpart. Having previously shown that targeting IL-1R leads to a reduction in the myeloid cell compartment also known for the regulation and production of angiogenic markers, an immunohistochemical evaluation of the angiogenic marker ERG was performed, showing a significantly diminished expression in tissue collected from LR/IL-1RΔ/Δ mice. Further studies assessing the role of angiogenic modulation by IL-1R in the context of KM-LUAD progression and its regulation by myeloid cells are currently under investigation. Overall, these findings provide insight into cell-specific mechanisms underlying the tumor-promoting effects of IL-1β signaling and support the role of tumor cell-intrinsic factors in tumor progression via shaping the tumor microenvironment. Citation Format: Avantika Krishna, Michael J. Clowers, Bo Yuan, Vivian Ha, Katherine Larsen, Nastaran Karimi, Arnav Gaitonde, Jocelynn Colunga, Maria T. Grimaldo, Maria Jose Arredondo Sancristobal, Valentina Villalba-Sabat, Angelica Baca De Anda, Yasmina Rezai, Jyotika Sharma, Humam Kadara, Seyed Javad Moghaddam. Lung epithelial specific IL-1R promotes K-ras mutant lung cancer by inducing angiogenesis that might be medicated via myeloid tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB359.

Abstract 3933: Comprehensive molecular characterization of mitochondrial mutational landscape across the evolution of lung adenocarcinoma

Abstract The human mitochondrial genome is prone to genetic alterations, which lead to somatic mutations, changes in mtDNA copy number and altered expression of respiratory chain subunits. This is in part due to the fact that mtDNA has a limited ability to repair itself when it is damaged. Although a buildup of somatic mutations in mtDNA has been associated with increased cancer risk, the role of mtDNA alterations in malignant transformation of lung adenocarcinoma has not been addressed. Therefore, a clear understanding of changes in mtDNA along the pathway of lung tumorigenesis is critical for identifying molecular biomarkers related to carcinogenesis and tumor progression. Like all solid tumors, lung adenocarcinoma is thought to be initiated and to progress through a series of genetic alterations, including changes in mtDNA. Lungs resected for primary adenocarcinomas often harbor minute discrete foci of cytologically atypical pneumocyte proliferations designated as atypical adenomatous hyperplasia (AAH). Evidence suggests that AAH represents an initial step in the progression to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and ultimately fully invasive adenocarcinoma (ADA). In this study we used a unique cohort of 52 patients with matched specimens (n=133) representing different steps of disease progression (AAH, AIS, and MIA) coupled with novel ultra-deep mitochondrial sequencing (mtDNA-Seq) method to assess the mtDNA mutational landscape throughout the continuum of lung adenocarcinoma development. Utilizing a custom bioinformatics workflow, somatic mutations were detected in a subset of the premalignant non-invasive lesions, with overall higher mutational load observed in MIA and ACA specimens. Additionally, large degree of inter-patient heterogeneity were observed for mtDNA copy numbers in conjunction with the clonal histological evolution of pulmonary neoplasia. Moreover, an appreciable number of coding and non-coding mutations from regulatory regions of the mtDNA were detectable in the precursor AAH lesions and the continuum of LUAD progression. Majority of shared mutations showed heteroplasmic transition with increase in fractional abundance in ADA, compared to the AHH lesions, thereby indicating spatial clonal expansion as they progressed histologically. Here we report the first comprehensive characterization of mitochondrial mutational landscape in dynamic evolution of lung adenocarcinoma, and provide insight into the heterogeneity of clonal events associated with the progression from noninvasive to malignant disease. Citation Format: Alka Singh, Santanu Dasgupta, Ashwin L. Koppayi, Lisa Rooper, Vasudha Mishra, David Sidransky, Nishant Agrawal, Karthik Suresh, Evgeny Izumchenko. Comprehensive molecular characterization of mitochondrial mutational landscape across the evolution of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3933.

Abstract 6997: Elucidating the tumorigenic properties of alveolar epithelial type 1 cells in EGFR-mediated LUAD tumorigenesis

Abstract Originating from within the distal lung, lung adenocarcinoma (LUAD) is the most common pathologic subtype of non-small cell lung carcinoma (NSCLC) and encompasses an assortment of histologic presentations. Colocalized within the distal alveolar epithelium are two alveolar epithelial cell (AEC) subpopulations: alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cells. We previously demonstrated that signatures unique to each AEC subpopulation were detected in LUAD tumors formed by oncogenic KRASG12D activation in mice and were associated with disparate survival outcomes, transcriptomic patterning, and histologic presentation. Epithelial growth factor receptor (EGFR) mutations are among the most frequent oncogenic drivers in thoracic oncology. Therefore, we set out to determine if EGFR oncogenic activation resulted in differential LUAD presentation and outcomes based on the cell of origin in which it was activated. To activate EGFR oncogenic mutations in AT1 or AT2 cells, we employed triple transgenic mouse models (AT1: Gramd2-CreERT2:EF1-LSL-tTA:TetO-EGFRdel20/T790 and AT2: Sftpc-CreERT2:EF1-LSL-tTA:TetO-EGFRdel20/T790), which allowed for EGFR activation in either Gramd2+ AT1 or Sftpc+ AT2 cells. Longitudinal analysis of hematoxylin and eosin-stained lungs over the course of 20 weeks was performed. Blinded pathology review demonstrated that EGFR oncogenic activation in Gramd2+ AT1 cells resulted in histologically defined LUAD with lepidic properties at early time points and solid adenocarcinoma properties at later time points. This differed from EGFR activation in Sftpc+ AT2 cells, which resulted in pre-carcinogenic atypical adenomatous hyperplasia (AAH) formation that did not progress to adenocarcinoma. While preliminary, our results suggest that cell of origin strongly influences EGFR-mediated lung oncogenesis and concomitant pathology and histologic presentation. This work may advance our understanding while informing patient stratification and treatment strategies for LUAD patients. Citation Format: Aaron M. Neely, Andrea Lanz, William Dean Wallace, Anthony W. Kim, Zea Borok, Crystal N. Marconett. Elucidating the tumorigenic properties of alveolar epithelial type 1 cells in EGFR-mediated LUAD tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6997.

Value of CT Quantitative Parameters in Prediction of Pathological Types of Lung Ground Glass Nodules

The pathological types of lung ground glass nodules (GGNs) show great significance to the clinical treatment. This study was aimed to predict pathological types of GGNs based on computed tomography (CT) quantitative parameters. 389 GGNs confirmed by postoperative pathology were selected, including 138 cases of precursor glandular lesions [atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS)], 109 cases of microinvasive adenocarcinoma (MIA) and 142 cases of invasive adenocarcinoma (IAC). The morphological characteristics of nodules were evaluated subjectively by radiologist, as well as artificial intelligence (AI). In the subjective CT signs, the maximum diameter of nodule and the frequency of spiculation, lobulation and pleural traction increased from AAH+AIS, MIA to IAC. In the AI quantitative parameters, parameters related to size and CT value, proportion of solid component, energy and entropy increased from AAH+AIS, MIA to IAC. There was no significant difference between AI quantitative parameters and the subjective CT signs for distinguishing the pathological types of GGNs. AI quantitative parameters were valuable in distinguishing the pathological types of GGNs.

Abstract PR007: Molecular subtyping of lung adenocarcinoma premalignant lesions identifies features associated with aggressive disease

Abstract Lung cancer is the leading cause of cancer-related death. The five year survival rate had remained stagnant for decades, but more effective screening protocols using low-dose computed tomographic screening for high-risk individuals, along with progress in treatment for advanced-stage lung cancer with targeted therapy and immunotherapy, have helped decrease lung cancer mortality. However, improved approaches to lung cancer prevention and early detection are still urgently needed. Adenocarcinoma (LUAD) is the most common form of lung cancer. Following surgical resection of pre-invasive adenocarcinoma in situ, the five-year survival rate approaches 100%. This emphasizes the need for improved understanding of characteristics of aggressive premalignant lesions that would benefit from early interventions. In contrast to the well-characterized histopathologic sequence of lung squamous cell carcinoma, atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) are the only known precursors in the sequence of LUAD pathogenesis. The features of AAH and AIS that lead to invasive LUAD are poorly characterized. The relationship of AIS and AAH to the histologically diverse subtypes of LUAD, ranging from the typically slow growing lepidic to aggressive solid subtypes, are also unclear. We hypothesized that transcriptomic changes in subsets of premalignant lesions are linked to distinct genomic and clinicopathologic features of malignant disease. To investigate this hypothesis, we performed exome sequencing and bulk RNA sequencing of laser capture microdissected tissue from tumor margins that included premalignant lesions, invasive tumor, and adjacent normal tissues. With our analysis, we discovered de novo subtypes of LUAD premalignant lesions based on gene expression. One of these subtypes had gene expression alterations similar to aggressive invasive LUAD solid tumors. This molecular adenomatous premalignant lesion subtype was also associated with an increased accumulation of cancer driver mutations. This subtype was further characterized by altered expression of immune-related pathways. Molecular signatures measured in adenomatous PML may thus enhance our understanding of pathway dysregulation and mutational heterogeneity occurring during LUAD carcinogenesis, and implicate immunotherapeutic strategies to prevent their progression to cancer. Citation Format: Kelley Anderson, Linh Tran, Kostyantyn Krysan, William Wallace, Gregory Fishbein, Emily Green, Gang Liu, Hanqiao Liu, Erin Kane, Sarah Mazzilli, Steven Dubinett, Avrum Spira, Marc Lenburg, Jennifer Beane. Molecular subtyping of lung adenocarcinoma premalignant lesions identifies features associated with aggressive disease [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR007.

Evaluation of expression of immunohistochemical markers high molecular weight cytokeratin (HMWCK) and alpha-methylacyl coa racemose (AMACR) in prostatic needle biopsies and transurethral resection of prostate (TURP) specimen – A one year observational study

In view of increasing incidence of Prostate cancer with age, its early detection and management is of utmost importance. Digital rectal examination, clinical picture and USG findings are non-specific. In prostatic lesions having a suspicious morphology, IHC staining (HMWCK and AMACR) is done to distinguish benign from malignant lesions. Absence of myoepithelial layer (HMWCK negative) along with cytoplasmic granular staining in glands (AMACR positive) is consistent with malignant diagnosis.To evaluate the utility of IHC markers HMWCK and AMACR in resolving morphologically suspicious foci on Prostatic needle core biopsies and TURP specimens.Observational StudyA total of 30 cases of prostatic lesions were studied. The specimens were fixed in 10% formalin and routinely processed. Haematoxylin-Eosin (H&amp;E) and IHC staining (HMWCK and AMACR) was done in all 30 cases.Data collected was analyzed using appropriate statistical test.A total of 30 cases including 19 cases prostatic needle core biopsies and 11 cases of TURP specimens were included in our study. Histopathological diagnosis included 1 case each of Adenosis, Atypical adenomatous hyperplasia and Transitional cell metaplasia; 9 cases of BPH with suspicious foci, 4 cases of LGPIN, 3 cases of HGPIN and 11 cases Prostatic adenocarcinoma. In 5 cases including 3 cases of BPH with suspicious foci and 1 case each of adenosis and AAH, the diagnosis was changed to Prostatic Adenocarcinoma after IHC analysis. We conclude that IHC staining should be done in cases where routine H&amp;E sections have an ambiguous morphology. HMWCK along with AMACR is a good marker combination to differentiate Benign from Malignant lesions.

The differential diagnosis of lung precursor glandular lesions, micro-invasive adenocarcinoma, and invasive adenocarcinoma using low dose spectral computed tomography perfusion imaging.

Few studies about the association between computed tomography (CT) perfusion imaging parameters and invasiveness in lung adenocarcinoma (LUAD) have been conducted using low dose spectral CT perfusion imaging. The purpose of this study was to investigate application of spectral revolution CT low-dose perfusion imaging in the differential diagnosis of different pathological subtypes of LUAD. This was a cross-sectional study based on historical data from January 2018 to May 2019 in Peking University Cancer Hospital & Institute. A total of 62 cases were enrolled, including 2 cases of atypical adenomatous hyperplasia (AAH), 3 cases of adenocarcinoma in situ (AIS), 4 cases of minimally invasive adenocarcinoma (MIA), and 53 cases of invasive adenocarcinoma (IAC), all confirmed with pathology. The inclusion and exclusion criteria were regulated. Using Revolution low-dose CT perfusion imaging (GE, USA), the CT perfusion parameters of hemodynamics were obtained: blood flow (BF), blood volume (BV), impulse residue function time of arrival (IRF TO), maximum slope of increase (MSI), mean transit time (MTT), permeability surface area product (PS), positive enhancement integral (PEI), and maximum enhancement time (Tmax). Univariate analysis of variance (ANOVA) or Kruskal-Wallis test was used to compare the differences of CT perfusion quantitative parameters among AAH, AIS, MIA, and IAC. Mann-Whitney test was used to compare the difference of CT perfusion imaging parameters between preinvasive lesions (AAH and AIS) and invasive lung cancer (MIA and IAC). Statistically significant differences in IRF TO were observed in LUAD with different invasiveness, namely, among AIS, MIA, and IAC groups (0.56±0.74 vs. 0.54±1.08 vs. 4.39±2.19, P=0.004). Statistically significant differences in IRF TO were also observed between pre-invasive lesions group (AAH and AIS) and invasive lung cancer group (MIA and IAC) (1.12±1.27 vs. 3.75±2.79, P=0.031), and between AAH + AIS + MIA groups and IAC group (0.83±1.13 vs. 4.12±2.69, P<0.001). There were no statistically significant differences in other CT perfusion parameters of hemodynamics among different pathological subtypes of LUAD (P>0.05). The low-dose perfusion parameter IRF TO of revolution CT has the potential to be employed in the differential diagnosis of different pathological subtypes of LUAD.

Precursor lesions of lung tumors

Lung cancer is the leading cause of cancer deaths globally with many new cases diagnosed each year. Recent studies have shown that an accumulation of various genetic abnormalities results in progressive morphologic changes in bronchial epithelium. Such changes are part of the continuum from precursor lesions to invasive lung cancers. Improvement in diagnostic modalities has made the detection of such preneoplastic lesions possible and resection at this stage confer excellent prognosis. The World Health Organization (WHO) has recognized atypical adenomatous hyperplasia/ adenocarcinoma in situ, squamous dysplasia/ squamous cell carcinoma in situ, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as the precursor lesions of adenocarcinoma, squamous cell carcinoma, and carcinoid tumors respectively. This review summarizes the key features of these preneoplastic lesions based on the current understanding and knowledge.

Development and evaluation of an integrated model based on a deep segmentation network and demography-added radiomics algorithm for segmentation and diagnosis of early lung adenocarcinoma.

Non-invasive early detection and differentiation grading of lung adenocarcinoma using computed tomography (CT) images are clinically important for both clinicians and patients, including determining the extent of lung resection. However, these are difficult to accomplish using preoperative images, with CT-based diagnoses often being different from postoperative pathologic diagnoses. In this study, we proposed an integrated detection and classification algorithm (IDCal) for diagnosing ground-glass opacity nodules (GGN) using CT images and other patient informatics, and compared its performance with that of other diagnostic modalities. All labeling was confirmed by a thoracic surgeon by referring to the patient's CT image and biopsy report. The detection phase was implemented via a modified FC-DenseNet to contour the lesions as elaborately as possible and secure the reliability of the classification phase for subsequent applications. Then, by integrating radiomics features and other patients' general information, the lesions were dichotomously reclassified into "non-invasive" (atypical adenomatous hyperplasia, adenocarcinoma in situ, and minimally invasive adenocarcinoma) and "invasive" (invasive adenocarcinoma). Data from 168 GGN cases were used to develop the IDCal, which was then validated in 31 independent CT scans. IDCal showed a high accuracy of GGN detection (sensitivity, 0.970; false discovery rate, 0.697) and classification (accuracy, 0.97; f1-score, 0.98; ROAUC, 0.96). In conclusion, the proposed IDCal detects and classifies GGN with excellent performance. Thus, it can be suggested that our multimodal prediction model has high potential as an auxiliary diagnostic tool of GGN to help clinicians.

Pathomic Features Reveal Immune and Molecular Evolution From Lung Preneoplasia to Invasive Adenocarcinoma

Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate pulmonary nodules, mark the significance of a comprehensive understanding of early lung carcinogenesis. Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer, and atypical adenomatous hyperplasia is the only recognized preneoplasia to ADC, which may progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and eventually to invasive ADC. Although molecular evolution during early lung carcinogenesis has been explored in recent years, the progress has been significantly hindered, largely due to insufficient materials from ADC precursors. Here, we employed state-of-the-art deep learning and artificial intelligence techniques to robustly segment and recognize cells on routinely used hematoxylin and eosin histopathology images and extracted 9 biology-relevant pathomic features to decode lung preneoplasia evolution. We analyzed 3 distinct cohorts (Japan, China, and United States) covering 98 patients, 162 slides, and 669 regions of interest, including 143 normal, 129 atypical adenomatous hyperplasia, 94 AIS, 98 MIA, and 205 ADC. Extracted pathomic features revealed progressive increase of atypical epithelial cells and progressive decrease of lymphocytic cells from normal to AAH, AIS, MIA, and ADC, consistent with the results from tissue-consuming and expensive molecular/immune profiling. Furthermore, pathomics analysis manifested progressively increasing cellular intratumor heterogeneity along with the evolution from normal lung to invasive ADC. These findings demonstrated the feasibility and substantial potential of pathomics in studying lung cancer carcinogenesis directly from the low-cost routine hematoxylin and eosin staining.

Expression Changes in Programmed Death Ligand 1 from Precancerous Lesions to Invasive Adenocarcinoma in Subcentimeter Pulmonary Nodules: A Large Study of 2022 Cases in China.

This large-scale, multicenter, retrospective observational study aimed to evaluate the clinicopathological and molecular profiles associated with programmed death-ligand 1 (PD-L1) expression in precancerous lesions and invasive adenocarcinoma in subcentimeter pulmonary nodules. Patients with histologically confirmed atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (ADC) were included. PD-L1 expression was evaluated at each center using a PD-L1 immunohistochemistry 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The tumor proportion score (TPS) cutoff values were set at ≥ 1% and ≥ 50%. A total of 2022 nodules from 1844 patients were analyzed. Of these, 9 (0.45%) nodules had PD-L1 TPS ≥ 50%, 187 (9.25%) had PD-L1 TPS 1-49%, and 1826 (90.30%) had PD-L1 TPS < 1%. A total of 378 (18.69%), 1016 (50.25%), and 628 (31.06%) nodules were diagnosed as AAH/AIS, MIA, and ADC, respectively, by pathology. A total of 1377 (68.10%), 591 (25.67%), and 54 (2.67%) nodules were diagnosed as pure ground-glass opacity (GGO), mixed GGO, and solid nodules, respectively, by computed tomography. There was a significant difference between PD-L1 expression and anaplastic lymphoma kinase (ALK) mutation status (P < 0.001). PD-L1 expression levels were significantly different from those determined using the International Association for the Study of Lung Cancer (IASLC) grading system (P < 0.001). PD-L1 expression was significantly associated with radiological and pathological invasiveness and driver mutation status in subcentimeter pulmonary nodules. The significance of PD-L1 expression in the evolution of early-stage lung adenocarcinoma requires further investigation.

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.

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. 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. 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). 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.

Lung adenocarcinoma associated with cystic airspaces: Predictive value of CT features in assessing pathologic invasiveness

ObjectivesLung adenocarcinoma associated with cystic airspaces (LACA) is a unique entity with limited understanding. Our aim was to evaluate the radiological characteristics of LACA and to study which criteria were predictive of invasiveness. MethodsA retrospective monocentric analysis of consecutive patients with pathologically confirmed LACA was performed. The diagnosed adenocarcinomas were classified into preinvasive (atypical adenomatous hyperplasia, adenocarcinoma in situ, or minimally invasive adenocarcinoma) and invasive adenocarcinomas. Eight clinical features and twelve CT features were evaluated. Univariable and multivariable analyses were performed to analyse the correlation between invasiveness, and CT and clinical features. The inter-observer agreement was evaluated using κ statistics and intraclass correlation coefficients. The predictive performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC). ResultsA total of 252 patients with 265 lesions (128 men and 124 women; mean age, 58.0 ± 11.1 years) were enrolled. Multivariable logistic regression indicated that multiple cystic airspaces (OR, 5.599; 95 % CI, 1.865–16.802), irregular shape of cystic airspace (OR, 3.236; 95 % CI, 1.073–9.761), entire tumour size (OR, 1.281; 95 % CI, 1.075–1.526), and attenuation (OR, 1.007; 95 % CI, 1.005–1.010) were independent risk factors for invasive LACA. The AUC of the logistic regression model was 0.964 (95 % CI, 0.944–0.985). ConclusionMultiple cystic airspaces, irregular shape of cystic airspace, entire tumour size, and attenuation were identified as independent risk factors for invasive LACA. The prediction model gives a good predictive performance, providing additional diagnostic information.

Clinical implications of the concentration of alveolar nitric oxide in non-small cell lung cancer.

Clinical implications of the concentration of alveolar nitric oxide in non-small cell lung cancer.

Thin-slice computed tomography enables to classify pulmonary subsolid nodules into pre-invasive lesion/minimally invasive adenocarcinoma and invasive adenocarcinoma: a retrospective study

The aim was to investigate the ability of thin-slice computed tomography (TSCT) to differentiate invasive pulmonary adenocarcinomas (IACs) from pre-invasive/minimally invasive adenocarcinoma (AAH-MIAs), manifesting as subsolid nodules (SSNs) of diameter less than 30 mm. The CT findings of 810 patients with single subsolid nodules diagnosed by pathology of resection specimens were analyzed (atypical adenomatous hyperplasia, n = 13; adenocarcinoma in situ, n = 175; minimally invasive adenocarcinoma, n = 285; and invasive adenocarcinoma, n = 337). According to the classification of lung adenocarcinoma published by WHO classification of thoracic tumors in 2015, TSCT features of 368 pure ground-glass nodules (pGGN) and 442 part-solid nodules (PSNs) were compared AAH-MIAs with IACs. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed. In pGGNs, multivariate analysis of factors found to be significant by univariate analysis revealed that higher mean-CT values (p = 0.006, OR 1.006, 95% CI 1.002–1.010), larger tumor size (p < 0.001, OR 1.483, 95% CI 1.304–1.688) with air bronchogram and non-smooth margins were significantly associated with IACs. The optimal cut-off tumor diameter for AAH-MIAs lesions was less than 10.75 mm (sensitivity, 82.8%; specificity, 80.6%) and optimal cut-off mean-CT value − 629HU (sensitivity, 78.1%; specificity, 50.7%). In PSNs, multivariate analysis of factors found to be significant by univariate analysis revealed that smaller tumor diameter (p < 0.001, OR 0.647, 95% CI 0.481–0.871), smaller size of solid component (p = 0.001, OR 83.175, 95% CI 16.748–413.079),and lower mean-CT value of solid component (p < 0.001, OR 1.009, 95% CI 1.004–1.014) were significantly associated with AAH-MIAs (p < 0.05). The optimal cut-off tumor diameter, size of solid component, and mean-CT value of solid component for AAH-MIAs lesions were less than 14.595 mm (sensitivity, 71.1%; specificity, 83.4%), 4.995 mm (sensitivity, 97.8%; specificity, 92.3%) and − 227HU (sensitivity, 65.6%; specificity, 76.3%), respectively. In subsolid nodules, whether pGGN or PSNs, the characteristics of TSCT can help in distinguishing IACs from AAH-MIAs.

Growth Regularity of Pulmonary Ground Glass Nodules Based on 3D Reconstruction Technology

Since the popularization of computed tomography (CT) technology, the detection rate of pulmonary ground glass nodules (GGNs) with imaging follow-up as the main management method has increased significantly. The purpose of this study is to quantitatively analyze the changes of pulmonary GGNs during the follow-up process with three-dimensional reconstruction technology, explore the natural progression of pulmonary GGNs, and provide effective basis for clinical guidance for patients to conduct reasonable management of nodules. A total of 115 cases of pulmonary GGNs with regular follow-up in the Combined Outpatient Department of Zhoushan Hospital from March 2015 to November 2022 were enrolled. Quantitative imaging features of nodules were extracted by semi-automatic segmentation of 3D Slicer software to evaluate the growth of nodules and clinical intervention during follow-up. The average baseline age of the patients was (56.9±10.1) yr. The mean follow-up time was (48.8±18.9) months. The two-dimensional diameter of baseline CT scan was (7.9±2.9) mm, and the maximum three-dimensional diameter was (10.1±3.4) mm. The two-dimensional diameter of the last CT scan was (9.9±4.7) mm, and the maximum three-dimensional diameter was (11.4±5.1) mm. A total of 27 cases (23.5%) showed an increase during follow-up, with a median volume doubling time of 822 days and a median mass doubling time of 1,007 days. 32 cases were surgically resected, including 6 cases of invasive adenocarcinoma (IAC), 16 cases of minimally invasive adenocarcinoma (MIA), 8 cases of adenocarcinoma in situ (AIS) and 2 cases of atypical adenomatous hyperplasia (AAH). Five nodules underwent surgical intervention due to the progression of two-dimensional diameter, which was pathologically confirmed as pre-invasive lesions, but their three-dimensional maximum diameter showed no significant change. Nodular morphology, lobulated sign, spiculated sign and vacuole signs all promoted the growth of nodules in univariate analysis. There were significant differences in age, baseline diameter, mean CT value, median CT value, 10% and 90% percentile CT number between the growth group and the stable group (P<0.05). Multivariate Logistic regression analysis showed that age and average CT value were risk factors for nodule growth (P<0.05). Receiver-operating characteristic (ROC) curve analysis results indicated that the age ≥63 years old, the baseline three-dimensional maximum diameter ≥9.2 mm, and the average CT value ≥-507.8 HU were more likely to accelerate the growth of GGNs. The maximum three-dimensional diameter ≥14.4 mm and the average CT value ≥-495.7 HU may be a higher malignant probability. GGNs show an inert growth process, and the use of three-dimensional measurements during follow-up is of greater significance. For persistent glass grinding nodules ≥63 years old, the baseline three-dimensional maximum diameter ≥9.2 mm, and the average CT value ≥-507.8 HU are more likely to increase. However, most nodules still have good prognosis after progression, and long-term follow-up is safe.

Reticulation Sign on Thin-Section CT: Utility for Predicting Invasiveness of Pure Ground-Glass Nodules.

Please see the Editorial Comment by Dexter Mendoza discussing this article. BACKGROUND. Pure ground-glass nodules (pGGNs) may represent a diverse range of histologic entities of varying aggressiveness. OBJECTIVE. The purpose of this study was to evaluate the use of the reticulation sign on thin-section CT images for predicting the invasiveness of pGGNs. METHODS. This retrospective study included 795 patients (mean age, 53.4 ± 11.1 [SD] years; 254 men, 541 women) with a total of 876 pGGNs on thin-section CT that underwent resection between January 2015 and April 2022. Two fellowship-trained thoracic radiologists independently reviewed unenhanced CT images to assess the pGGNs for a range of features, including diameter, attenuation, location, shape, air bronchogram, bubble lucency, vascular change, lobulation, spiculation, margins, pleural indentation, and the reticulation sign (defined as multiple small linear opacities resembling a mesh or a net); differences were resolved by consensus. The relationship between the reticulation sign and lesion invasiveness on pathologic assessment was evaluated. RESULTS. On pathologic assessment, the 876 pGGNs included 163 nonneoplastic and 713 neoplastic pGGNs (323 atypical adenomatous hyperplasias [AAHs] or adenocarcinomas in situ [AISs], 250 minimally invasive adenocarcinomas [MIAs], and 140 invasive adenocarcinomas [IACs]). Interobserver agreement for the reticulation sign, expressed as kappa, was 0.870. The reticulation sign was detected in 0.0% of nonneoplastic lesions, 0.0% of AAHs/AISs, 6.8% of MIAs, and 54.3% of IACs. The reticulation sign had sensitivity of 24.0% and specificity of 100.0% for a diagnosis of MIA or IAC and sensitivity of 54.3% and specificity of 97.7% for a diagnosis of IAC. In multivariable regression analyses including all of the assessed CT features, the reticulation sign was a significant independent predictor of IAC (OR, 3.64; p = .001) but was not a significant independent predictor of MIA or IAC. CONCLUSION. The reticulation sign, when observed in a pGGN on thin-section CT, has high specificity (albeit low sensitivity) for invasiveness and is an independent predictor of IAC. CLINICAL IMPACT. Those pGGNs that show the reticulation sign should be strongly suspected to represent IAC; this suspicion may guide risk assessments and follow-up recommendations.