Adenomatous Hyperplasia Research Articles

Targeted next-generation sequencing for analyzing the genetic alterations in atypical adenomatous hyperplasia and adenocarcinoma in situ.

Atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) have been defined as preinvasive pulmonary adenocarcinoma lesions according to the 2015 World Health Organization lung adenocarcinoma classification. We aimed to search for the most common gene mutations in patients with AAH and AIS and investigate the distinctions between the two groups at the molecular level. We performed targeted next-generation sequencing on 18 cases with AAH and 28 cases with AIS to screen for mutations with the Ion Torrent Oncomine Solid Tumor DNA panel. ALK and ROS1 fusions were detected by real-time PCR. Forty-six mutations were identified in 29 cases (76.1%), including 9 (50%) of 18 cases with AAH and 20 (71.4%) of 28 cases with AIS, in the following genes: EGFR, BRAF, KRAS, ERBB2, TP53, and FGFR3. The mutations in EGFR, BRAF, KRAS, ERBB2, and TP53 genes were more common in AIS lesions than in AAH lesions, whereas the FGFR3 gene was more frequently mutated in AAH compared to AIS. ALK and ROS1 fusions were not detected in any of the lesions. Based on the molecular evidence, the proposal that AAH and AIS are preinvasive lesions of pulmonary adenocarcinomas is of great significance, and it is necessary to distinguish AAH from AIS. Our study provided insights into the genetic alterations in the early stage of lung adenocarcinoma, which could be beneficial for the pathologic diagnosis and early detection of these lesions.

The identification of sub-centimetre nodules by near-infrared fluorescence thoracoscopic systems in pulmonary resection surgeries

Current surgical procedures lack high-sensitivity intraoperative imaging guidance, leading to undetected micro tumours. In vivo near-infrared (NIR) fluorescence imaging provides a powerful tool for identifying small nodules. The aim of this study was to examine our experience of using 2 different NIR devices in pulmonary resection surgery. From August 2015 to October 2016, 36 patients with lung nodules underwent NIR fluorescence imaging thoracoscopic surgery. Two NIR devices: a D-Light P system and a SUPEREYE system were used. Patients were administered an injection of indocyanine green (ICG) through the peripheral vein 24 h preoperatively. During surgery, traditional white-light thoracoscopic exploration was performed first, followed by ICG-fluorescent-guided exploration. All detected nodules were resected and examined by a pathologist. Of the 36 patients, 76 nodules were resected. ICG-fluorescent imaging identified 68 nodules during in vivo exploration. The mean signal-to-background ratio of lung nodules in NIR exploration was 3.29 ± 1.81. The application of NIR devices led to the detection of 9 additional nodules that were missed using traditional detection methods (1 mm computed tomography scan and white-light thoracoscopic exploration) in 7 patients (19.4%). Four of the 9 nodules were confirmed as malignant or atypical adenomatous hyperplasia (44.4%). The other 5 nodules were confirmed as false-positive nodules. The sensitivities and positive predictive values of the ICG-fluorescent imaging for lung tumours were 88.7% and 92.6%, respectively. This study demonstrated the feasibility and safety of using ICG-fluorescent imaging for multiple lung nodules identification in video-assisted thoracoscopic surgery pulmonary resection. NCT02611245.

Genomic Landscape of Atypical Adenomatous Hyperplasia and Their Progression to Lung Adenocarcinomas

Genomic Landscape of Atypical Adenomatous Hyperplasia and Their Progression to Lung Adenocarcinomas

多层螺旋CT在肺内≤1 cm纯磨玻璃结节浸润性腺癌与浸润前病变鉴别诊断中的价值

Objective To analyze CT imaging features of lung pure ground-glass nodule (pGGN) of 1 cm or less, and to discuss the differential diagnosis value of multi-slice spiral CT (MSCT) of lung pGGN of 1 cm or less in lung infiltrating adenocarcinoma and before infiltration. Methods A total of 103 patients with lung pGGN≤1 cm admitted to the First Hospital of Handan from January 2012 to August 2016 were selected. Of the 103 lung pGGN lesions, there were 67 preinvasive lesions (the preinvasive lesion group) confirmed by operation, including 28 atypical adenomatous hyperplasia and 39 adenocarcinoma in situ. There were 36 invasive lesions (the infiltration group), including 21 minimally invasive adenocarcinoma and 15 invasive adenocarcinoma. All the patients underwent MSCT scanning, and the lesion location, size, CT value, internal density, edge, peripheral vessel and lung-tumor interface were compared between the two pathological types. The receiver operating characteristic curves of the size of the infiltrating lesion and before infiltration were drawn, and the boundary values of the size of the two kinds of pGGN were analyzed and identified. Results The differences of the lesion location (χ2=0.529, P=0.746), vacuole sign (χ2=1.581, P=0.209), aerated bronchus sign (χ2=1.639, P=0.201), edge of the lesion (χ2=0.614, P=0.722) between the two groups were not statistically significant. The proportion of clear lung-tumor interface in infiltration group was higher than that in preinvasive lesion group (86.11% vs. 44.78%; χ2=16.568, P<0.001). The proportion of type Ⅰ in the classification of pulmonary vascular relationships in infiltration group was lower than that in preinvasive lesion group (5.56% vs. 41.79%; χ2=14.894, P<0.001), and the proportion of type Ⅲ in infiltration group was higher than that in preinvasive lesion group (38.89% vs.1.49%; χ2=26.320, P<0.001). The average maximum diameter of the infiltration group [(0.85±0.17)cm] was greater than that of the preinvasive lesion group [(0.76±0.16)cm], and the difference was statiscally significant (t=2.663, P=0.009). The boundary value to identify the size of the preinvasive and invasive lesions was 0.81 cm, and its sensitivity and specificity rates were 62.1% and 63.5%, and the area under the curve was 0.622. Conclusion Of lung pGGN≤1 cm, invasive lesions are larger, lung-tumor interface is more clear, and the proportion of type Ⅲ in the classification of pulmonary vascular relationships is bigger. MSCT can present the above imaging characteristics of lesions, and it has the important value in differential diagnosis of lung pGGN≤1 cm in infiltrating adenocarcinoma and before infiltration. Key words: Lung neoplasms; Coin lesion, pulmonary; Tomography, spiral computed; Carcinoma in situ; Infiltration

The role of volume and mass doubling times of pulmonary pure ground glass nodules in differentiating invasive adenocarcinomas from minimally invasive adenocarcinomas and preinvasive lesions

Objective To evaluate volume doubling time (VDT) and net mass doubling time of tumor (nMDT) of pulmonary pure ground glass nodules (PGGN) of different pathological types and to investigate whether VDT and nMDT can help to differentiate invasive pulmonary adenocarcinomas from minimally invasive adenocarcinomas and preinvasive lesions. Methods Fifty-one pathologically confirmed pGGNs in 46 patients were retrospectively evaluated, in whom at least two HRCT scans were obtained preoperatively (median scan times, 3 times; range, 2—6 times) with 1-month or longer follow-up interval(median follow-up interval, 251 days; range, 30-1 552 days). According to the rechecked results of the postoperative pathological section, 51 pGGNs were divided into two groups: group A, invasive adenocarcinoma (IAC), 30 pGGNs (58.8%); group B, 21 pGGNs (41.2%), including 8 minimally invasive adenocarcinoma (MIA), 7 adenocarcinomas in situ (AIS) and 6 atypical adenomatous hyperplasia (AAH). The volume, cumulative percentage of volume growth and VDTs of pGGNs were automatically acquired by Lung VCAR (advantage windows 4.6, GE HealthCare). Subsequently, the mass, cumulative percentage of mass growth and nMDTs of pGGNs were calculated. The count data and measurement data between two groups were compared using Fisher exact probability and Mann-Whitney U test, respectively. A pairwise comparision were performed by using Wilcoxon signed-rank test. Subsequently, the receiver operating characteristic (ROC) curve was used to determine the optimal cut-off values of VDT and nMDT for the differential diagnosis of IAC and MIA/AIS/AAH, and calculated the area under the curve (AUC). Results The median VDT and nMDT of 51 pGGNs were 1 854.11 days (range, 165.22—+∞ days) and 1 138.45 days (range, 95.92—+∞ days), respectively. The median nMDT was shorter than the median VDT, and the difference was significant (Z=-2.444, P=0.015). The median VDTs of IAC and MIA/AIS/AAH were 847.07 days (165.22—+∞ days) and 4 460.09 days (691.14—+∞ days), respectively. The median nMDTs of IAC, MIA/AIS/AAH were 769.93 days (95.92—+∞ days) and 3814.77 days (611.56—+∞ days), respectively. The median VDT and nMDT of IAC were significantly shorter than those of MIA/AIS/AAH (Z=-3.443,-3.860, P<0.01, respectively). Differentiating IAC from MIA/AIS/AAH, the optimal cutoff value of VDT was 2095.86 days (sensitivity, 71.4%; specificity, 80.0%), the optimal cutoff value of nMDT was 1 169.77 days (sensitivity, 81.0%; specificity, 76.7%). Conclusions In pulmonary pGGNs, IAC showed significantly shorter VDT and nMDT than MIA/AIS/AAH. When VDT is shorter than 2 095.86 days or nMDT is shorter than 1 169.77 days, IAC is suggested. Key words: Lung neoplasms; Tomography, X-ray computed; Ground glass nodule; Volume doubling time; Mass doubling time

Can we differentiate minimally invasive adenocarcinoma and non-invasive neoplasms based on high-resolution computed tomography features of pure ground glass nodules?

ObjectiveThe purpose of our study was to assess the differentially diagnostic value of radiographic characteristics of pure ground glass nodules (GGNs) between minimally invasive adenocarcinoma and non-invasive neoplasm.MethodsSixty-seven pure GGNs (28 minimally invasive adenocarcinomas (MIA) and 39 pre-invasive lesions) were analyzed from June 2012 to June 2015. Pre-invasive lesions consisted of 15 atypical adenomatous hyperplasia (AAH) and 24 adenocarcinomas in situ (AIS). High-resolution computed tomography (HRCT) features and volume of MIA and pre-invasive lesions were assessed. Fisher exact test, independent sample t test, Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were performed.ResultsInter-observer agreement indexes for the diameter, mean HRCT attenuations and volume of pure GGNs were all high (ICC>0.75). Univariate analyses showed that lesion diameter, mean HRCT attenuation, and volume value differed significantly between two groups. Among HRCT findings, GGN shape as round or oval (F = 13.456, P = 0.002) and lesion borders as smooth or notched (F = 15.742, P = 0.001) frequently appeared in pre-invasive lesions in comparison with MIA. Type II and type III of the relationship between blood vessels and pure GGNs suggested higher possibility of malignancy than type I.ConclusionsHRCT features of pure GGNs can help to differentiate MIA from non-invasive neoplasms.

Endometrial Biopsy: American College of Nurse-Midwives.

Endometrial biopsy can be used to diagnose endometrial hyperplasia, endometrial cancer, and uterine infections. This cost-effective procedure has minimal side effects, and complications are rare. The purpose of this clinical bulletin is to provide clinicians with guidance about endometrial biopsy including the procedure's advantages and disadvantages, indications and contraindications, and side effects. In addition, step-by-step instructions for performing endometrial biopsy, the equipment required, selection of sampling devices, and care before and after the procedure are discussed.

Abstract 5383: Non-invasive diagnosis of early-stage lung cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA)

Abstract Current state-of-the-art lung cancer early screening involves using low-dose CT scan to identify lung nodules smaller than 3cm in diameter. However, it’s still a clinical dilemma to differentiate between malignant and benign nodules. We took the approach of methylation profiling by high-throughput bisulfite DNA sequencing in tissue samples to identify specific methylation signatures. We learned methylation patterns that differentiate malignant vs. benign lesions from tissue samples by in-depth data mining, and then used pattern matching to classify plasma samples. Given the usual low amount of ctDNA in plasma, we also developed an ultra-sensitive library preparation method to perform targeted bisulfite DNA sequencing from as low as 1ng of cfDNA or 1mL of plasma. From a training set of 88 tissue samples, which includes 60 malignant specimens with different subtypes (invasive adenomas, IA; minimally invasive adenomas, MIA; atypical adenomatous hyperplasia, AAH; adenocarcinoma in situ, AIS; carcinoid; lymphoepithelioma-like carcinoma of the lung, LELC; squamous carcinoma, SC; as well as 28 benign specimens in different categories including hematomas, granuloma, tuberculosis, inflammatory pseudotumor (IPT), sclerosing hemangiomas (SHL) and infections, we were able to achieve a sensitivity of 95% for identification of malignant lesions, with a specificity of 78.6%. From an independent validation set of 45 plasma samples, we achieved a sensitivity of 94.7% and a specificity of 85.7% for differentiating patients with malignant tumor from patients with benign lesions. Specifically, our assay is demonstrated to be highly sensitive towards early-stage lung cancer detection, with a sensitivity of 93.3% in a total of 15 patients with stage IA/B lung cancer. In summary, we have developed a highly sensitive blood-based non-invasive diagnostic assay for identification of early stage lung cancer, which can aid clinical decisions for patients with a CT scan positive for lung nodules. This approach can also be extended to non-invasive early screening for various cancer types. Citation Format: Xuyu Cai, Yangbin Gao, Hui Shen, Peter Laird, Jian-bing Fan, Weihong Xu, Wenhua Liang, Jianxing He. Non-invasive diagnosis of early-stage lung cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5383. doi:10.1158/1538-7445.AM2017-5383

Lung adenocarcinoma: from molecular basis to genome-guided therapy and immunotherapy.

Although adenocarcinoma (ADC) is the most frequent lung cancer, its diagnosis is often late, when the local invasion is important and/or the metastases have already appeared. Therefore, the mortality at 5 years is still very high, ranging from 51% to 99%, depending on the stage. The implementation of different molecular techniques has allowed genomic studies even in relatively small histological samples such as obtained with non-invasive or minimally invasive techniques, facilitating a better phenotyping of lung ADC. Thus, current classification differentiates between preinvasive lesions (atypical adenomatous hyperplasia and in situ ADC), minimally invasive ADC (MIA) and invasive ADC. 'Field cancerization' is a concept that refers to progressive loco-regional changes occurring in tissues exposed to carcinogens, due to the interaction of the latter with a predisposing genetic background and an appropriate tissue microenvironment. Somatic genetic alterations, including mutations but also other changes, are necessary for oncogenesis, being especially frequent in lung ADC. Changes in the epidermal growth factor receptor (EGFR) gene, Kirsten rat sarcoma viral oncogene (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), gene encoding neurofibromin (NF1), anaplastic lymphoma kinase (ALK) and ROS1 are the main genes that suffer alterations in the tumors of patients with ADC. Molecular profiling of these tumors allows more targeted treatments through two distinct strategies, genome-guided therapy and immunotherapy. The former, targets the aberrant pathways secondary to the genomic alteration, whereas the latter may be based on the administration of antibodies [such as those against cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the programmed cell death ligand 1/protein 1 pathway (PD-L1/PD-1)] or the stimulation of the patient's own immune system to produce a specific response. These strategies are obtaining better results in selected ADC patients.

Abstract 1016: Evaluation of progression associated neoepitopes and immune contexture in pulmonary premalignancy

Abstract Lung cancer is the leading cause of cancer death in the US and in the world. Over the past 30 years, the five-year survival rate for lung cancer has increased by only 5%. With the widespread implementation of screening programs, detection of premalignant and early stage disease is increasing. A better understanding of genomic alterations and the microenvironment along the spectrum of early disease could lead to identification of progression-associated mutations (PAMs), defined as those shared between premalignant lesions and invasive cancer, and their neoepitopes. Unleashing the immune response against pulmonary premalignancy could transform therapy and outcomes. FFPE tissue blocks from patients with resected lung adenocarcinoma (ADC) were obtained from the UCLA Lung Cancer Tissue Repository. For each patient, the following regions were dissected from distal airways utilizing Laser Capture Microdissection: a) normal airway epithelial cells (1-3 regions), b) premalignant atypical adenomatous hyperplasia (AAH, 2-4 regions), c) adenocarcinoma in situ (AIS, when present) and d) ADC, 1-3 regions followed by whole exome sequencing. Forty-one complete cases have been sequenced to date. Our data suggest that premalignant lesions from the same patient may a) have different mutational profiles and b) bear progression-associated mutations, common with the primary lung tumor. This inter-lesion heterogeneity suggests that a progression-associated mutational landscape could be defined in longitudinal studies of pulmonary premalignancy which will be the focus of future investigations. Next, utilizing the mutational data, we performed in silico neoantigen analysis to identify potential neoepitopes among the genes mutated in premalignant lesions. The neoantigen analysis demonstrated that among the top 11 peptides with high binding avidity for autologous MHC, 9 were derived from PAMs. This suggests that neoepitopes exist in premalignancy that could serve as targets for development of future vaccines. Finally, we performed the quantitative immunohistochemical (IHC) and immunofluorescence (IF) staining for Granzyme B, PD-1, PDL-1, CD4+, CD8+ and FOXP3 to evaluate cell-mediated immunity on the same samples that were utilized for WES. We found both infiltration of T effector cells as well as upregulation of checkpoints in premalignancy and detected a significant inter-lesional heterogeneity. Our studies lay the ground work for identification of neoepitopes that can be targeted before the development of invasive lung cancer, thus shifting the approach to disease interception through immunoprevention and treatment of the very earliest phase of the disease. Citation Format: Kostyantyn Krysan, Linh M. Tran, Brandon S. Grimes, Tonya C. Walser, William D. Wallace, Steven M. Dubinett. Evaluation of progression associated neoepitopes and immune contexture in pulmonary premalignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1016. doi:10.1158/1538-7445.AM2017-1016

Hypercortisolism and pregnancy

In this study we retrospectively analyzed data from 221 autopsy protocols of maternal mortality 1996-2015 years. Pathology of adrenal cortex detected in 11 dead. Microadenoma with or without adenomatous hyperplasia of adrenal cortex detected in 8 dead, simple hyperplasia detected in 3 dead. In one case detected bilateral diffuse nodular hyperplasia adrenal cortex in combination with focal adenomatous hyperplasia basophil adenocytes pituitary. In this article presented the background pathology analysis, course and outcomes of the last pregnancy. The conclusion was that the microadenomas of adrenal cortex rarely remain asymptomatic incidentalomas, but more often occur the subclinical or clinical hypercortisolism. The pregnancy on their background carries a high risk of developing of serious complications.

Multiregion whole exome seuquencing of pre- and early neoplastic lung lesions.

e20042 Background: The widespread use of CT for lung cancer screening and other reasons has resulted in a dramatic increase in the number of indeterminate ground glass opacities (GGOs). While many of GGOs can be resected with minimal morbidity, the cost has been called into question. Furthermore, multifocality is a relatively common, which makes decisions on extent of surgical resection and potential benefit less clear. Chemoprevention is a theoretically appealing approach to reduce lung cancer incidence and mortality. However, randomized trials have been disappointing to date. This may be due to the constellation of many factors including lack of reliable biomarkers to identify high-risk patients, lack of appropriate molecular targets and appropriate drugs because of our rudimentary knowledge on early carcinogenesis of lung cancers. It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that can progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, the biology of these lesions is poorly understood and the definition and management of these lesions remain controversial. Methods: Study on early carcinogenesis is hampered by the small size of lesions and challenge of obtaining longitudinal samples at different stages of disease progression. Multiregion sequencing can depict genomic events relative to molecular time with early events ubiquitously present in all regions and late mutations confined to spatially separated regions of lesions. Using this approach, our recent work has reported that 20/21 canonical cancer gene mutations were early genetic events. Results: With intent to delineate the pivotal molecular events driving early carcinogenesis of lung cancer, we have collected 154 resected GGOs with including AAH (N = 40), AIS (N = 39), MIA (N = 55) and ADC (N = 20) based on the IASLC/ATS/ERS classification from 89 patients including 38 patients presenting with multifocal GGOs and 18 patients carry more than one type of pathology. Two to five spatially separated regions from each of the 154 lesions are subjected to whole exome sequencing. Conclusions: The data will be ready to present at the meeting.

Remedial localization after dislodgement of primary mechanical localization in lung surgery.

Unhooking or displacement of hookwire or microcoil due to technical failures is rather common. We aim to establish a new technique for remedial localization in the case of displacement or unhooking of primary mechanical localization during lung surgery. From February 2014 to September 2015, 18 consecutive cases of intraoperative dislodgement during video-assisted thoracoscopic surgery (VATS) were enrolled. Nodule's projection on body surface was located by analyzing computed tomography (CT) images, and a needle was inserted into thoracic cavity through this point. The lung was then inflated, and a small burn was made where the needle tip touched the visceral plural. Wedge resections were subsequently performed for these impalpable small lesions. Eighteen solitary pulmonary nodules (SPNs) from 18 patients were scheduled for VATS wedge resections in this series, including 6 (33.3%) hookwire localization and 12 (66.7%) microcoil localization. Fifteen (83.3%) of 18 nodules were pure ground glass opacity (pGGO) and 3 (16.7%) mixed ground glass opacity (mGGO). The mean diameter of SPNs was 7.7±3.6 mm. The mean distance from SPN to pleura was 12.2±10.9 mm. During remedial localization, 17 (94.4%) nodules were removed successfully by wedge resection, and segmentectomy was performed only in one case with failed outcome. Paraffin pathology showed 2 (11.1%) atypical adenomatous hyperplasia (AAH), 11 (61.1%) adenocarcinoma in situ (AIS), 4 (22.2%) minimally invasive adenocarcinoma (MIA), and 1 (5.6%) inflammatory disease. This remedial localization technique is practical and reliable. It is a good backup plan in the case of dislodgement, and it can help prevent extended lung resection.

Nodules en verre dépoli et adénocarcinome EGFR muté

Ground-glass opacities nodules are frequently detected with the advances of radiological imaging. These can be preinvasive lesions such as atypical adenomatous hyperplasia but also invasive lesions. It leads to question in patients with lung cancer about treatment strategy and follow up. We report the case of a 72 years-old woman followed for a lung adenocarcinoma with an EGFR mutation of the right upper lobe stage IIb. The CT scan shows multiple pure ground-glass opacities in the same lobe of the primitive tumor but also in the other lobe. On the piece of lobectomy, histopathology of two ground-glass opacities showed atypical adenomatous hyperplasia. Ground-glass opacities nodules could be found in patients with an operable lung cancer. These can be multiple and match with atypical adenomatous hyperplasia but also carcinomas lesions. The radiological surveillance is still the standard. The strategy for surgical resection has to be defined especially in case of multiple lesions which can require repeated surgical resection.

CT and histopathologic characteristics of lung adenocarcinoma with pure ground-glass nodules 10 mm or less in diameter.

To evaluate CT and histopathologic features of lung adenocarcinoma with pure ground-glass nodule (pGGN) ≤10 mm in diameter. CT appearances of 148 patients (150 lesions) who underwent curative resection of lung adenocarcinoma with pGGN ≤10 mm (25 atypical adenomatous hyperplasias, 42 adenocarcinoma in situs, 38 minimally invasive adenocarcinomas, and 45 invasive pulmonary adenocarcinomas) were analyzed for lesion size, density, bubble-like sign, air bronchogram, vessel changes, margin, and tumour-lung interface. CT characteristics were compared among different histopathologic subtypes. Univariate and multivariate analysis were used to assess the relationship between CT characteristics of pGGN and lesion invasiveness, respectively. There were statistically significant differences among histopathologic subtypes in lesion size, vessel changes, and tumour-lung interface (P<0.05). Univariate analysis revealed significant differences of vessel changes, margin and tumour-lung interface between preinvasive and invasive lesions (P<0.05). Logistic regression analysis showed that the vessel changes, unsmooth margin and clear tumour-lung interface were significant predictive factors for lesion invasiveness, with odds ratios (95% CI) of 2.57 (1.17-5.62), 1.83 (1.25-2.68) and 4.25 (1.78-10.14), respectively. Invasive lesions are found in 55.3% of subcentimeter pGGNs in our cohort. Vessel changes, unsmooth margin, and clear lung-tumour interface may indicate the invasiveness of lung adenocarcinoma with subcentimeter pGGN. • Invasive lesions were found in 55.3% of lung adenocarcinomas with subcentimeter pGGNs • Lesion size, vessel changes, and tumour-lung interface showed different among histopathologic subtypes • Vessel changes, unsmooth margin and clear tumour-lung interface were predictors for lesion invasiveness.

Imaging features of TSCT predict the classification of pulmonary preinvasive lesion, minimally and invasive adenocarcinoma presented as ground glass nodules

ObjectivesTo comprehensively investigate the role of thin section computed tomography(TSCT) features to distinguish invasive adenocarcinoma(IA) from preinvasive or minimally invasive adenocarcinoma(MIA) appearing as pure or mixed ground glass nodules (pGGNs, mGGNs), and to distinguish adenocarcinoma in situ (AIS) from atypical adenomatous hyperplasia (AAH) in pGGNs. Materials and methodsThree hundred thirteen patients with 334 pathologically diagnosed GGNs according to the 2011 IASLC/ATS/ERS classification were included into this study. The TSCT features of the AAH-MIAs and IAs were compared and analyzed respectively in pGGNs (158 cases) and mGGNs (176 cases). Additionally, AIS (30 cases) and AAH (33 cases) were further analyzed in pGGNs. Receiver operating characteristic(ROC) analysis were performed to determine the cutoff values for the qualitative variables and their diagnostic performances. ResultsIn pGGNs, significant differences were found in the tumor volume(p=0.017, OR=4.98, 95%CI 1.33–18.62) and tumor mass(p=0.03, OR=5.04, 95%CI 1.17–21.59) between AAH-MIAs (AAH, AIS, MIA) group and IAs group, and tumor mass(p=0.037, OR=4.32, 95%CI 1.09–17.10) and standard deviation(SD) (p=0.019, OR=13.92, 95%CI 1.53–126.57) could distinguish AIS from AAH. In mGGNs, significant differences were found in consolidation size (p=0.006, OR=21.98, 95%CI 2.46–196.67) and consolidation mean CT value (p=0.011, OR=18.20, 95%CI1.96–168.88) between AAH-MIAs group and IAs group. Multivariate and ROC analyses revealed that in pGGNs, tumor size (≥1125mm) and mass (>386) were significantly associated with IAs. SD (≥68) and mass (≥70) were significant in distinguishing AIS from AAH. Larger consolidation of nodules (≥8.1mm) and higher CT values of the solid components (≥−222 HU) in mGGNs were significantly associated with IAs. ConclusionTSCT features can help distinguish IAs from AAH-MIAs both in pGGNs and mGGNs, and identify AIS from AAH in pGGNs, which indicated that imaging features may be helpful to guide the therapeutic choice for patients with GGNs which were considered as high risk of malignant diseases.

Relevance Between Programmed Death Ligand 1 and Radiologic Invasiveness in Pathologic Stage I Lung Adenocarcinoma

Programmed death ligand 1 (PD-L1) was reported to predict the response of immunotherapy; however, the association between PD-L1 expression and radiologic and pathologic features has yet to be elucidated. In all, 292 patients with resected pathologic stage I adenocarcinoma were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and the radiologic/pathologic invasiveness. Specifically, the radiologic invasiveness and noninvasiveness were determined based on the consolidation/tumor ratio, with a cutoff value of 0.25 by thin-section computed tomography. Among 292 patients, 47 (16.1%) were positive for PD-L1 expression; the remaining 245 patients (83.9%) were negative for PD-L1 expression. Fisher's exact test demonstrated that PD-L1 expression was significantly associated with a higher consolidation/tumor ratio (p=0.029) and higher maximum standardized uptake value (p= 0.004). The mean values of consolidation/tumor ratio and maximum standardized uptake in patients with and without PD-L1 expression were 0.845 ± 0.052 and 7.241 ± 0.795, and 0.607 ± 0.023 and 3.60 ± 0.364, respectively (p < 0.001 and p < 0.001, respectively). Among 47 adenocarcinomas harboring PD-L1 expression, the frequencies of PD-L1 expression for consolidation/tumor ratios of 0, 0.1 to 0.25, 0.26 to 0.5, and 0.51 or more were 6.4%, 2.1%, 4.3%, and 87.2%, respectively (p=0.007). Pathologically, PD-L1 was identified exclusively only in more invasive subtypes, not in less invasive ones, such as atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant ones (p < 0.001). Expression of PD-L1 was significantly associated with radiologic/pathologic invasive adenocarcinomas. This study provides the first evidence of the radiologic and pathologic invasiveness in resected pathologic stage I adenocarcinoma with PD-L1 expression.

Nontypeable Haemophilus influenzae–Promoted Proliferation of Kras-Induced Early Adenomatous Lesions Is Completely Dependent on Toll-Like Receptor Signaling

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. COPD is characterized by chronic airway inflammation and lung infections. The airways of patients with COPD are frequently colonized with bacteria [eg, nontypeable Haemophilus influenzae (NTHi)] that cause pulmonary inflammation and exacerbations. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the KRAS gene. We determined the function of Toll-like receptor (TLR) signaling on the progression of Kras-induced early adenomatous lesions in the lung. Wild-type (WT) mice and mice doubly deficient in Tlr-2 and -4 (Tlr2/4-/-), both with an oncogenic Kras allele in lung epithelium, were exposed to NTHi for 4 weeks. Exposure to NTHi resulted in increased tumor proliferation and growth in WT mice, but not in Tlr2/4-/- mice. Alveolar adenomatous hyperplasia and adenocarcinoma were significantly increased in WT mice compared with Tlr2/4-/- mice. The average size of tumors was significantly larger in WT mice, whereas there was no difference in the number of alveolar lesions between WT and Tlr2/4-/- mice. NTHi-induced pulmonary neutrophilic inflammation and tumor-associated neutrophils were reduced in Tlr2/4-/- mice. Thus, subsequent to a driver mutation, NTHi-induced inflammation promotes proliferation of early adenomatous lesions in a TLR-dependent manner.

Surgical Treatment of Small Pulmonary Nodules Under Video-assisted Thoracoscopy (A Report of 129 Cases)

背景与目的影像技术的发展导致肺部微小结节尤其是肺磨玻璃结节（ground-glass opacity, GGO）检出逐年增多，但术前定性困难。本研究探讨肺部微小结节的临床诊断及微创手术治疗的必要性和可行性、病理诊断，微创切除及淋巴结切除的手术方式。方法对2013年12月-2016年11月接受电视胸腔镜手术（video-assisted thoracic surgery, VATS）治疗并有明确病理诊断的共129例患者的临床资料回顾性分析。所有患者术前行薄层计算机断层扫描（computed tomography, CT）扫描，其中21个微小结节术前行CT引导下Hook-wire定位，并根据病理性质及患者身体状况采用不同手术方式。结果共129个微小结节，实性结节（solid pulmonary nodule, SPN）37个，恶性比例是24.3%（9/37），术后病理结果为：肺原发性鳞状细胞癌3个，浸润性腺癌（invasive adenocarcioma, IA）3个，转移癌2个，小细胞肺癌（small cell lung cancer, SCLC）1个，错构瘤16个，其他炎症等良性病变12个；49个混合性GGO（mixed ground-glass opacity, mGGO）的恶性比例是63.3%（31/49），术后病理结果为：IA 19个，微浸润腺癌（micro invasive adenocarcioma, MIA）6个，原位腺癌（adenocarcioma in situ, AIS）4个，非典型性腺瘤样增生（atipical adenomatous hyperplasia, AAH）1个，SCLC 1个，炎症等良性病变18个；43个纯GGO（pure ground-glass opacity, pGGO）的恶性比例是86.0%（37/43），术后病理结果为：AIS 19个，MIA 6个，IA 6个，AAH 6个，炎症等良性病变6个；GGO总的恶性比例是73.9%（68/92）。52个良性病变均采用VATS肺楔形切除；原发性非小细胞肺癌（non-small cell lung cancer, NSCLC）共73例，VATS肺叶切除和淋巴结清扫33例，VATS肺楔形切除和选择性淋巴结切除6例，VATS肺段切除和选择性淋巴结切除6例，VATS肺楔形切除28例；2个转移癌和2个SCLC，采用VATS肺楔形切除术。另有6例患者术中冰冻病理存在误差，其中2例选择二次手术行肺叶切除和淋巴结清扫。45例有淋巴结病理结果NSCLC只有两例以SPN为表现的IA出现纵隔淋巴结转移，其余均未出现淋巴结转移。术后随访1个月-35个月，平均（15.1±10.2）个月，无复发及转移。结论肺部微小结节尤其是GGO，是恶性病灶的概率大，应积极外科处理；围手术期应与患者及家属充分告知冰冻病理结果存在误差可能性，避免医疗纠纷。

P1.03-023 Ground-Glass Opacity (GGO) with Semi-Consolidation: Clinicopathological and Radiological Correlations Compared to Pure-GGOs of the Lung

There has been a great advancement in understanding natural history of ground-glass opacity (GGO), which represents histological lepidic growth in early stage pulmonary adenocarcinoma. Among them, some GGO lesions reveal increased density of GGOs without obvious consolidation on thin-section computed tomography (TSCT), i.e., GGO with semi-consolidation. However, little is known regarding clinicopathological and radiological relationship of this new entity. During 2004 and 2016, we underwent AAA (2327) surgical resections for clinical-stage IA lung cadenocarcinoma. Among them, 286 (12.3%) GGO lesions without any consolidations were identified based on the findings on TSCT. They were categorized into two groups; pure-GGO (PG) and GGO with semi-consolidation (SC) according to the radiological findings. Semi-consolidation is defined as GGO with increased homogenous density without consolidation on TSCT. Clinicopathological factors were analyzed between these two groups. Survivals were calculated by Kaplan-Meier estimation methods. Of the cases, 172 (60.1%) showed PG and 114 (39.8%) showed SC. Significant or marginal differences were clinically observed between PG and SG groups regarding age (59.4y vs. 63.0y, p=0.02), pack-year smoking status (10.2 vs. 11.6, p=0.084), tumor size (12.2cm vs. 13.9cm, p=0.06), respectively. Noninvasive lesions including atypical adenomatous hyperplasia, adenocarcinoma in situ or minimally invasive adenocarcinoma were observed in 144 patients (83.7%) of PG and 74 (64.9%) of SC, however, the frequency of invasive adenocarcinoma or lymph-vascular invasions were significantly higher in SC group compared to PG group (15.7% vs 33.9%, p=0.001: 4.3% vs 0.5%, p=0.040) despite their GGO appearances. There was no lymph node metastasis in both PG and SC groups. Overall lung-cancer specific survival is 100% to date in both PG/SC groups with mean follow-up period of 97months. Despite the conventionally same category as a native GGO appearance on TSCT, invasive adenocarcinoma was frequently observed in radiologically dense GGO lesions, indicating that PG might progress to SC over time. Surgical outcome for both groups are excellent. Therefore, more studies regarding optimal surgical procedures and long-term outcome of these two groups should be warranted.