Whole-Exome Sequencing Reveals the Genomic Features of the Micropapillary Component in Ground-Glass Opacities.

BACKGROUND: Micropapillary components are observed in a considerable proportion of ground-glass opacities (GGOs) and contribute to the poor prognosis of patients with invasive lung adenocarcinoma (LUAD). However, the underlying mutational processes related to the presence of micropapillary components remain obscure, limiting the development of clinical interventions. METHODS: We collected 31 GGOs, which were separated into paired micropapillary and non-micropapillary components using microdissection. Whole-exome sequencing (WES) was performed on the GGO components, and bioinformatics analysis was conducted to reveal the genomic features of the micropapillary component in invasive LUAD. RESULTS: The micropapillary component had more genomic variations, including tumor mutation burden, intratumoral heterogeneity, and copy number variation. We also observed the enrichment of AID/APOBEC mutation signatures and an increased activation of the RTK/Ras, Notch, and Wnt oncogenic pathways within the micropapillary component. A phylogenetic analysis further suggested that ERBB2/3/4, NCOR1/2, TP53, and ZNF469 contributed to the micropapillary component's progression during the early invasion of LUAD, a finding that was validated in the TCGA cohort. CONCLUSIONS: Our results revealed specific mutational characteristics of the micropapillary component of invasive LUAD in an Asian population. These characteristics were associated with the formation of high-grade invasive patterns. These preliminary findings demonstrated the potential of targeting the micropapillary component in patients with early-stage LUAD.

Evaluation of dynamic image progression of minimally invasive and preinvasive lung adenocarcinomas.

BACKGROUND: The target of our study was to investigate if the size (greater than and less than 1 cm) of ground-glass opacities (GGOs) of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) of the lung influences the rate of their evolution. METHODS: We retrospectively analyzed patients with AIS and MIA who underwent surgery at Shanghai Chest Hospital, Shanghai Jiao Tong University between January 2018 and July 2019, focusing on histopathology, surgical procedure, epidermal growth factor receptor (EGFR) mutations, and computed tomography (CT) images. RESULTS: A total of 224 AIS (n=117) and MIA (n=107) tumors were analyzed. The patients with a tumor diameter <1 cm were distinctly younger than those with tumors >1 cm in size (P<0.001). Pure ground-glass opacities (pGGO) occurred significantly more in patients with nodules <1 cm, while part-solid/mixed ground-glass opacities (mGGO) predominated in patients with nodules >1 cm (P=0.047). There was no significant difference in GGO evolution for GGOs of different sizes. Mutations of EGFR were more common in patients with MIA than in those with AIS (P<0.001). CONCLUSIONS: We found that GGO size and variation (pGGO or mGGO) did not correlate to tumor stability, therefore larger GGOs can undergo standard follow-up protocols to evaluate their evolution over time.

Genomic landscape of ground glass opacities (GGOs) in East Asians.

BACKGROUND: Understanding the genomic landscape of early-stage lung adenocarcinoma (LUAD) may provide new insights into the molecular evolution in the early stages of LUAD. METHODS: Through sequencing of 79 spatially distinct regions from 37 patients with ground glass opacities (GGOs), we provided a comprehensive mutational landscape of GGOs, highlighting the importance of ancestry differences. RESULTS: Our study had several interesting features. First, epidermal growth factor receptor (EGFR), BRAF (v-RAF murine sarcoma viral oncogene homologue B1), and ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2, also known as HER2) were more frequently mutated in our study, which supports the notion that EGFR is considered to be a major driver and tends to drive the occurrence of LUAD. Second, Signature 1, Signature 3, and Signature 6 were identified in patients with GGOs. Our results further suggested that Signature 1 was more prominent among early mutations. Third, compared with LUADs, GGOs exhibited significantly lower levers of arm-level copy number variation (CNV)-which alter the diploid status of DNA, and lower focal CNVs. CONCLUSIONS: In our study, 79 samples of patients were included to analyze the GGO gene profile, revealing the genetic heterogeneity of GGO in East Asian population, and providing guidance for prognosis analysis of GGO patients by comparison with LUAD. Our study revealed that GGOs had fewer genomic alterations and simpler genomic profiles than LUADs. The most commonly altered processes were related to the receptor tyrosine kinase (RTK)/Ras/phosphatidylinositol-3-kinase (PI3K) signaling pathways in GGOs, and EGFR alterations were the dominant genetic changes across all targetable somatic changes.

Tailing effect of PD-1 antibody results in the eradication of unresectable multiple primary lung cancer presenting as ground-glass opacities: a case report.

There is currently no standard treatment for multiple primary lung cancer (MPLC). We report a case of synchronous MPLC presenting as one ground-glass opacity (GGO) with predominant consolidation accompanied by at least parietal pleura involvement, and another with >30 GGOs distributed across bilateral lungs, which was ineligible for complete resection. CT-guided percutaneous biopsy of the nearly pure-solid mass showed invasive lung adenocarcinoma mainly composed of acinar type. Capture-based, ultra-deep targeted sequencing (Burning Rock, Guangzhou, China) was performed on the tumor tissue biopsy. The result revealed no druggable mutations according to the guideline and a high TMB of 34.1 Mb. Immunohistochemical staining (22C3; Dako, Denmark) was positive for PD-L1 expression with a tumor expression level of 30%. Based on the clinical information and patient's decision, he received 3 cycles of pemetrexed plus pembrolizumab and was subsequently forced to withdraw due to acquired immune-related pneumonitis. After discontinuation of corticosteroids, he was subjected to wedge resection for the nearly pure-solid lesion, and then refused further treatment for the other tumors. After a follow-up of 12 months from termination of immunotherapy, almost all GGOs achieved radiographically complete remission, attributed to the tailing effect of the programmed cell death protein 1 (PD-1) antibody of pembrolizumab. Through the case study we found that unresectable synchronous MPLC presenting as GGOs may respond well to immunotherapy.

Hybrid operating room for the intraoperative CT-guided localization of pulmonary nodules.

Video-assisted thoracic surgery (VATS) requires preoperative computed tomography (CT)-guided localization of small pulmonary nodules or ground glass opacities (GGOs). However, this traditional two-stage approach is not devoid of potential complications, including wire dislodgement, pneumothorax, and/or hemothorax. With the advent of hybrid operating rooms (HORs), simultaneous single-stage localization and removal of such lesions has become possible. Here, we review the technical developments and the state-of-the-art in the field of intraoperative CT-guided localization and resection of small pulmonary nodules performed within a HOR.

Image-guided video-assisted thoracoscopic surgery for small ground glass opacities: a case series.

BACKGROUND: This case series demonstrated the feasibility of the image-guided video-assisted thoracoscopic surgery (iVATS) for localization and removal of ground glass opacities (GGOs). The procedure was performed in a hybrid operating room (OR) using C-arm cone-beam computed tomography (CBCT) equipped with a laser-guided navigation system. METHODS: Between October 1st 2016 to July 31st 2017, 14 consecutive patients presenting with GGOs underwent iVATS procedure. The efficacy and safety of the procedure were assessed through a retrospective chart review. RESULTS: The median GGOs size was 7 mm [interquartile range (IQR): 4-10 mm] with a median depth-to-size (D-S) ratio of 1.16 (IQR: 0-2.3). All of the lesions were visible on intraoperative CBCT images and localizations were successful in all patients with a median localization time of 22 min (IQR: 16-44 min). No patient required a conversion to thoracotomy. There was no operative mortality and the median length of postoperative stay was 4 days (IQR: 3-6 days). The final pathological diagnoses were as follows: primary lung cancer (n=6), lung metastases (n=2), and benign lung lesions (n=6). CONCLUSIONS: Our study suggests the iVATS could be a helpful tool for single-stage detection and removal of GGOs.