Intrapulmonary Metastases Research Articles

Association of MUC19 Mutation With Clinical Benefits of Anti-PD-1 Inhibitors in Non-small Cell Lung Cancer.

Although anti-PD-1 inhibitors exhibit impressive clinical results in non-small cell lung cancer (NSCLC) cases, a substantial percentage of patients do not respond to this treatment. Moreover, the current recommended biomarkers are not perfect. Therefore, it is essential to discover novel molecular determinants of responses to anti-PD-1 inhibitors. We performed Whole Exome Sequencing (WES) in a cohort of 33 Chinese NSCLC patients. Patients were classified into the durable clinical benefit (DCB) and no durable benefit (NDB) groups. Infiltrating CD8+ cells in the tumor microenvironment (TME) were investigated by immunohistochemistry. We also used public datasets to validate our results. In our cohort, good clinical responses to anti-PD-1 inhibitors were more pronounced in younger patients with lower Eastern Cooperative Oncology Group (ECOG) scores and only extra-pulmonary metastasis. More importantly, we identified a novel MUC19 mutation, which was significantly enriched in DCB patients (P = 0.015), and MUC19-mutated patients had a longer progression-free survival (PFS) (hazard ratio = 0.3, 95% CI 0.1–0.9; P = 0.026). Immunohistochemistry results indicated that the MUC19 mutation was associated with increased infiltration by CD8+ T cells in the TME (P = 0.0313). When combining MUC19 mutation with ECOG scores and intra-pulmonary metastasis status, patients with more positive predictors had longer PFS (P = 0.003). Furthermore, MUC19 mutation was involved in immune responses and associated with a longer PFS in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Collectively, we identified that MUC19 mutations were involved in immune responses, and NSCLC tumors harboring mutated MUC19 exhibited good responses to anti-PD-1 inhibitors.

Next-generation sequencing facilitates differentiating between multiple primary lung cancer and intrapulmonary metastasis: a case series

BackgroundIn lung cancer management, differential diagnosis between multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IMP) is a critical point that is of direct therapeutic and clinical importance. However, this process often suffers from absence of a gold standard, resulting in equivocal cases. Herein, we present a series of three cases, in which genomic alteration patterns revealed by next-generation sequencing (NGS) facilitated the differential diagnosis between MPLC and IMP.Case presentationCase 1 was a 57-year-old female with two separate lesions in the upper lobe and the lower lobe of left lung, which were both histopathologically determined as T2aN0M0 adenocarcinomas. NGS identified an EGFR L858R in one lesion and an EGFR 20 exon insertion in the other one, suggestive of double primary malignancies. The patient underwent wedge resections and received an adjuvant treatment of icotinib and chemotherapy. She had a disease-free survival (DFS) of 19 months and counting. Case 2 was a 55-year-old female with multiple small lesions in both lungs. Histopathological examinations of resected lesions from right upper lobe revealed three subtypes: atypical adenomatous hyperplasia of alveolar epithelium, adenocarcinomas in situ and minimally invasive adenocarcinoma. NGS identified two different BRAF driver mutations G466E and V600_K601delinsE in two lesions of adenocarcinoma in situ, and a BRAF K601E in a lesion of minimally invasive adenocarcinoma. Case 3, a 68-year-old male, had the right upper lobe lesion histophathologically classified as a stage T3NxM0 mixed adenoneuroendocrine carcinoma and the left upper lobe lesion as a stage T1aN0M0 adenocarcinoma. NGS performed with different loci of surgical tissues revealed a rare sensitizing EGFR mutation G719A shared by the right upper lobe lesion and lymph node, and two EGFR mutations L861Q and G719S in left upper lobe lesion. The patient received icotinib treatment postoperatively and achieved a stable disease with a progression-free survival of 5 months.ConclusionOur cases provide evidence for utility of NGS in facilitating diagnosis and treatment decisions.

ES25.04 Multiple Pulmonary Lesions: Metastasis vs Multiple Primaries, From Martini's Criteria to Molecular Profiling

ES25.04 Multiple Pulmonary Lesions: Metastasis vs Multiple Primaries, From Martini's Criteria to Molecular Profiling

Does histological assessment accurately distinguish separate primary lung adenocarcinomas from intrapulmonary metastases? A study of paired resected lung nodules in 32 patients using a routine next-generation sequencing panel for driver mutations

AimVarious approaches have been reported for distinguishing separate primary lung adenocarcinomas from intrapulmonary metastases in patients with two lung nodules. The aim of this study was to determine whether histological...

Morphological and genetic heterogeneity of synchronous multifocal lung adenocarcinoma in a Chinese cohort

BackgroundSynchronous multifocal lung cancer (SMLC) is diagnosed with increasing frequency in clinical practice globally. Due to innate variation in clinical management and outcome, it is vital to properly distinguish between synchronous multifocal primary lung cancer (SMPLC) and intrapulmonary metastasis (IM). The pathologic features and principal classification criteria of multifocal lung cancer remain unclear. Our objective was to evaluate the diagnostic value of histological morphologic features and driver gene mutations in SMLC classification.MethodsWe collected a unique cohort of Chinese patients with SMLC, and fully explored the morphologic, immunohistochemical, and molecular features of the disease. Twenty-one SMLC patients with a total of 50 tumours were included in our study. The pathological features that were presented by these patients were analysed, including the tumours location, tumours size, pathological types, predominant pattern of adenocarcinoma, and immunohistochemical staining. We conducted molecular testing of nine driver oncogenes that are associated with lung cancer, namely, EGER, KRAS, BRAF, NRAS, ALK, ROS1, RET, HER2, and PIK3CA.ResultsAccording to the Martini-Melamed classification and refined standard, 8 and 17 patients, respectively, were considered to have SMPLCs. Gene mutations were identified in 18 tumours (36%). Twelve patients had different gene mutations.ConclusionsWe demonstrate that conventional morphological assessment is not sufficient to clearly establish the clonal relationship of SMPLCs. Instead, the evaluation of histological subtypes, including nonmucinous adherent components, is required. Multiplex genotypic analysis may also prove to be a useful additional tool.

A multidisciplinary approach for the differential diagnosis between multiple primary lung adenocarcinomas and intrapulmonary metastases

PurposeThe distinction between multiple primary lung cancers (MPLCs) and intrapulmonary metastases has a significant impact on tumor staging and therapeutic choices. Several criteria have been proposed to solve this diagnostic issue, but a definitive consensus is still missing. We tested the efficacy of a combined clinical, histopathological and molecular (“real world”) approach for the correct classification of multiple lung tumors in a selected cohort of patients. Methods24 multiple lung tumors with a diagnosis of adenocarcinoma from 10 patients were retrospectively reviewed. Radiological, pathological and clinical information, including follow-up, were integrated with molecular profiling via a routine multigene panel sequencing. ResultsComprehensive histologic assessment revealed readily distinguishable histologic patterns between multiple tumors suggesting unrelated lesions in 7 cases, in agreement with clinical, radiological and molecular data, thus leading to final diagnosis of MPLCs. In the remaining 3 cases, the differential diagnosis between MPLCs and intrapulmonary metastases was challenging, since the histologic features of the lesions were similar or identical. The final interpretation (2 MPLCs and 1 most likely intrapulmonary metastases) was reached thanks to the integration of all available data, and was confirmed by follow-up. ConclusionsA multidisciplinary approach including a routinely affordable multigene panel sequencing is a useful tool to discriminate MPLCs from intrapulmonary metastases in multiple lung nodules sharing the adenocarcinoma histotype.

Radiomics signature on CECT as a predictive factor for invasiveness of lung adenocarcinoma manifesting as subcentimeter ground glass nodules

Controversy and challenges remain regarding the cognition of lung adenocarcinomas presented as subcentimeter ground glass nodules (GGNs). Postoperative lymphatic involvement or intrapulmonary metastasis is found in approximately 15% to 20% of these cases. This study aimed to develop and validate a radiomics signature to identify the invasiveness of lung adenocarcinoma appearing as subcentimeter ground glass nodules. We retrospectively enrolled 318 subcentimeter GGNs with histopathology-confirmed adenocarcinomas in situ (AIS), minimally invasive adenocarcinomas (MIA) and invasive adenocarcinomas (IAC). The radiomics features were extracted from manual segmentation based on contrast-enhanced CT (CECT) and non-contrast enhanced CT (NCECT) images after imaging preprocessing. The Lasso algorithm was applied to construct radiomics signatures. The predictive performance of radiomics models was evaluated by receiver operating characteristic (ROC) analysis. A radiographic-radiomics combined nomogram was developed to evaluate its clinical utility. The radiomics signature on CECT (AUC: 0.896 [95% CI 0.815–0.977]) performed better than the radiomics signature on NCECT data (AUC: 0.851[95% CI 0.712–0.989]) in the validation set. An individualized prediction nomogram was developed using radiomics model on CECT and radiographic model including type, shape and vascular change. The C index of the nomogram was 0.915 in the training set and 0.881 in the validation set, demonstrating good discrimination. Decision curve analysis (DCA) revealed that the proposed model was clinically useful. The radiomics signature built on CECT could provide additional benefit to promote the preoperative prediction of invasiveness in patients with subcentimeter lung adenocarcinomas.

Analysis of metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation.

BackgroundMost lung cancer patients are diagnosed at an advanced stage with metastases. There was no population-based data on metastases in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. This study focused on the metastases in NSCLC patients with EGFR mutation.MethodsIn our research, we retrospectively studied 365 NSCLC patients with EGFR mutation (EGFR positive-mutant group) were not resistant to first-generation EGFR TKIs and 316 NSCLC patients with T790M mutation (T790M-mutant group) who were resistant to first-generation EGFR TKIs. In the study, we also investigated sex, smoking status, age at diagnosis, histology, T, N, and M stage, and mutation status. In addition, we analyzed metastatic sites in stage IV patients.ResultsAmong the EGFR positive-mutant group, 248 (67.95%) patients were stage IV disease. Among them, 41 patients had brain metastases, 86 patients had bone metastases, 16 patients had liver metastases, 168 patients had intrapulmonary metastases, and 39 patients had metastases in other sites. Among the T790M-mutant group, 277 (87.66%) patients were stage IV disease. Among them, 158 patients had brain metastases, 82 patients had bone metastases, 241 patients had liver metastases, 53 patients had intrapulmonary metastases, and 229 patients had metastases in other sites. We also found that lung cancer patients in the T790M-mutant group had higher incidences of the brain (P<0.001), bone (P<0.001), liver (P=0.001), and intrapulmonary metastases (P<0.001). Moreover, wherever the metastatic site was, the metastasis time all centrally distributed in the first two months after diagnosis.ConclusionsFor patients with metastatic lung cancer, most metastases happened before diagnosis, which indicated that metastases related to driving mutations, such as EGFR positive mutation or T790M mutation, but not to the survival time. Lung cancer patients with T790M mutation were more likely to metastasize before the diagnosis.

Synchronous Multiple Lung Cancers with Lymph Node Metastasis and Different EGFR Mutations: Intrapulmonary Metastasis or Multiple Primary Lung Cancers?

BackgroundThere is no consensus on whether patients with synchronous multiple lung cancers (SMLC) who present with lymph node metastasis (LNM) but whose epidermal growth factor receptor (EGFR) mutations are different are considered to have intrapulmonary metastases or multiple primary lung cancers. Few studies on these patients have been reported.MethodsThe electronic medical records of patients with surgically resected multiple lung cancers between February 2016 and July 2019 were retrospectively reviewed, focusing on the clinical characteristics and prognosis of patients with LNM and different EGFR mutations.ResultsA total of 125 patients were diagnosed with SMLC, and only 8 patients had LNM and different EGFR mutations. Their mean age was 61.43 ± 8.08 years (range 47–69 years). EGFR detection suggested that 4 patients had completely different mutation types, and 4 patients had mutations in only 1 tumor. Only 1 of the 17 total lesions was squamous cell carcinoma, the rest were adenocarcinoma. All patients underwent adjuvant therapy after surgery. Except for 1 patient who underwent chemotherapy, the rest received tyrosine kinase inhibitor-targeted therapy. As at 15 October 2020, the average follow-up time was 28.68 ± 10.74 months (range 10.5–40.5 months), and all patients were alive except 1 who died from extensive pleural metastasis.ConclusionThe current study highlights the clinical importance of EGFR detection in SMLC, especially in patients with LNM. SMLC with LNM and different EGFR mutations should be considered multiple primary lung cancers rather than intrapulmonary metastases, and comprehensive treatment based on surgery may be preferable in these patients due to a good prognosis.

First-Line EGFR-TKIs Treatment in Stage I Non-Small-Cell Lung Cancer Patients Harboring EGFR Gene Mutations with Postoperative Intrapulmonary Recurrence.

BackgroundThe epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is an effective treatment for advanced lung cancer harboring EGFR gene mutations, and has improved progression-free survival in several clinical trials.MethodsWe investigated 30 stage I non-small-cell lung cancer patients harboring EGFR gene mutations with postoperative intrapulmonary recurrence. Progression-free survival and response rate were analyzed.ResultsPartial response was achieved in 23 patients and stable disease was found in 7 patients. The objective response rate was 76.7% and disease control rate was 100%. The median progression-free survival (PFS) time was 24.5 months. The median PFS in patients with only intrapulmonary recurrence was significantly superior to patients with both intrapulmonary recurrence and metastasis (32.0 months vs 14.0 months, P = 0.003). The median PFS observed in patients who underwent icotinib treatment was significantly longer than in patients who underwent gefitinib treatment (30.5 months vs 12.0 months, p = 0.005). There were no statistical differences in median PFS between patients with tumors harboring exon 21 mutation and exon 19 deletion, age <65 and ≥65, male and female, smoker and non-smoker.ConclusionOur result reveals that first-line EGFR-TKIs treatment for stage I non-small-cell lung cancer patients harboring EGFR gene mutations with postoperative intrapulmonary recurrence is effective and could be a useful option in practical setting.

Are there imaging characteristics that can distinguish separate primary lung carcinomas from intrapulmonary metastases using next-generation sequencing as a gold standard?

ObjectivesDistinguishing separate primary lung carcinomas (SPLCs) from intrapulmonary metastases (IPMs) in non-small cell lung cancer (NSCLC) patients is a challenging dilemma in clinical practice. Next-generation sequencing (NGS) was recently shown to represent a robust molecular method for clonal discrimination in this setting. In this study, using clonal relationships established by comprehensive NGS as the ground truth, we investigated whether NSCLC patients with SPLCs versus IPMs exhibit distinct imaging characteristics. Material and methodsThis retrospective study included patients who underwent pre-treatment computed tomography (CT) and/or positron emission tomography/CT (PET/CT) imaging followed by surgical resection for >1 NSCLC. Nodular, parenchymal, pleural, and ancillary CT features, as well as maximum standardized uptake values (SUVs) on PET/CT were recorded. Rao–Scott chi-square, Wilcoxon rank-sum, and Fisher’s exact tests were used in patient- and lesion-level comparisons. ResultsThis study included 60 patients (median age = 69 years, 68 % female) with 127 individual tumors comprising 51 SPLC vs 23 IPM tumor pairs based on NGS profiling. SPLCs were associated with subsolid consistency (P = 0.005) and spiculated contours (P < 0.001), while IPMs were associated with greater difference of size between lesions (P = 0.017) or pure solid consistency of the smaller lesion (P = 0.011). Lymph node involvement was more frequent in IPMs than SPLCs (P = 0.036). SUV measurements were not useful for differentiation (P > 0.05). ConclusionSelected preoperative CT features are distributed differentially in SPLCs and IPMs, suggesting that imaging may have a role in distinguishing clonal relationships of tumors in patients with >1 NSCLC.

Establishment of Criteria for Molecular Differential Diagnosis of MPLC and IPM.

BackgroundsDifferential diagnosis of multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) is one difficulty in lung cancer diagnosis, and crucial for establishment of treatment strategies and prognosis prediction. This study aims to establish the criteria for molecular differential diagnosis of synchronous MPLC and IPM by the next-generation sequencing (NGS) method.MethodsTraining cohort included 30 synchronous MPLC (67 samples) patients and 5 synchronous IPM (13 samples) patients with adenocarcinoma. Criteria of MPLC/IPM differential diagnosis were established by results from a NGS-based 605-gene panel test. Subsequently, 16 patients (36 samples) were recruited as the validation cohort to verify the criteria.ResultsIPM lesions showed a high degree of mutation overlap with an average concordance rate of 60.2% (range: 15.8%–91.7%). IPM lesions had at least three common alterations, including both high-frequency driver gene alterations and low-frequency gene alterations. In contrast, the average concordance rate of MPLC was 11.0% (range: 0.0%–100.0%), among which 66.7% (20/30) of patients had no common alterations (concordance rate: 0%). In the remaining 10 patients, 9 had only one overlapping alteration while 1 had two overlapping alterations, in which 6 patients had EGFR L858R overlapping mutation. Alterations were classified into trunk, shared, and branch subtypes. Branch alterations accounted for 94.4% of mutations in MPLC, while accounted for only 45.0% in IMP. In contrast, the ratio of trunk (38.3%) and shared (16.7%) alterations in IPM was significantly higher. The criteria for differentiating MPLC from IPM using 605-gene panel was established: 1) MPLC can be interpreted if no overlapping alterations is found; 2) MPLC is recommended if one overlapping high-frequency drive gene alteration and/or one overlapping low-frequency gene alteration are/is found; 3) IPM can be interpreted if more than three common alterations are found. Subsequently, 16 patients were recruited as the validation cohort in the single-blind manner to verify the criteria, and 14 MPLC and 2 IPM were identified, which was 100% consistent with the results from independent imaging and pathological diagnosis.ConclusionsNGS detection can distinguish synchronous MPLC from IPM and is a useful tool to assist differential diagnosis.

Structural alteration of lung parenchyma in patients with NF1: a phenotyping study using multidetector computed tomography (MDCT)

BackgroundDiffuse interstitial lung disease have been described in Neurofibromatosis type 1 (NF1), but its diversity and prevalence remain unknown. The aim of this study was to assess the prevalence and characteristics of (NF1)-associated lung manifestations in a large single-center study using multidetector computed tomography (MDCT) and to evaluate the smoking history, patients’ age, genetics, and the presence of malignant peripheral nerve sheath tumors (MPNST) as potential influencing factors for lung pathologies.MethodsIn this retrospective study, 71 patients with NF1 were evaluated for the presence of distinctive lung manifestations like reticulations, consolidations, type of emphysema, pulmonary nodules and cysts. All patients underwent F-18-FDG PET/CT scans, which were reviewed by two experienced radiologists in consensus. Patients’ subgroups were formed based on their smoking history (current smokers/previous smokers/never smokers), age (< 12 years, 12–18 years, > 18 years), and presence of MPNST (MPNST/no MPNST). In 57 patients (80%), genetic analysis of sequences coding for the neurofibromin on chromosome 17 was performed, which was correlated with different lung pathologies.ResultsAmong all NF1 patients (33 ± 14 years, 56% females), 17 patients (24%) were current smokers and 62 patients (87%) were > 18 years old. Pulmonary cysts, nodules, and paraseptal emphysema were the most common pulmonary findings (35%, 32%, 30%). The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking. Cysts were observed only in adults, whereas no significant correlation between age and all other pulmonary findings was found (p > 0.05). Presence of MPNST was accompanied by higher rates of intrapulmonary nodules and pulmonary metastasis. Neither the presence nor absence of any of the specific gene mutations was associated with any particular lung pathology (p > 0.05).ConclusionsAll pulmonary findings in NF1 patients occurred independently from specific mutation subtypes, suggesting that many NF1 mutations can cause various pulmonary pathologies. The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking, indicating the value of smoking secession or the advice not to start smoking in NF1 patients as preventive strategy for clinicians. For screening of pulmonary manifestations in NF1 patients, an MDCT besides medical history and physical examination is mandatory in clinical routine.

Integrating NGS-derived mutational profiling in the diagnosis of multiple lung adenocarcinomas

MicroAbstractIntegration of Next Generation Sequencing (NGS) information for use in distinguishing between Multiple Primary Lung Cancer and intrapulmonary metastasis was evaluated. We used a probabilistic model, comprehensive histologic assessment and NGS to classify patients. Integrating NGS data confirmed initial diagnosis (n = 41), revised the diagnosis (n = 12), while resulted in non-informative data (n = 8). Accuracy of diagnosis can be significantly improved with integration of NGS data. BackgroundDistinguishing between multiple primary lung cancers (MPLC) and intrapulmonary metastases (IPM) is challenging. The goal of this study was to evaluate how Next Generation Sequencing (NGS) information may be integrated in the diagnostic strategy. Patients and MethodsPatients with multiple lung adenocarcinomas were classified using both the comprehensive histologic assessment and NGS. We computed the joint probability of each pair having independent mutations by chance (thus being classified as MPLC). These probabilities were computed using the marginal mutation rates of each mutation, and the known negative dependencies between driver genes and different gene loci. With these NGS-driven data, cases were re-classified as MPLC or IPM. ResultsWe analyzed 61 patients with a total of 131 tumors. The most frequent mutation was KRAS (57.3%) which occured at a rate higher than expected (p < 0.001) in lung cancer. No mutation was detected in 25/131 tumors (19.1%). Discordant molecular findings between tumor sites were found in 46 patients (75.4%); 11 patients (18.0%) had concordant molecular findings, and 4 patients (6.6%) had concordant molecular findings at 2 of the 3 sites. After integration of the NGS data, the initial diagnosis was confirmed for 41 patients (67.2%), the diagnosis was revised for 12 patients (19.7%) or was considered as non-informative for 8 patients (13.1%). ConclusionIntegrating the information of NGS data may significantly improve accuracy of diagnosis and staging.

OTUD7B suppresses Smac mimetic-induced lung cancer cell invasion and migration via deubiquitinating TRAF3

BackgroundSmac mimetics are a type of drug that can induce apoptosis by antagonizing IAP family members in cancer treatment. However, a recent study showed that Smac mimetics can trigger cell invasion and migration in cancer cells by activating the NF-κB pathway.MethodsWe assessed lung cancer cell elongation, invasion and migration under treatment with the Smac mimetic LCL161. Functional analyses (in vitro and in vivo) were performed to detect the contribution of NIK and OTUD7B to LCL161-induced cell invasion and migration. The role of OTUD7B in regulation of the TRAF3/NIK/NF-κB pathway under LCL161 treatment was analysed by immunoblotting, immunoprecipitation, luciferase and ubiquitin assays, shRNA silencing and plasmid overexpression. Expression levels of OTUD7B, NIK and TRAF3 in tissue samples from lung cancer patients were examined by immunohistochemistry.ResultsWe found that LCL161 stimulates lung cancer cell elongation, invasion and migration at non-toxic concentrations. Mechanistically, LCL161 results in NIK accumulation and activates the non-canonical rather than the canonical NF-κB pathway to enhance the transcription of target genes, such as IL-2 and MMP-9. Importantly, knockdown of NIK dramatically suppresses LCL161-induced cell invasion and migration by reducing the proteolytic processing of p100 to p52 and target gene transcription. Interestingly, we discovered that OTUD7B increases TRAF3 and decreases NIK to inhibit the non-canonical NF-κB pathway and that overexpression of OTUD7B suppresses LCL161-induced cell invasion and migration. Notably, OTUD7B directly binds to TRAF3 rather than to NIK and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing NIK accumulation and NF-κB pathway activation. Furthermore, the OTU domain of OTUD7B is required for the inhibition of LCL161-induced cell invasion and migration, as demonstrated by transfection of the C194S/H358R(CH) mutant OTUD7B. Finally, we investigated whether OTUD7B inhibits LCL161-induced lung cancer cell intrapulmonary metastasis in vivo, and our analysis of clinical samples was consistent with the above findings.ConclusionsOur study highlights the importance of OTUD7B in the suppression of LCL161-induced lung cancer cell invasion and migration, and the results are meaningful for selecting lung cancer patients suitable for LCL161 treatment.

Application of large-scale targeted sequencing to distinguish multiple lung primary tumors from intrapulmonary metastases

The effective differentiation between multiple primary lung tumors (MPs) and intrapulmonary metastases (IMs) in patients is imperative to discover the exact disease stage and to select the most appropriate treatment. In this study, the authors was to evaluate the efficacy and validity of large-scale targeted sequencing (LSTS) as a supplement to estimate whether multifocal lung cancers (MLCs) are primary or metastatic. Targeted sequencing of 520 cancer-related oncogenes was performed on 36 distinct tumors from 16 patients with MPs. Pairing analysis was performed to evaluate the somatic mutation pattern of MLCs in each patient. A total of 25 tumor pairs from 16 patients were sequenced, 88% (n = 22) of which were classified as MPs by LSTS, consistent with clinical diagnosis. One tumor pair from a patient with lymph node metastases had highly consistent somatic mutation profiles, thus predicted as a primary-metastatic pair. In addition, some matched mutations were observed in the remaining two paired ground-glass nodules (GGNs) and classified as high-probability IMs by LSTS. Our study revealed that LSTS can potentially facilitate the distinction of MPs from IMs. In addition, our results provide new genomic evidence of the presence of cancer invasion in GGNs, even pure GGNs.

Study on Clinicopathological Features and Prognostic Factors of Multifocal Lung Cancer

To analyze the clinicopathological characteristics and prognostic factors of multifocal lung cancer (MFLC) patients. From January 2012 to January 2018, 187 MFLC patients whose largest lesion diameter was ≤4 cm and without lymphatic involvement or systemic metastases, were retrospectively reviewed. All the patients received surgical treatment. The Kaplan-Meier method was used for survival analysis, and a multivariable Cox proportional hazards regression model was used to assess the independent prognostic factors. Among 187 cases, 173 were simultaneous MFLC (SMFLC) and 14 were metachronous MFLC (MMFLC). The 5-year disease-free survival (DFS) and overall survival (OS) rates of this group MFLC patients were 63.5% and 89.1%, respectively. In the SMFLC group, according to the American College of Chest Physicians (ACCP) guidelines (3 rd edition), 133 patients were defined as synchronous multiple primary lung cancer (SMPLC) while 40 patients had intrapulmonary metastases, there was no statistical difference in DFS between the two subgroups ( P=0.531). EGFR mutation status (same mutations, different mutations, all wild-type) had no statistically significant effect on DFS of SMFLC ( P=0.388). Univariate and multivariate regression analysis revealed that radiographic feature of solid nodules (hazard ratio ( HR)=7.4, P=0.008) and MMFLC ( HR=5.6, P=0.001) were independent risk factors for poor prognosis. MFLC can achieve a favorable prognosis with early surgical treatment. Tumor density and metachronous lesions are two important prognostic predictors.

Differentiating synchronous double primary lung adenocarcinomas from intrapulmonary metastasis by CT features, EGFR mutations and ALK rearrangement status.

BackgroundDifferentiating synchronous double primary lung adenocarcinoma (SDPLA) from interpulmonary metastasis (IPM) has significant therapeutic and prognostic implications. This retrospective study aimed to investigate the potential of computed tomography (CT) features and two known oncogenic driver mutations [epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK)] to discriminate synchronous double primary lung adenocarcinoma from one primary pulmonary adenocarcinoma with intrapulmonary metastasis.MethodsPatients with SDPLA were selected at our hospital, and those with IPM served as the control group. All 60 patients (40 with SDPLA and 20 with IPM) were tested for EGFR mutations and ALK status, and they underwent chest CT prior to any treatment. Independent-sample Student’s t-test was used for comparisons between two groups of normally distributed variables, and the Chi-square test was used to compare categorical variables.ResultsThe discordance rate of EGFR mutations was significantly higher in patients with SDPLA than in patients with IPM (40% vs. 5%, P<0.001). The incidence of ALK-positive status was 15%, and patients with IPM were more likely to be ALK-positive than patients with SDPLA (35% vs. 5%, P<0.001). Compared to IPM, SDPLA more frequently occurred in different lobes (P=0.024), presented with less lymphadenopathy (P=0.014), showed a smaller difference in diameter (Äd) between tumors (P=0.001) and more commonly presented as lobulated tumors (P<0.001), spiculated masses (P<0.001), ground-glass opacities (GGOs) (P=0.001) and air bronchograms (P=0.020).ConclusionPatients with SDPLA showed higher discordance with EGFR mutations and were less frequently ALK-positive than those with IPM. Thus, the CT characteristics are significantly different between SDPLA and IPM.

Multiple Primary Lung Cancers: A New Challenge in the Era of Precision Medicine.

With the widespread implementation of lung cancer screening, more and more patients are being diagnosed with multiple primary lung cancers (MPLCs). In the era of precision medicine, many controversies remain in differentiating MPLCs from intrapulmonary metastasis and the optimum treatment choice, especially in patients exhibiting similar histology. In this review, we summarize common diagnostic criteria and novel discrimination methods with a special emphasis on the emerging value of broad panel next-generation sequencing (NGS) for the diagnosis of MPLCs. We then discuss current advances regarding therapeutic approaches for MPLCs. Radical surgery is the main treatment modality, while stereotactic body radiotherapy (SBRT) is safe and feasible for early-stage MPLC patients with inoperable tumors. In addition, immunotherapy and targeted therapy, particularly epidermal growth factor receptor-tyrosine kinase inhibitors, are emerging therapeutic strategies that are still in their infancy. Characteristics of both genomic profiles and tumor microenvironment are currently being evaluated but warrant further exploration to facilitate the application of targeted systematic therapies in MPLC patients.

A comprehensive algorithm to distinguish between MPLC and IPM in multiple lung tumors patients.

BackgroundDiagnosis of multiple lung nodules has become convenient and frequent due to the improvement of computed tomography (CT) scans. However, to distinguish intrapulmonary metastasis (IPM) from multiple primary lung cancer (MPLC) remains challenging. Herein, for the accurate optimization of therapeutic options, we propose a comprehensive algorithm for multiple lung carcinomas based on a multidisciplinary approach, and investigate the prognosis of patients who underwent surgical resection.MethodsPatients with multiple lung carcinomas who were treated at West China Hospital of Sichuan University from April, 2009 to December, 2017, were retrospectively identified. A comprehensive algorithm combining histologic assessment, molecular analysis, and imaging information was used to classify nodules as IPM or MPLC. The Kaplan-Meier method was used to estimate survival rates, and the relevant factors were evaluated using the log-rank test or Cox proportional hazards model.ResultsThe study included 576 patients with 1,295 lung tumors in total. Significant differences were observed between the clinical features of 171 patients with IPM and 405 patients with MPLC. The final classification consistency was 0.65 and 0.72 compared with the criteria of Martini and Melamed (MM) and the American College of Chest Physicians (ACCP), respectively. Patients with independent primary tumors had better overall survival (OS) than patients with intra-pulmonary metastasis (HR =3.99, 95% CI: 2.86–5.57; P<0.001). Nodal involvement and radiotherapy were independent prognostic factors.ConclusionsThe comprehensive algorithm was a relevant tool for classifying multifocal lung tumors as MPLC or IPM, and could help doctors with precise decision-making in routine clinical practice. Patients with multiple lesions without lymph node metastasis or without radiotherapy tended to have a better prognosis.