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The debate continues whether the expression of the same rare genetic mutation in multiple primary lung cancers suggests intrapulmonary metastasis or truly multiple primary lung cancers. We report a case of a 54-year-old female patient who presented with multiple nodules in the right lung discovered during a routine examination, persisting for six months. The patient had three central lesions in the right lung's upper, middle, and lower lobes. She underwent thoracoscopic wedge resection, and the postoperative pathology reported two minimally invasive adenocarcinoma and one adenocarcinoma in situ. Interestingly, genetic testing for lung cancer-related driver genes revealed the presence of the rare RET mutation in all three nodules. This led us to speculate that these nodules might have the exact origin rather than being multiple primaries. To verify this hypothesis, we conducted further testing on these nodules, including whole-exome sequencing (The NGS data was generated from the Illumina sequencing platform by Novogene Co. Ltd, Beijing, China). The results indicated that although all three nodules expressed the RET mutation, there was significant heterogeneity in the gene mutations (differences in the number of cellular mutations, substitution composition levels, and clustering analysis of the three nodules). Thus, the patient was considered to have multiple primary lung cancers. In such cases, whole-exome sequencing can distinguish whether the nodules have the exact origin. [ABSTRACT FROM AUTHOR]

Objectives: To provide molecular and immunological attributes mechanistic insights for the management of radiologically distinctive multiple primary lung cancer (MPLC). Methods: The Bulk RNA-seq data of MPLC were obtained from our center. The Bulk RNA-seq data and CT images of patients with single primary lung cancer (SPLC) were obtained from GSE103584. Immune infiltration algorithms were performed to investigate the disparities in the immunological microenvironment between the two groups. Single-cell gene analysis was used to explore immune cells composition and communication relationships between cells in MPLC. Results: In MPLC, 11 pure ground-glass opacity nodules (pGGN) and 10 mixed GGN (mGGN) were identified, while in SPLC, the numbers were 18 pGGN and 22 mGGN, respectively. In MPLC, compared to pGGN, mGGN demonstrated a significantly elevated infiltration of CD8+ T cells. Single-cell gene analysis demonstrated that CD8+ T cells play a central role in the signaling among immune cells in MPLC. The transcription factors including MAFG, RUNX3, and TBX21 may play pivotal roles in regulation of CD8+ T cells. Notably, compared to SPLC nodules for both mGGN and pGGN, MPLC nodules demonstrated a significantly elevated degree of tumor-infiltrating immune cells, with this difference being particularly pronounced in mGGN. There was a positive correlation between the proportion of immune cells and consolidation/tumor ratio (CTR). Conclusions: Our findings provided a comprehensive description about the difference in the immune microenvironment between pGGN and mGGN in early-stage MPLC, as well as between MPLC and SPLC for both mGGN and pGGN. The findings may provide evidence for the design of immunotherapeutic strategies for MPLC. [ABSTRACT FROM AUTHOR]

Multiple primary lung cancer (MPLC), can be categorized as synchronous multiple primary lung cancer (sMPLC) and metachronous multiple primary lung cancer (mMPLC), which are becoming increasingly common in clinical practice. A precise differential diagnosis between MPLC and intrapulmonary metastases (IPM) is essential for determining the appropriate management strategy. MPLC is primarily diagnosed through histology, imaging, and molecular methods. Imaging serves as an essential foundation for preoperative diagnosis, while histology is a critical tool for establishing a definitive diagnosis. As molecular biology advances, the diagnosis of MPLC has stepped into the era of molecular precision. Surgery is the preferred treatment approach, with stereotactic radiotherapy and ablation being viable options for unresectable lesions. Targeted therapy and immunotherapy can be considered for specific patients. A multidisciplinary team approach to evaluation and the application of combination therapy can benefit more patients. Looking ahead, the development of more authoritative guidelines will be instrumental in streamlining the diagnosis and management of MPLC. [ABSTRACT FROM AUTHOR]

Management of multiple primary lung cancer (MPLC) remains challenging, partly due to its increasing incidence, especially with the significant rise in cases of multiple lung nodules caused by low‐dose computed tomography screening. Moreover, the indefinite pathogenesis, diagnostic criteria, and treatment selection add to the complexity. In recent years, there have been continuous efforts to dissect the molecular characteristics of MPLC and explore new diagnostic approaches as well as treatment modalities, which will be reviewed here, with a focus on newly emerging evidence and future perspectives, hope to provide new insights into the management of MPLC and serve as inspiration for future research related to MPLC. [ABSTRACT FROM AUTHOR]

Objective: At present, the incidence of synchronous multiple primary lung cancer (SMPLC) is increasing, and the treatment is still a challenge. This study aims to investigate the appropriate surgical procedure for treating bilateral primary lung cancer simultaneously. Methods: A retrospective analysis was conducted on clinical data from 32 patients who underwent simultaneous bilateral lung cancer surgery in our team. This data included patient characteristics, pulmonary function indicators, surgical procedures, operation duration, chest tube removal time, postoperative hospital stay, and postoperative complications. Results: Out of the 32 patients, 15 were male, and 17 were female, with an average age of 56.4 ± 8.8 years. The average maximum diameter of the main and minor tumors was 1.8 ± 1.0 cm and 1.0 ±.5 cm, respectively. All surgeries were performed thoracoscopically through intercostal approach. The procedure for the minor tumor was performed first, followed by the main tumor operation after turning over. One case was converted to thoracotomy during the main tumor operation because of bleeding. Postoperative complications occurred in one patient. No instances of respiratory insufficiency or failure were observed after the operation, and there were no perioperative deaths or readmissions within 90 days. Conclusion: Simultaneous bilateral thoracoscopic surgery is deemed a secure and feasible option for eligible patients with bilateral primary lung cancer, and it is advisable to commence the operation on the minor tumor first. [ABSTRACT FROM AUTHOR]

The debate continues whether the expression of the same rare genetic mutation in multiple primary lung cancers suggests intrapulmonary metastasis or truly multiple primary lung cancers. We report a case of a 54-year-old female patient who presented with multiple nodules in the right lung discovered during a routine examination, persisting for six months. The patient had three central lesions in the right lung’s upper, middle, and lower lobes. She underwent thoracoscopic wedge resection, and the postoperative pathology reported two minimally invasive adenocarcinoma and one adenocarcinoma in situ. Interestingly, genetic testing for lung cancer-related driver genes revealed the presence of the rare RET mutation in all three nodules. This led us to speculate that these nodules might have the exact origin rather than being multiple primaries. To verify this hypothesis, we conducted further testing on these nodules, including whole-exome sequencing (The NGS data was generated from the Illumina sequencing platform by Novogene Co. Ltd, Beijing, China). The results indicated that although all three nodules expressed the RET mutation, there was significant heterogeneity in the gene mutations (differences in the number of cellular mutations, substitution composition levels, and clustering analysis of the three nodules). Thus, the patient was considered to have multiple primary lung cancers. In such cases, whole-exome sequencing can distinguish whether the nodules have the exact origin.

Abstract Introduction The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. Method We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. Results In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P

The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC. [ABSTRACT FROM AUTHOR]

The co-occurrence of distinct lung cancer types within the same lobe is an exceedingly rare phenomenon. Here, we present a unique case wherein primary invasive squamous cell carcinoma and invasive adenocarcinoma concurrently manifested in the identical lung lobe. Additionally, we provide a comprehensive overview of the diagnosis and treatment approaches for multiple primary lung cancers, along with highlighting existing challenges based on the most recent guidelines. Our case underscores the importance of sampling each lesion individually, conducting separate diagnostic procedures, and determining the histological subtype for effective treatment planning irrespective of their location or size. [ABSTRACT FROM AUTHOR]

Introduction: The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. Method: We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. Results: In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P < 0.05). Sex was an independent prognostic factor for sMPLC (5-year survival, female vs. male, 88.0% vs. 69.5%, P < 0.05), and in multiple tumors, the highest tumor stage was an independent prognostic factor for all categories of MPLC. Conclusions: The different disease patterns of MPLC have significantly different characteristics and prognoses. Clinicians should place treatment emphasis on the tumor with the highest stage as it is the main contributor to the prognosis of all categories of MPLC patients. [ABSTRACT FROM AUTHOR]

Abstract Purpose The purpose of the study was to investigate the effect of spread through air spaces (STAS) on the postoperative prognosis of patients with multiple primary lung cancers staged from IA to IB based on tumor size. Methods Clinicopathological and follow-up data of 122 patients with multiple primary lung cancers diagnosed at stages IA-IB and surgically treated at the Department of Thoracic Surgery, Shenzhen people’s Hospital from January 2019 to December 2021 were retrospectively analyzed. The study involved 42 males and 80 females. STAS status was used to divide them into two groups (87 cases in STAS (-) and 35 cases in STAS (+)). A logistic regression analysis, univariate and multivariate Cox regression analysis, and Kaplan-Meier curves (K-M) were used to determine how STAS affected recurrence-free survival (RFS) in patients. Results STAS (+) had a significantly higher recurrence rate than STAS (-). STAS was predicted by smoking history (P = 0.044), main tumor diameter (P = 0.02), and solid nodules on chest CT (P = 0.02). STAS incidence was not significantly different between lobectomy and sublobar resection groups (P = 0.17). Solid nodules on CT, tumor diameter, vascular invasion, pleural invasion, and STAS were significant predictors of recurrence in the univariate Cox regression analysis. Tumor diameter, pleural invasion and STAS were significant prognostic factors for recurrence in the multivariate Cox regression analysis. Furthermore, STAS (+) group was at greater risk of recurrence than STAS (-) group (34% vs. 0%, P

Introduction: Treatments for multiple ground-glass opacities (GGOs) for which the detection rate is increasing are still controversial. Next-generation sequencing (NGS) may provide additional key evidence for differential diagnosis or optimal therapeutic schedules. Case presentation: We first reported a rare case in which more than 100 bilateral pulmonary GGOs (91.7% of the GGOs were pure GGOs) were diagnosed as both multiple primary lung cancer and intrapulmonary metastasis. We performed NGS with an 808-gene panel to assess both somatic and germline alterations in tissues and plasma. The patient (male) underwent three successive surgeries and received osimertinib adjuvant therapy due to signs of metastasis and multiple EGFR-mutated tumors. The patient had multiple pure GGOs, and eight tumors of four pathological subtypes were evaluated for the clonal relationship. Metastasis, including pure GGOs and atypical adenomatous hyperplasia, was found between two pairs of tumors. Circulating tumor DNA (ctDNA) monitoring of disease status may impact clinical decision-making. Conclusions: Surgery combined with targeted therapies remains a reasonable alternative strategy for treating patients with multifocal GGOs, and NGS is valuable for facilitating diagnostic workup and adjuvant therapy with targeted drugs through tissue and disease monitoring via ctDNA. [ABSTRACT FROM AUTHOR]

Minute pulmonary meningothelial-like nodules (MPMNs) are benign small lesions in the lungs, with similar pathological characteristics to the meningeal epithelium. MPMNs have similar imaging manifestations to malignant tumors, which can lead to misdiagnosis in clinical practice. There is no consensus on the pathogenesis of MPMNs, with some suggest that MPMNs derive from reactive proliferation, while others suggest that MPMNs share a common origin and molecular mechanism with meningiomas in the central nervous system. Understanding the characteristics of MPMNs and studying their pathogenesis will help improve the understanding and diagnosis of MPMNs. In this article, we reviewed the clinical, pathological, imaging characteristics, differential diagnosis and pathogenesis of MPMNs. We also analyze the existing research advances regarding the pathogenesis and propose prospects for further research.

Background: We aimed to identify prognostic factors for mortality and survival in patients operated on for metachronous primary lung cancer (MPLC). Materials and methods: The data of 67 non-small cell lung cancer patients with MPLC, diagnosed and operated upon between January 2000 and December 2015, were retrospectively analyzed. Results: Of the 67 included patients, 63 (94%) were male and 4 (6%) were female. The overall survival rate after second surgery was 53.6% at 5 years and 34.1% at 10 years. The mean survival time was 64 months (95% confidence interval: 35–92 months). Adjuvant treatment improved survival (p ​= ​0.039). Although the survival of grade N0 and N1 patients did not differ, four grade N2 patients exhibited poor survival (p ​= ​0.02). Cox's regression analysis revealed that grade N2 disease decreased survival 5.3- fold, the absence of adjuvant treatment decreased survival 2 fold and pT4 grade decreased survival 3.4 fold. Conclusions: New lung tumors may be detected during follow-up of lung cancer patients who have been definitively treated. In such cases, if extrapulmonary metastases and N2 lymphatic involvement are absent, there is no recurrence in the surgical margins of the first operation, and there is only one new tumor, we suggest that surgical treatment should be initially chosen for patients with adequate cardiopulmonary reserves regardless of the time of appearance of the second tumor, whether or not the histopathological type is the same as that of the first tumor.

Objectives Multiple lung cancers may present as multiple primary lung cancers (MPLC) or intrapulmonary metastasis (IPM) with variations in clinical stage, treatment, and prognosis. However, the existing differentiation criteria based on histology do not fully meet the clinical needs. Next-generation sequencing (NGS) may play an important role in assisting the identification of different pathologies. Here, we extended the relevant data by combining histology and NGS to develop detailed identification criteria for MPLC and IPM. Materials and Methods Patients with lung cancer (each patient had ≥2 tumors) were enrolled in the training (n = 22) and validation (n = 13) cohorts. Genomic profiles obtained from 450-gene-targeted NGS were analyzed, and the new criteria were developed based on our findings and pre-existing Martini & Melamed criteria and molecular benchmarks. Results The analysis of the training cohort indicated that patients identified with MPLC had no (or

IntroductionTreatments for multiple ground-glass opacities (GGOs) for which the detection rate is increasing are still controversial. Next-generation sequencing (NGS) may provide additional key evidence for differential diagnosis or optimal therapeutic schedules.Case presentationWe first reported a rare case in which more than 100 bilateral pulmonary GGOs (91.7% of the GGOs were pure GGOs) were diagnosed as both multiple primary lung cancer and intrapulmonary metastasis. We performed NGS with an 808-gene panel to assess both somatic and germline alterations in tissues and plasma. The patient (male) underwent three successive surgeries and received osimertinib adjuvant therapy due to signs of metastasis and multiple EGFR-mutated tumors. The patient had multiple pure GGOs, and eight tumors of four pathological subtypes were evaluated for the clonal relationship. Metastasis, including pure GGOs and atypical adenomatous hyperplasia, was found between two pairs of tumors. Circulating tumor DNA (ctDNA) monitoring of disease status may impact clinical decision-making.ConclusionsSurgery combined with targeted therapies remains a reasonable alternative strategy for treating patients with multifocal GGOs, and NGS is valuable for facilitating diagnostic workup and adjuvant therapy with targeted drugs through tissue and disease monitoring via ctDNA.

Purpose: Surgical strategy for second primary lung cancer (SPLC) may be more conservative due to influence of first primary lung cancer (FPLC). The optimal surgical method for SPLC warrants discussion. We aimed to explore a more suitable surgical approach for early-stage (T1-T2N0, ≤ 3 cm) SPLC and provide insights for clinical practice. Methods: A retrospective study was conducted using data from the Surveillance, Epidemiology and End Results database between 2004 and 2018, and data of patients with early-stage SPLC who underwent secondary surgery were collected. Propensity score matching (PSM) reduced potential bias between lobar and sublobar resection groups. The effect of lobar and sublobar resection on overall survival (OS) was assessed in all patients and subgroups. Results: A total of 714 patients who met the study entry criteria were enrolled, including 476 patients in the sublobar resection group (66.67%) and 238 patients in the lobar resection group (33.33%). There was no difference in OS between the lobar and sublobar resection groups before and after PSM (P = 0.289) and (P = 0.608), respectively. Subgroup analyses showed that lobar resection achieved a significantly better OS than sublobar resection only in patients with an SPLC tumor size of 2–3 cm (P < 0.05). Conclusion: The OS of sublobar resection was not significantly different from that of lobar resection for early-stage SPLC. For SPLC with a 2–3 cm tumor size, lobar resection is more advantageous than sublobar resection. [ABSTRACT FROM AUTHOR]

AIM: To explore the effect of microRNA-184 (miR-184) on compensatory lung growth (CLG) after lobectomy in multiple primary lung cancer (MPLC) and its mechanism. METHODS: (l) Lung tissue samples (na= 16) from MPLC patients and patients with good recovery after lobectomy (CLG) were collected, and the expression of miR-184 was measured by RT-qPCR. (2) Human alveolar epithelial cells were divided into NC-mimic group, miR-184 mimic group, OE-NC group, tissue inhibitor of metalloproteinase-2 (TIMP-2) overexpression (OE-TIMP-2) group, and miR-184 mimic+OE-TIMP-2 group according to the transfection (n=3). The expression of miR-184, TIMP-2 mRNA and matrix metalloproteinase-14 (MMP-14) mRNA was measured by RT-qPCR, and the protein expression of TIMP-2 and MMP-14 was determined by Western blot. The proliferation of the cells was measured by CCK-8 and colony formation assays. (3) C57BL/6J mice were divided into pneumonectomy (PNX) group and PNX+miR-184 mimic group (n=5). The flexiVent system was used to measure the vital capacity and lung compliance of the mice. Lung volume was measured by water displacement method, and lung tissue changes were observed by HE staining. RESULTS: The expression of miR-184 was significantly higher in the patients with better recovery after lobectomy (P<0.01). Overexpression of miR-184 promoted the proliferation of human alveolar epithelial cells and the recovery of lung function in mice after PNX. In terms of mechanism, miR-184 showed targeted binding with TIMP-2, and overexpression of miR-184 promoted the expression of MMP-14 by inhibiting TIMP-2, thereby promoting the proliferation of human alveolar epithelial cells and the recovery of mouse lung function after PNX. CONCLUSION: miR-184 promotes CLG after PNX through the TIMP-2/MMP-14 axis. [ABSTRACT FROM AUTHOR]

Introduction: With the advancements in early diagnosis, more and more patients with multiple primary lung cancer (MPLC) have been identified. However, the progression of MPLC involves complex changes in cell composition and metabolic function, which remains largely controversial. Objective: Our study aims to comprehensively reveal the cellular characteristics and inter‐cellular connections of MPLC. Methods: We performed scRNA‐seq from 23 samples of six MPLC patients, combined with bulk whole‐exome sequencing. We performed trajectory analysis to investigate the transition of different cell types during the development of MPLC. Results: A total of 1 67 397 cells were sequenced derived from tumour and adjacent tissues of MPLC patients, and tumour, normal, immune and stromal cells were identified. Two states of epithelial cells were identified, which were associated with immune response and cell death, respectively. Furthermore, both CD8+ naïve and memory T cells participated in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells were exhausted T cells and cytotoxic T cells, which positively regulated cell death and were implicated in the regulation of cytokine production, respectively. Two main subpopulations of B cells with distinct functions were identified, which participate in the regulation of the immune response and antigen presentation, respectively. In addition, we found a specific type of endothelial cells that were abundant in tumour samples, with an increasing trend from normal to tumour samples. Conclusions: Our study showed the comprehensive landscape of different cells of MPLC, which might reveal the key cellular mechanisms and, therefore, may provide new insights into the early diagnosis and treatment of MPLC. [ABSTRACT FROM AUTHOR]

Abstract Introduction With the advancements in early diagnosis, more and more patients with multiple primary lung cancer (MPLC) have been identified. However, the progression of MPLC involves complex changes in cell composition and metabolic function, which remains largely controversial. Objective Our study aims to comprehensively reveal the cellular characteristics and inter‐cellular connections of MPLC. Methods We performed scRNA‐seq from 23 samples of six MPLC patients, combined with bulk whole‐exome sequencing. We performed trajectory analysis to investigate the transition of different cell types during the development of MPLC. Results A total of 1 67 397 cells were sequenced derived from tumour and adjacent tissues of MPLC patients, and tumour, normal, immune and stromal cells were identified. Two states of epithelial cells were identified, which were associated with immune response and cell death, respectively. Furthermore, both CD8+ naïve and memory T cells participated in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells were exhausted T cells and cytotoxic T cells, which positively regulated cell death and were implicated in the regulation of cytokine production, respectively. Two main subpopulations of B cells with distinct functions were identified, which participate in the regulation of the immune response and antigen presentation, respectively. In addition, we found a specific type of endothelial cells that were abundant in tumour samples, with an increasing trend from normal to tumour samples. Conclusions Our study showed the comprehensive landscape of different cells of MPLC, which might reveal the key cellular mechanisms and, therefore, may provide new insights into the early diagnosis and treatment of MPLC.

Introduction: Staging of multiple primary lung cancer (MPLC) cases and planning the treatment are of great importance in terms of the prognosis of the disease. Size of lung lesion (T) and lymph node status (N) are of the most reliable indicators of prognosis in patients with lung cancer. In this study, we evaluated whether there was a survival difference in T and N status in the survival analysis of the seventh and eighth edition of staging in MPLC who underwent curative radical surgery. Methods: A total of 55 patients diagnosed with MPLC in our clinic between January 2000 and April 2016 were retrospectively screened. These patients were divided into 2 main groups: 20 synchronous and 35 metachronous lung cancers. Survivals for both groups were calculated according to both the seventh and eighth edition of TNM staging systems (TNM7 and TNM8), taking into account the tumor sizes at first operation, stages, lymph node presence, histopathological type, and tumor localization. Results: In our study, a statistically significant difference was found in terms of survival between tumor sizes and stages in TNM7 staging system, according to the results of the pairwise comparison test applied in synchronous lung cancers (p<0.05). However, no statistically significant difference was found in terms of survival in TNM8 staging system (p>0.05). In metachronous lung cancers, no statistically significant difference was found in terms of tumor size and survival between stages in both TNM7 and TNM8 staging systems according to the results of the pairwise comparison test (p>0.05). A statistically significant difference was found between lymph node groups in terms of survival in TNM8 staging system in synchronous and metachronous lung cancers (p<0.05). Staging according to the TNM8 staging system in synchronous lung cancers changed in 11 of our patients and in 22 patients in metachronous lung cancers. Discussion and Conclusion: TNM7 staging was found to be more sensitive in terms of survival difference according to tumor size and stages in synchronous tumors, while TNM8 staging was found to be more sensitive in terms of survival difference due to lymph node involvement in both synchronous and metachronous tumors. In cases with MPLC, the proposed eighth edition of staging system is superior to the seventh edition as descriptors of tumor sizes are elaborated. [ABSTRACT FROM AUTHOR]

Abstract Background An increasing number of patients are being diagnosed with synchronous multiple primary lung cancer (SMPLC) with the popularization of lung cancer screening programs. However, a strategy for accurate location and suitable surgery therapy is still lacking. The present study aimed to explore the accuracy and feasibility of electromagnetic navigation bronchoscopy (ENB)‐guided thoracoscopic sublobectomy for stage IA SMPLC. Methods Patients with SMPLC who underwent ENB‐guided sublobectomy from January 2020 to June 2022 were enrolled in this study. The analysis of localization accuracy of ENB and surgical outcome was conducted. Results Overall, 138 patients with 353 malignant nodules were enrolled. The tumor size was 0.7 cm (range from 0.5 to 1.1 cm). ENB localization was performed on 162 nodules, and a customized scoring system was developed to evaluate localization accuracy. The success rate of localization was 98.3% (178/181). Notably, localization accuracy was positively correlated with bronchial signs (p

Abstract Background Synchronous multiple primary lung cancers associated with small non-dominant nodules are commonly encountered. However, the incidence, follow-up, and treatment of small non-dominant tumors have been but little studied. We explored the prevalence and management of small non-dominant tumors and factors associated with interval growth. Methods This observational, consecutive, retrospective single-center study enrolled patients diagnosed with synchronous multiple primary lung cancers and small non-dominant tumors (≤ 6 mm in diameter) who underwent resection of the dominant tumor. The incidence, follow-up, and management of small non-dominant tumors and predictors of nodule growth were analyzed. Results There were 88 patients (12% of all lung cancer patients) with pathological diagnoses of synchronous multiple primary lung cancers. A total of 131 (18%) patients were clinically diagnosed with at least one small (≤ 6 mm in diameter) multiple primary lung cancer non-dominant tumor. 94 patients with 125 small-nodule non-dominant tumors clinically diagnosed as multiple primary lung cancers were followed-up for at least 6 months. A total of 29 (29/125, 23.2%) evidenced small pulmonary nodules (≤ 6 mm in diameter) that exhibited interval growth on follow-up computed tomography (CT). On multivariate analysis, a part-solid nodule (compared to a pGGN) (OR 1.23; 95% CI 1.08–1.40) or a solid nodule (compared to a pGGN) (OR 3.50; 95% CI 1.94–6.30) predicted small nodule interval growth. Conclusion We found a relatively high incidence of multiple primary lung cancers with small non-dominant tumors exhibiting interval growth on follow-up CT, suggesting that resection of non-dominant tumors at the time of dominant tumor resection, especially when the nodules are part-solid or solid, is the optimal treatment.

CT screening has markedly reduced the lung cancer mortality in high-risk population and increased the detection of early-stage pulmonary neoplasms, including multiple pulmonary nodules, especially those with a ground-glass appearance on CT. Multiple primary lung cancer (MPLC) constitutes a specific subtype of lung cancer with indolent biological behaviors, which is predominantly early-stage adenocarcinoma. Although MPLC progresses slowly with rare lymphatic metastasis, existence of synchronous lesions and distributed location of these nodules still pose difficulty for the management of such patients. One single operation is usually insufficient to eradicate all neoplastic lesions, whereas repeated surgical procedures bring about another dilemma: whether clinical benefits of surgical treatment outweigh loss of pulmonary function following multiple operations. Therefore, despite the anxiety for treatment among MPLC patients, whether and how to treat the patient should be assessed meticulously. Currently there is a heated discussion upon the timing of clinical intervention, operation mode and the application of local therapy in MPLC. Based on clinical experience of our multiple disciplinary team, we have summarized and commented on the evaluation, surgical treatment, non-surgical local treatment, targeted therapy and immunotherapy of MPLC in this article to provide further insight into this field. [ABSTRACT FROM AUTHOR]

Background: In addition to CT images and pathological features, many other molecular characteristics remain unknown about multiple primary lung cancer (MPLC) from intrapulmonary metastatic lung cancer. Case presentation: In this study, we reported a patient with an early-stage MPLC with both adenocarcinoma in situ (AIS) subtype and minimally invasive adenocarcinoma (MIA) subtype. The patient was diagnosed with more than 10 nodules and underwent precise surgery assisted by three-dimensional (3D) reconstruction at the left upper lung lobe. Whole-exome sequencing (WES) and multiple immunohistochemistry (mIHC) were performed to reveal the genomic profiling and tumor microenvironments of multiple nodules in this patient with MPLC. Based on 3D reconstruction location information, we found that the genomic and pathological results of adjacent lymph nodes were quite different. On the other hand, PD-L1 expression and the proportion of infiltrating lymphocytes in tumor microenvironments were all at a low status and did not vary in adjacent lymph nodes. Additionally, maximum diameter and tumor mutational burden levels were found to be significantly associated with CD8+ T cell proportion (p<0.05). Besides, CD163+ macrophages and CD4+ T cell proportion were higher in MIA nodules than in AIS nodules (p<0.05). This patient reached a recurrence-free survival of 39 months. Conclusion: Generally, in addition to CT imaging and pathological results, genomic profiling and tumor microenvironments may facilitate identifying the potential molecular mechanisms and clinical outcomes in patients with earlystage MPLC. [ABSTRACT FROM AUTHOR]

Objective: To understand the characteristics of genetic mutation in multiple primary lung cancer so as to guide clinical decisions in targeted therapy. Methods: We analyzed a total of 265 tumors from 111 patients who underwent surgery for multiple lung cancers. Individual tumors were subjected to histological evaluation and gene mutation analysis using ABI 7500 Fluorescence quantitative PCR. Results: In this study, we analyzed demographic and clinical parameters such as age, gender, smoking, alcohol consumption, pathological type, number of nodules, and other details of 111 patients with early multiple primary lung cancer. We also compared the clinicopathologic characteristics of different populations based on the gene mutation status of pulmonary nodules. Subsequently, we performed a clinicopathological analysis of all 265 pulmonary nodules from these patients. Results showed significant differences in clinicopathological features of pulmonary nodules in different genetic mutations. Conclusion: This study revealed the gene mutation characteristics and clinicopathological features in early multiple primary lung cancer. We found that the gene mutation status between different nodules in patients with early multiple primary lung cancer was inconsistent in most cases. Therefore, the use of targeted therapy based on the genetic sequencing of only one nodule, is unreliable. We hope this study can be helpful in guiding clinical treatment decisions. [ABSTRACT FROM AUTHOR]

The wide application of lung CT scan and lung cancer screening significnatly improves the detection rate of multiple primary lung cancer (MPLC) , namely, lung cancer patients have two or more primaries at the same time. It is a tough problem all the time that how to distinguish between MPLC and intrapulmonary metastases (IM) . Although histological feature analysis is a good means to distinguish them in some circumstances, molecular analysis is also needed generally. Such as the application of next generation sequencing (NGS) is useful for the distinguish between MPLC and IM. For MPLC, surgery remains the main treatment modality. For inoperable MPLC, radiotherapy and local ablation are important treatments. NGS and new therapies such as targeted drug therapy and immune checkpoint inhibitors have become new altenatives for the diagnosis and treatment of MPLC. This article reviews recent advances in the diagnosis and treatment of MPLC.

BackgroundIn addition to CT images and pathological features, many other molecular characteristics remain unknown about multiple primary lung cancer (MPLC) from intrapulmonary metastatic lung cancer.Case presentationIn this study, we reported a patient with an early-stage MPLC with both adenocarcinoma in situ (AIS) subtype and minimally invasive adenocarcinoma (MIA) subtype. The patient was diagnosed with more than 10 nodules and underwent precise surgery assisted by three-dimensional (3D) reconstruction at the left upper lung lobe. Whole-exome sequencing (WES) and multiple immunohistochemistry (mIHC) were performed to reveal the genomic profiling and tumor microenvironments of multiple nodules in this patient with MPLC. Based on 3D reconstruction location information, we found that the genomic and pathological results of adjacent lymph nodes were quite different. On the other hand, PD-L1 expression and the proportion of infiltrating lymphocytes in tumor microenvironments were all at a low status and did not vary in adjacent lymph nodes. Additionally, maximum diameter and tumor mutational burden levels were found to be significantly associated with CD8+ T cell proportion (p

Background: Multiple primary lung cancer (MPLC) is becoming increasingly common in clinical practice. Imaging examination is sometimes difficult to differentiate from intrapulmonary metastasis (IM) or single primary lung cancer (SPLC) before surgery. There is a lack of effective blood biomarkers as an auxiliary diagnostic method. Participants and Methods A total of 179 patients who were hospitalized and operated in our department from January to June 2019 were collected, and they were divided into SPLC with 136 patients, MPLC with 24 patients, and IM with 19 patients. In total, 96 healthy people without lung cancer were enrolled. Medical history, imaging, and pathology data were assembled from all participants. Plasma metabolomics analysis was performed by quadrupole time-of-flight tandem mass spectrometry, and data were analyzed using SPSS19.0/Simca 14.1/MetaboAnalyst5.0 software. Significant metabolites were selected by variable importance in projection, P value, and fold change. The area under the receiver operating characteristic curve was used to evaluate their diagnostic ability. Results There were significant differences in plasma metabolite profiles between IM and MPLC. Seven metabolites were screened out. Two metabolites had higher levels in IM, and five metabolites had higher levels in MPLC. All had favorable discriminating capacity. Phosphatidyl ethanolamine (38:5) showed the highest sensitivity (0.95) and specificity (0.92). It was followed by L-histidine with sensitivity 0.92 and specificity 0.84. L-tyrosine can be used to identify SPLC and MPLC. The panel composed of related metabolites exhibited higher diagnostic ability. Eight principal metabolites caused remarkable differences between healthy people and MPLC, and five of them had area under the curves greater than 0.85, showing good discriminating power. Conclusion Through the study of plasma metabolomics, it was found that there were obvious differences in the metabolite profiles of MPLC, IM, SPLC, and the healthy population. Some discovered metabolites possessed excellent diagnostic competence with high sensitivity and specificity. They had the potential to act as biomarkers for the screening and differential diagnosis of MPLCs. [ABSTRACT FROM AUTHOR]

Abstract Background Endobronchial microwave ablation via flexible catheter offers the potential for local therapy for inoperable peripheral lung cancer. The study aimed to evaluate the feasibility and safety of navigation bronchoscopy‐guided water‐cooled microwave ablation catheter for nonsurgical peripheral lung cancer. Methods This was a prospective single arm pilot study. Patients with early stage or multiple primary peripheral lung cancer who were nonsurgical candidates for surgery were enrolled in the study. Bronchoscopic microwave ablation was performed via a flexible water‐cooled microwave ablation antenna under the guidance of navigation bronchoscopy. Radial probe endobronchial ultrasound combined with fluoroscopy was used to confirm the position. Treatment outcomes were evaluated based on follow‐up chest CT and positron emission tomography scans. Primary endpoints were technical success and safety. Secondary endpoints were complete ablation rate, 2‐year local control rate, and progression‐free survival. Results Thirteen patients were enrolled in the study from April 2018 to July 2019. A total of 19 sessions of microwave ablation were performed on 14 tumors under the guidance of navigation bronchoscopy. The technical success was 100%. Treatment‐related complications occurred in two patients. The complete ablation rate was 78.6% (11/14). The 2‐year local control rate was 71.4%. Median progression‐free survival was 33 months for all patients. Conclusions In this pilot study, bronchoscopic microwave ablation appears to be feasible with acceptable occurrence of complication in the treatment of peripheral lung cancer under the guidance of navigation bronchoscopy.

With the development of technologies, multiple primary lung cancer (MPLC) has been detected more frequently. Although large-scale genomics studies have made significant progress, the aberrant gene mutation in MPLC is largely unclear. In this study, 141 and 44 lesions from single and multiple primary lung adenocarcinoma (SP- and MP-LUAD) were analyzed. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tumor tissue and sequenced by using the next-generation sequencing-based YuanSu450TM gene panel. We systematically analyzed the clinical features and gene mutations of these lesions, and found that there were six genes differently mutated in MP-LUAD and SP-LUAD lesions, including RBM10, CDK4, ATRX, NTRK1, PREX2, SS18. Data from the cBioPortal database indicated that mutation of these genes was related to some clinical characteristics, such as TMB, tumor type, et al. Besides, heterogeneity analysis suggested that different lesions could be tracked back to monophyletic relationships. We compared the mutation landscape of MP-LUAD and SP-LUAD and identified six differentially mutated genes (RBM10, CDK4, ATRX, NTRK1, PREX2, SS18), and certain SNV loci in TP53 and EGFR which might play key roles in lineage decomposition in multifocal samples. These findings may provide insight into personalized prognosis prediction and new therapies for MP-LUAD patients. [ABSTRACT FROM AUTHOR]

Background: Synchronous multiple primary lung cancers associated with small non-dominant nodules are commonly encountered. However, the incidence, follow-up, and treatment of small non-dominant tumors have been but little studied. We explored the prevalence and management of small non-dominant tumors and factors associated with interval growth.Methods: This observational, consecutive, retrospective single-center study enrolled patients diagnosed with synchronous multiple primary lung cancers and small non-dominant tumors (≤ 6 mm in diameter) who underwent resection of the dominant tumor. The incidence, follow-up, and management of small non-dominant tumors and predictors of nodule growth were analyzed.Results: There were 88 patients (12% of all lung cancer patients) with pathological diagnoses of synchronous multiple primary lung cancers. A total of 131 (18%) patients were clinically diagnosed with at least one small (≤ 6 mm in diameter) multiple primary lung cancer non-dominant tumor. 94 patients with 125 small-nodule non-dominant tumors clinically diagnosed as multiple primary lung cancers were followed-up for at least 6 months. A total of 29 (29/125, 23.2%) evidenced small pulmonary nodules (≤ 6 mm in diameter) that exhibited interval growth on follow-up computed tomography (CT). On multivariate analysis, a part-solid nodule (compared to a pGGN) (OR 1.23; 95% CI 1.08-1.40) or a solid nodule (compared to a pGGN) (OR 3.50; 95% CI 1.94-6.30) predicted small nodule interval growth.Conclusion: We found a relatively high incidence of multiple primary lung cancers with small non-dominant tumors exhibiting interval growth on follow-up CT, suggesting that resection of non-dominant tumors at the time of dominant tumor resection, especially when the nodules are part-solid or solid, is the optimal treatment. [ABSTRACT FROM AUTHOR]

Multiple primary lung tumor is garnering attention from clinicians, with adenocarcinoma emerging as the predominant histological type. Because of the heterogeneity and diffuse distribution of lesions in the same patient, the treatment of multiple primary lung adenocarcinoma (MPLA) is a significant challenge. As a kind of variation unaffected by tumor heterogeneity, germline alterations may play a key role in the development of MPLA. Here, whole-exome sequencing (WES) of peripheral blood was employed to obtain germline alteration data. Intergroup comparative analyses on rare and deleterious alterations of MPLA, solitary lung adenocarcinoma, and healthy individuals in a MPLA family were performed to clarify the candidate alterations. WES and targeted Sanger sequencing were performed in 27 disseminated MPLA patients to detect the mutation site that had been screened. A rare and deleterious germline alteration, EPHB4R91H, was found in all of the patients of an MPLA family and a patient with disseminated MPLA. It was revealed that EPHB4R91H was able to enhance the proliferation, migration, and invasion ability of A549 cells through increased binding affinity to ephrinB2, which in turn activated the EPHB4/ERK/JNK/MAPK pathway. Our findings corroborate that germline alterations are involved in the development of MPLA. And it was found for the first time that the EPHB4R91H mutation promotes the development of MPLA by enhancing its affinity for ephrinB2 and thereby active EPHB4/ERK/JNK/MAPK pathway., (© The Author(s) 2024. Published by Oxford University Press.)

Multiple primary lung cancer (MPLC), can be categorized as synchronous multiple primary lung cancer (sMPLC) and metachronous multiple primary lung cancer (mMPLC), which are becoming increasingly common in clinical practice. A precise differential diagnosis between MPLC and intrapulmonary metastases (IPM) is essential for determining the appropriate management strategy. MPLC is primarily diagnosed through histology, imaging, and molecular methods. Imaging serves as an essential foundation for preoperative diagnosis, while histology is a critical tool for establishing a definitive diagnosis. As molecular biology advances, the diagnosis of MPLC has stepped into the era of molecular precision. Surgery is the preferred treatment approach, with stereotactic radiotherapy and ablation being viable options for unresectable lesions. Targeted therapy and immunotherapy can be considered for specific patients. A multidisciplinary team approach to evaluation and the application of combination therapy can benefit more patients. Looking ahead, the development of more authoritative guidelines will be instrumental in streamlining the diagnosis and management of MPLC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dong, Tian, Xin, Jiang, Guo, Wan and Han.)

Abstract Background To explore the genetic and immunophenotyping heterogeneities between patients with intrapulmonary metastasis (IPM) or multiple primary lung cancer (MPLC). Methods Whole exome sequencing (WES) and transcriptome sequencing (RNA‐seq) were performed on the tissue and blood samples of IPM and MPLC patients to comprehensively analyze the clonal evolution, molecular typing and immunophenotyping. Results There was no significant difference in genetic mutation, tumor mutational burden (TMB) value and mutant allele tumor heterogeneity (MATH) value between IPM and MPLC patients. Notably, the loss of heterozygosity (LOH) of human leukocyte antigen (HLA) appeared in all IPM patients, while there was also no significant difference between the two groups. In addition, expression of immune checkpoint‐related genes including CTLA‐4, BTLA, TIGIT and HAVCR2 in the MPLC group was significantly higher than those in IPM group. At the same time, 86 differentially expressed genes (DEGs) were observed between IPM and MPLC patients with transcriptome sequencing, of which 56 DEGs were upregulated and 30 were downregulated in the IPM group compared with the MPLC group. The cluster analysis revealed that the 86 DEGs could be distinguished in IPM and MPLC samples. Moreover, only the infiltration levels of CD56dim natural killer cells in the IPM group was significantly higher than that in the MPLC group, and the infiltration levels of the remaining 27 immune cell subsets were similar in both groups. Conclusions IPM and MPLC are roughly similar in genetic and immune characteristics indicating that genomics alone may not be able to effectively distinguish between IPM and MPLC, which still needs to be comprehensively evaluated with clinical manifestations, imaging, and pathological characteristics.

Multiple primary lung cancer (MPLC) refers to lung cancer in which two or more primary lesions occurred simultaneously or successively in different parts of the same patient’s lungs. The diagnosis interval is 6 months. MPLC is divided into synchronous MPLC (sMPLC) and metachronous MPLC (mMPLC). sMPLC and intrapulmonary metastasis (IM) are different in treatment strategies and prognosis. However, there are many controversies about the distinction between the two in clinical practice. This article summarizes the current main methods of diagnosing MPLC, and focuses on the latest research progress in distinguishing MPLC from IM. It aims to provide a theoretical basis for accurate diagnosis and treatment of patients with multifocal lung cancer.

Background: The paramount issue regarding multiple lung cancer (MLC) is whether it represents multiple primary lung cancer (MPLC) or intrapulmonary metastasis (IPM), as this directly affects both accurate staging and subsequent clinical management. As a classic method, histology has been widely utilized in clinical practice. However, studies examining the clinical value of histology in MLC have yielded inconsistent results; thus, this remains to be evaluated. Here, we performed a meta-analysis to assess the differential diagnostic value of histology in MPLC and IPM and to provide evidence-based medicine for clinical work. Methods: PubMed, Embase, and Web of Science databases were searched to collect relevant literature according to PRISMA, and inclusion and exclusion criteria were set up to screen and assess the literature. The data required for reconstructing a 2 × 2 contingency table were extracted directly or calculated indirectly from the included studies, and statistical analysis was carried out by using Stata 15, Meta-DiSc 1.4, and Review Manager 5.4 software. Results: A total of 34 studies including 1,075 pairs of tumors were included in this meta-analysis. Among these studies, 11 were about the M-M standard and the pooled sensitivity and specificity were 0.78 (95% CI: 0.71–0.84) and 0.47 (95% CI: 0.38–0.55), respectively; 20 studies were about CHA and the pooled sensitivity and specificity were 0.76 (95% CI: 0.72–0.80) and 0.74 (95% CI: 0.68–0.79), respectively; and 3 studies were about the "CHA & Lepidic" criteria and the pooled sensitivity and specificity were 0.96 (95% CI: 0.85–0.99) and 0.47 (95% CI: 0.21–0.73), respectively. The combined pooled sensitivity, specificity, PLR, NLR, DOR, and the area under the SROC curve of the 34 studies were 0.80 (95% CI: 0.73–0.86), 0.64 (95% CI: 0.51–0.76), 2.25 (95% CI: 1.59–3.17), 0.31 (95% CI: 0.23–0.43), 7.22 (95% CI: 4.06–12.81), and 0.81 (95% CI: 0.77–0.84), respectively. Conclusion: The current evidence indicated that histology had a moderate differential diagnostic value between MPLC and IPM. Among the three subgroups, the "CHA & Lepidic" criteria showed the highest sensitivity and CHA showed the highest specificity. Further research is necessary to validate these findings and to improve clinical credibility. Systematic Review Registration: PROSPERO, identifier CRD42022298180. [ABSTRACT FROM AUTHOR]

Background: Endobronchial microwave ablation via flexible catheter offers the potential for local therapy for inoperable peripheral lung cancer. The study aimed to evaluate the feasibility and safety of navigation bronchoscopy‐guided water‐cooled microwave ablation catheter for nonsurgical peripheral lung cancer. Methods: This was a prospective single arm pilot study. Patients with early stage or multiple primary peripheral lung cancer who were nonsurgical candidates for surgery were enrolled in the study. Bronchoscopic microwave ablation was performed via a flexible water‐cooled microwave ablation antenna under the guidance of navigation bronchoscopy. Radial probe endobronchial ultrasound combined with fluoroscopy was used to confirm the position. Treatment outcomes were evaluated based on follow‐up chest CT and positron emission tomography scans. Primary endpoints were technical success and safety. Secondary endpoints were complete ablation rate, 2‐year local control rate, and progression‐free survival. Results: Thirteen patients were enrolled in the study from April 2018 to July 2019. A total of 19 sessions of microwave ablation were performed on 14 tumors under the guidance of navigation bronchoscopy. The technical success was 100%. Treatment‐related complications occurred in two patients. The complete ablation rate was 78.6% (11/14). The 2‐year local control rate was 71.4%. Median progression‐free survival was 33 months for all patients. Conclusions: In this pilot study, bronchoscopic microwave ablation appears to be feasible with acceptable occurrence of complication in the treatment of peripheral lung cancer under the guidance of navigation bronchoscopy. [ABSTRACT FROM AUTHOR]

Abstract Background In 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 presentation Case 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. Conclusion Our cases provide evidence for utility of NGS in facilitating diagnosis and treatment decisions.

Bo Cheng,* Hongsheng Deng,* Yi Zhao,* Feng Zhu, Hengrui Liang, Caichen Li, Ran Zhong, Jianfu Li, Shan Xiong, Zhuxing Chen, Wenhua Liang, Jianxing He Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenhua Liang; Jianxing HeDepartment of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, 151, Yanjiang Road, Guangzhou, 510120, People’s Republic of ChinaTel +86-20-83337792Fax +86-20-83350363Email liangwh1987@163.com; drjianxing.he@gmail.comAbstract: There are increasing numbers of synchronous multiple primary lung cancer (SMPLC) patients in clinical practice, with most lesions presenting as ground-glass opacity (GGO). For SMPLC patients, surgical resection should be a prior option for all lesions suspected of being malignant, if medically and technically feasible. However, it is frequently a dilemma for the management of residual GGO lesions that were unresected simultaneously with the main tumor in SMPLC patients. We report a case of SMPLC, in which the patient underwent surgical resection of the major lesion with EGFR mutation and then received compelling EGFR-TKI treatment for one enlarging residual GGO lesion after 12 months since operation. Furthermore, a comprehensive literature review about the risk for the progress of GGOs unresected simultaneously with the main lesion and the management of these residual GGOs was also summarized. With the treatment of EGFR-TKI gefitinib for 3 months, the biggest residual GGO lesion (more than 10mm) achieved a complete response (CR), three lesions reduced in size, and the other three lesions remained stable in this case. Surgical resection for major lesion and EGFR-TKI treatment on unresected GGOs might bring favorable outcome for patients with EGFR-mutated multifocal lung cancer. This strategy is safe and effective, which could be a promising therapeutic approach for unresectable GGO lesions in EGFR-mutated SMPLC patients after primary surgery. Notably, folate receptor-positive circulating tumor cell (FR+-CTC) for therapeutic monitoring was more sensitive for GGO-featured lung adenocarcinoma than serum markers.Keywords: multiple primary lung cancer, ground-glass opacity, epidermal growth factor receptor-tyrosine kinases inhibitor, folate receptor-positive circulating tumor cell, literature review

BackgroundThe paramount issue regarding multiple lung cancer (MLC) is whether it represents multiple primary lung cancer (MPLC) or intrapulmonary metastasis (IPM), as this directly affects both accurate staging and subsequent clinical management. As a classic method, histology has been widely utilized in clinical practice. However, studies examining the clinical value of histology in MLC have yielded inconsistent results; thus, this remains to be evaluated. Here, we performed a meta-analysis to assess the differential diagnostic value of histology in MPLC and IPM and to provide evidence-based medicine for clinical work.MethodsPubMed, Embase, and Web of Science databases were searched to collect relevant literature according to PRISMA, and inclusion and exclusion criteria were set up to screen and assess the literature. The data required for reconstructing a 2 × 2 contingency table were extracted directly or calculated indirectly from the included studies, and statistical analysis was carried out by using Stata 15, Meta-DiSc 1.4, and Review Manager 5.4 software.ResultsA total of 34 studies including 1,075 pairs of tumors were included in this meta-analysis. Among these studies, 11 were about the M-M standard and the pooled sensitivity and specificity were 0.78 (95% CI: 0.71–0.84) and 0.47 (95% CI: 0.38–0.55), respectively; 20 studies were about CHA and the pooled sensitivity and specificity were 0.76 (95% CI: 0.72–0.80) and 0.74 (95% CI: 0.68–0.79), respectively; and 3 studies were about the “CHA & Lepidic” criteria and the pooled sensitivity and specificity were 0.96 (95% CI: 0.85–0.99) and 0.47 (95% CI: 0.21–0.73), respectively. The combined pooled sensitivity, specificity, PLR, NLR, DOR, and the area under the SROC curve of the 34 studies were 0.80 (95% CI: 0.73–0.86), 0.64 (95% CI: 0.51–0.76), 2.25 (95% CI: 1.59–3.17), 0.31 (95% CI: 0.23–0.43), 7.22 (95% CI: 4.06–12.81), and 0.81 (95% CI: 0.77–0.84), respectively.ConclusionThe current evidence indicated that histology had a moderate differential diagnostic value between MPLC and IPM. Among the three subgroups, the “CHA & Lepidic” criteria showed the highest sensitivity and CHA showed the highest specificity. Further research is necessary to validate these findings and to improve clinical credibility.Systematic Review RegistrationPROSPERO, identifier CRD42022298180.

The incidence of lung cancer in Xuanwei area of Yunnan Province ranks first in China,which is a typical air pollution related lung cancer. In recent years,Xuanwei lung cancer incidence rate continues to grow rapidly,showing a clear phenomenon of family aggregation. The incidence of lung cancer in the Xuanwei area is earlier than that of adenocarcinoma and multiple primary lung cancer. Hypertension,diabetes and other cancers are common. The gene mutation spectrum and genetic background of family lung cancer patients are unique. Xuanwei family lung cancer is an ideal object to study the environment,genetics and occurrence of lung cancer. This paper reviews the research progress of family lung cancer in Xuanwei area of Yunnan Province. [ABSTRACT FROM AUTHOR]

Multiple primary lung cancer (MPLC) is considered relatively rare. This report presents an unusual case of multiple pulmonary nodules in a 74-year-old man who presented with three independent synchronous tumors in the right upper lobe. The tumors were diagnosed as peripheral squamous cell carcinoma (SCC), adenocarcinoma, and pulmonary mixed squamous cell and glandular papilloma (mixed papilloma). Mixed papilloma is an extremely rare, benign pulmonary tumor with a typical papillary appearance, showing squamous and glandular epithelial differentiation. The histological and immunohistochemical features of each tumor were analyzed. In addition, molecular pathological examination for epidermal growth factor receptor (EGFR) showed no mutation in two primary cancers. Mixed papilloma showed no BRAF V600E mutation or HPV infection. The present case report provides a clinicopathological understanding of an instance in which three tumors of different pathological types are present in the same lung lobe. Furthermore, it provides a literature review regarding multiple lung nodules, focusing on the clinicopathological diagnosis, clinical treatment, and prognostic assessment of these nodules. This is the first case report of mixed papilloma arising in MPLC. [ABSTRACT FROM AUTHOR]

Multiple primary lung cancer (MPLC) is defined as two or more primary lung cancers occurring in the same patient and can be classified as synchronous multiple primary lung cancer (sMPLC) and metachronous multiple primary lung cancer (mMPLC). Due to various clinicopathological characteristics and genetic features, MPLC is increasingly encountered in clinical practice. The distinction between MPLC and intrapulmonary metastasis (IM) is of great importance to clinical treatment and prognosis. However, there are currently no golden diagnostic criteria for MPLC due to tumor heterogeneity. Here, we report the case of a patient with four lung cancers (tumor 1, named T1, in the right middle lobe seven years earlier; tumor 2, named T2, in the left lower lobe; tumor 3 and tumor 4, named T3 and T4, in the left upper lobe) and two tumors (T1 and T2) which shared the mutation in epidermal growth factor receptor (EGFR) L858R/T790M based on targeted multigene sequencing, which indicate that these two tumors might have originated from a common ancestor. However, based on previously published guidelines, these three tumors (T2T4) were diagnosed as mMPLC.

Abstract Background Routine clinical and pathological examinations usually cannot fully conclusively determine the relationship between different lesions of lung cancer. Detailed genetic analysis of tumor samples may supply important additional information and identify second primary lung cancers. Case presentation In the present study, we report a case of synchronous multiple primary lung cancer (MPLC) composed of two distinct pathological subtypes with epidermal growth factor receptor (EGFR) gene mutations L858R of the acinar adenocarcinoma subtype and EML4–ALK rearrangement of the squamous cell carcinoma. Conclusion The present report highlights the clinical importance of molecular cancer biomarkers detection to guide management decisions in MPLC cases.

Background: To explore the genetic and immunophenotyping heterogeneities between patients with intrapulmonary metastasis (IPM) or multiple primary lung cancer (MPLC). Methods: Whole exome sequencing (WES) and transcriptome sequencing (RNA‐seq) were performed on the tissue and blood samples of IPM and MPLC patients to comprehensively analyze the clonal evolution, molecular typing and immunophenotyping. Results: There was no significant difference in genetic mutation, tumor mutational burden (TMB) value and mutant allele tumor heterogeneity (MATH) value between IPM and MPLC patients. Notably, the loss of heterozygosity (LOH) of human leukocyte antigen (HLA) appeared in all IPM patients, while there was also no significant difference between the two groups. In addition, expression of immune checkpoint‐related genes including CTLA‐4, BTLA, TIGIT and HAVCR2 in the MPLC group was significantly higher than those in IPM group. At the same time, 86 differentially expressed genes (DEGs) were observed between IPM and MPLC patients with transcriptome sequencing, of which 56 DEGs were upregulated and 30 were downregulated in the IPM group compared with the MPLC group. The cluster analysis revealed that the 86 DEGs could be distinguished in IPM and MPLC samples. Moreover, only the infiltration levels of CD56dim natural killer cells in the IPM group was significantly higher than that in the MPLC group, and the infiltration levels of the remaining 27 immune cell subsets were similar in both groups. Conclusions: IPM and MPLC are roughly similar in genetic and immune characteristics indicating that genomics alone may not be able to effectively distinguish between IPM and MPLC, which still needs to be comprehensively evaluated with clinical manifestations, imaging, and pathological characteristics. [ABSTRACT FROM AUTHOR]

Introduction: Multiple primary lung cancers (MPLCs) occur in common carcinogenetic risks such as lifestyle, biological aging, immune responses, hormones, and metabolism. Although MPLCs harbor various genetic profiles within the same individuals, differences in the tumor microenvironment (TME) are unclear. We investigated the impact of genetic aberrations, non-intrinsic factors, and pathological subtypes on tumor immunity. Materials and Methods: In total, 73 surgically resected specimens from 32 patients with MPLC were analyzed. PD-L1 expression in tumor cells (TCs) and immune cells (ICs), CD3-positive tumor-infiltrating lymphocytes (TILs), CD8/CD3 ratios, and FOXP3-positive TILs that compose TMEs were evaluated by immunohistochemistry and classified on a score of 0–2. 38 tumors were sequenced for somatic mutations in 409 cancer-associated genes. Results: Females and never or light smokers had a higher incidence of PD-L1-negative tumors and a higher concordance rate. PD-L1 positivity in TCs and ICs was significantly less frequent in EGFR-mutated than in wild-type tumors. Differences in the score of TMEs were observed between the KRAS-mutated-only tumor and the KRAS and TP53-co-mutated tumors, and between the KRAS-mutated-only tumor and the KRAS and STK11-co-mutated tumors. Significantly more FOXP3-high TILs were observed in invasive pathological subtypes than in non-invasive ones. Conclusion: Comparing TMEs among MPLCs revealed that non-smokers or light smokers and females were unlikely to express PD-L1 regardless of tumor site and confirmed that the EGFR mutations and co-occurring KRAS and STK11 or TP53 mutations were associated with TME. Pathological subtypes may impact the efficacy of immune therapy due to their potential correlations with regulatory T cells.

Abstract Background As there is no consensus on the optimal surgery strategy for multiple primary lung cancer (MPLC), we conducted this study to address this issue by comparing the prognosis of MPLC patients underwent different surgical strategies including sublobar resection and the standard resection through a systemic review and meta-analysis. Methods Relevant literature was obtained from three databases including PubMed, Embase and Web of Science. Inclusion and exclusion criteria were set for the screening of articles to be selected for further conduction of systemic review and meta-analysis. The HRs of OS of the sublobar group compared with standard resection group were extracted directly or calculated indirectly from included researches. Results Ten researches published from 2000 to 2017 were included in this study, with 468 and 445 MPLC cases for the standard resection group and sublobar resection group respectively. The result suggested that OS of MPLC patients underwent sublobar resection (segmentectomy or wedge resection for at least one lesion) was comparable with those underwent standard resection approach (lobectomy or pneumonectomy for all lesions), with HR 1.07, 95% CI 0.67–1.71, p = 0.784. Further analysis found no difference in subgroups of synchronous and metachronous (from second metachronous lesion), different population region and dominant sex type. Conclusions This study may reveal that sublobar resection is acceptable for patients with MPLC at an early stage, because of the equivalent prognosis to the standard resection and better pulmonary function preservation. Further research is needed to validate these findings.