The diagnostic frequency of multiple pulmonary tumor nodules has increased significantly in clinical practice. Among patients with multiple pulmonary nodules, distinguishing between separate primary lung carcinomas and intrapulmonary metastases is critical for accurate tumor staging, therapeutic decision-making, and prognostic evaluation. The consensus document "Differentiating separate primary lung adenocarcinomas from intrapulmonary metastases with emphasis on pathological and molecular considerations: Recommendations from the International Association for the Study of Lung Cancer Pathology Committee" highlights the pivotal role of integrated pathological and molecular analyses in diagnosing and differentiating primary lung adenocarcinomas from intrapulmonary metastatic lesions. It further proposes a combined four-step histologic and molecular classification algorithm for addressing multiple pulmonary tumor nodules of adenocarcinoma histology, providing clinicians with enhanced diagnostic tools to refine staging accuracy, guide therapeutic strategies, and improve prognostic predictions for lung adenocarcinoma. Building on current advancements in global research, this article offers a comprehensive interpretation of the consensus recommendations.
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| 1. | Mansuet-Lupo A, Barritault M, Alifano M, et al. Proposal for a combined histomolecular algorithm to distinguish multiple primary adenocarcinomas from intrapulmonary metastasis in patients with multiple lung tumors. J Thorac Oncol, 2019, 14(5): 844-856. |
| 2. | Warth A, Macher-Goeppinger S, Muley T, et al. Clonality of multifocal nonsmall cell lung cancer: Implications for staging and therapy. Eur Respir J, 2012, 39(6): 1437-1442. |
| 3. | Hsu HH, Ko KH, Chou YC, et al. SUVmax and tumor size predict surgical outcome of synchronous multiple primary lung cancers. Medicine (Baltimore), 2016, 95(6): e2351. |
| 4. | Mascalchi M, Comin CE, Bertelli E, et al. Screen-detected multiple primary lung cancers in the ITALUNG trial. J Thorac Dis, 2018, 10(2): 1058-1066. |
| 5. | Chou TY, Dacic S, Wistuba I, et al. Differentiating separate primary lung adenocarcinomas from intrapulmonary metastases with emphasis on pathological and molecular considerations: Recommendations from the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol, 2025, 20(3): 311-330. |
| 6. | Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg, 1975, 70(4): 606-612. |
| 7. | Girard N, Deshpande C, Lau C, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol, 2009, 33(12): 1752-1764. |
| 8. | Chansky K, Detterbeck FC, Nicholson AG, et al. The IASLC Lung Cancer Staging Project: External validation of the revision of the TNM stage groupings in the eighth edition of the TNM classification of lung cancer. J Thorac Oncol, 2017, 12(7): 1109-1121. |
| 9. | Detterbeck FC, Bolejack V, Arenberg DA, et al. The IASLC Lung Cancer Staging Project: Background data and proposals for the classification of lung cancer with separate tumor nodules in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol, 2016, 11(5): 681-692. |
| 10. | Detterbeck FC, Franklin WA, Nicholson AG, et al. The IASLC Lung Cancer Staging Project: Background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol, 2016, 11(5): 651-665. |
| 11. | Detterbeck FC, Marom EM, Arenberg DA, et al. The IASLC Lung Cancer Staging Project: Background data and proposals for the application of TNM staging rules to lung cancer presenting as multiple nodules with ground glass or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol, 2016, 11(5): 666-680. |
| 12. | Suh YJ, Lee HJ, Sung P, et al. A novel algorithm to differentiate between multiple primary lung cancers and intrapulmonary metastasis in multiple lung cancers with multiple pulmonary sites of involvement. J Thorac Oncol, 2020, 15(2): 203-215. |
| 13. | Chang JC, Alex D, Bott M, et al. Comprehensive next-generation sequencing unambiguously distinguishes separate primary lung carcinomas from intrapulmonary metastases: Comparison with standard histopathologic approach. Clin Cancer Res, 2019, 25(23): 7113-7125. |
| 14. | Miyamoto A, Kurosaki A, Fujii T, et al. HRCT features of surgically resected invasive mucinous adenocarcinoma associated with interstitial pneumonia. Respirology, 2017, 22(4): 735-743. |
| 15. | Serın G, Savaş P, İşgör İŞ, et al. Prognostic impact of mitosis and necrosis in non-mucinous lung adenocarcinomas and correlation with IASLC grading system. Histol Histopathol, 2024, 39(6): 703-714. |
| 16. | Yang SR, Chang JC, Leduc C, et al. Invasive mucinous adenocarcinomas with spatially separate lung lesions: Analysis of clonal relationship by comparative molecular profiling. J Thorac Oncol, 2021, 16(7): 1188-1199. |
| 17. | Kim M, Hwang J, Kim KA, et al. Genomic characteristics of invasive mucinous adenocarcinoma of the lung with multiple pulmonary sites of involvement. Mod Pathol, 2022, 35(2): 202-209. |
| 18. | Shim HS, Kenudson M, Zheng Z, et al. Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung. J Thorac Oncol, 2015, 10(8): 1156-1162. |
| 19. | Chang JC, Offin M, Falcon C, et al. Comprehensive molecular and clinicopathologic analysis of 200 pulmonary invasive mucinous adenocarcinomas identifies distinct characteristics of molecular subtypes. Clin Cancer Res, 2021, 27(14): 4066-4076. |
| 20. | Lee HY, Cha MJ, Lee KS, et al. Prognosis in resected invasive mucinous adenocarcinomas of the lung: Related factors and comparison with resected nonmucinous adenocarcinomas. J Thorac Oncol, 2016, 11(7): 1064-1073. |
| 21. | Matsui T, Sakakura N, Koyama S, et al. Comparison of surgical outcomes between invasive mucinous and non-mucinous lung adenocarcinoma. Ann Thorac Surg, 2021, 112(4): 1118-1126. |
| 22. | Detterbeck FC, Boffa DJ, Kim AW, et al. The eighth edition lung cancer stage classification. Chest, 2017, 151(1): 193-203. |
| 23. | Shao J, Wang C, Li J, et al. A comprehensive algorithm to distinguish between MPLC and IPM in multiple lung tumors patients. Ann Transl Med, 2020, 8(18): 1137. |
| 24. | Kakinuma R, Noguchi M, Ashizawa K, et al. Natural history of pulmonary subsolid nodules: A prospective multicenter study. J Thorac Oncol, 2016, 11(7): 1012-1028. |
| 25. | Rami-Porta R, Nishimura KK, Giroux DJ, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for revision of the TNM stage groups in the forthcoming (ninth) edition of the TNM classification for lung cancer. J Thorac Oncol, 2024, 19(7): 1007-1027. |
| 26. | Lee HW, Jin KN, Lee JK, et al. Long-term follow-up of ground-glass nodules after 5 years of stability. J Thorac Oncol, 2019, 14(8): 1370-1377. |
| 27. | Aokage K, Ishii G, Yoshida J, et al. Histological progression of small intrapulmonary metastatic tumor from primary lung adenocarcinoma. Pathol Int, 2010, 60(12): 765-773. |
| 28. | Nicholson AG, Torkko K, Viola P, et al. Interobserver variation among pathologists and refinement of criteria in distinguishing separate primary tumors from intrapulmonary metastases in lung. J Thorac Oncol, 2018, 13(2): 205-217. |
| 29. | Dacic S, Ionescu DN, Finkelstein S, et al. Patterns of allelic loss of synchronous adenocarcinomas of the lung. Am J Surg Pathol, 2005, 29(7): 897-902. |
| 30. | Shen C, Xu H, Liu L, et al. "Unique trend" and "contradictory trend" in discrimination of primary synchronous lung cancer and metastatic lung cancer. BMC Cancer, 2013, 13: 467. |
| 31. | Shimizu S, Yatabe Y, Koshikawa T, et al. High frequency of clonally related tumors in cases of multiple synchronous lung cancers as revealed by molecular diagnosis. Clin Cancer Res, 2000, 6(10): 3994-3999. |
| 32. | Sorscher S, Lopiccolo J, Heald B, et al. Rate of pathogenic germline variants in patients with lung cancer. JCO Precis Oncol, 2023, 7: e2300190. |
| 33. | Costa JL, Meijer G, Ylstra B, et al. Array comparative genomic hybridization copy number profiling: A new tool for translational research in solid malignancies. Semin Radiat Oncol, 2008, 18(2). |
| 34. | Murphy SJ, Harris FR, Kosari F, et al. Using genomics to differentiate multiple primaries from metastatic lung cancer. J Thorac Oncol, 2019, 14(9): 1567-1582. |
| 35. | Murphy SJ, Aubry MC, Harris FR, et al. Identification of independent primary tumors and intrapulmonary metastases using DNA rearrangements in non-small-cell lung cancer. J Clin Oncol, 2014, 32(36): 4050-4058. |
| 36. | Sherwood J, Dearden S, Ratcliffe M, et al. Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: A literature review. J Exp Clin Cancer Res, 2015, 34(1): 92. |
| 37. | Yatabe Y, Matsuo K, Mitsudomi T. Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma. J Clin Oncol, 2011, 29(22): 2972-2977. |
| 38. | Chen H, Huang D, Lin G, et al. The prevalence and real-world therapeutic analysis of Chinese patients with KRAS-Mutant Non-Small Cell lung cancer. Cancer Med, 2022, 11(19): 3581-3592. |
| 39. | Melosky B, Kambartel K, Häntschel M, et al. Worldwide prevalence of epidermal growth factor receptor mutations in non-small cell lung cancer: A meta-analysis. Mol Diagn Ther, 2022, 26(1): 7-18. |
| 40. | Ning B, Su Z, Mei N, et al. Toxicogenomics and cancer susceptibility: Advances with next-generation sequencing. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev, 2014, 32(2): 121-158. |
| 41. | Curtius K, Wright NA, Graham TA. An evolutionary perspective on field cancerization. Nat Rev Cancer, 2018, 18(1): 19-32. |
| 42. | Asmar R, Sonett JR, Singh G, et al. Use of oncogenic driver mutations in staging of multiple primary lung carcinomas: A single-center experience. J Thorac Oncol, 2017, 12(10): 1524-1535. |
| 43. | Yang CY, Yeh YC, Wang LC, et al. Genomic profiling with large-scale next-generation sequencing panels distinguishes separate primary lung adenocarcinomas from intrapulmonary metastases. Mod Pathol, 2023, 36(3): 100047. |
| 44. | Jasper K, Stiles B, Mcdonald F, et al. Practical management of oligometastatic non-small-cell lung cancer. J Clin Oncol, 2022, 40(6): 635-641. |
| 45. | Wu TC, Luterstein E, Neilsen BK, et al. Accelerated hypofractionated chemoradiation followed by stereotactic ablative radiotherapy boost for locally advanced, unresectable non-small cell lung cancer: A nonrandomized controlled trial. JAMA Oncol, 2024, 10(3): 352-359. |
| 46. | Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med, 2020, 383(18): 1711-1723. |
| 47. | Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage ⅠB-ⅢA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet, 2021, 398(10308): 1344-1357. |
| 48. | Hu C, Zhao L, Liu W, et al. Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers. J Immunother Cancer, 2021, 9(12): e003773. |
| 49. | Goodwin D, Rathi V, Conron M, et al. Genomic and clinical significance of multiple primary lung cancers as determined by next-generation sequencing. J Thorac Oncol, 2021, 16(7): 1166-1175. |
| 50. | Cortiula F, Reymen B, Peters S, et al. Immunotherapy in unresectable stageⅢ non-small-cell lung cancer: State of the art and novel therapeutic approaches. Ann Oncol, 2022, 33(9): 893-908. |
| 51. | Stinchcombe TE, Wang X, Damman B, et al. Secondary analysis of the rate of second primary lung cancer from Cancer and Leukemia Group B 140503 (Alliance) trial of lobar versus sublobar resection for T1aN0 non-small-cell lung cancer. J Clin Oncol, 2024, 42(10): 1110-1113. |
| 52. | Burr R, Leshchiner I, Costantino CL, et al. Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors. Nat Cancer, 2024, 5(11): 1681-1696. |
| 53. | Li M, Hao B, Zhang M, et al. Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development. Signal Transduct Target Ther, 2021, 6(1): 330. |
| 54. | Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med, 2023, 389(6): 491-503. |
| 55. | Sutera PA, Shetty AC, Hakansson A, et al. Transcriptomic and clinical heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer. Ann Oncol, 2023, 34(7): 605-614. |
| 56. | Finley DJ, Yoshizawa A, Travis W, et al. Predictors of outcomes after surgical treatment of synchronous primary lung cancers. J Thorac Oncol, 2010, 5(2): 197-205. |
| 57. | Zhang Z, Gao S, Mao Y, et al. Surgical outcomes of synchronous multiple primary non-small cell lung cancers. Sci Rep, 2016, 6: 23252. |
| 58. | Tanvetyanon T, Finley DJ, Fabian T, et al. Prognostic factors for survival after complete resections of synchronous lung cancers in multiple lobes: Pooled analysis based on individual patient data. Ann Oncol, 2013, 24(4): 889-894. |
| 59. | Jiang L, He J, Shi X, et al. Prognosis of synchronous and metachronous multiple primary lung cancers: Systematic review and meta-analysis. Lung Cancer, 2015, 87(3): 303-310. |
- 1. Mansuet-Lupo A, Barritault M, Alifano M, et al. Proposal for a combined histomolecular algorithm to distinguish multiple primary adenocarcinomas from intrapulmonary metastasis in patients with multiple lung tumors. J Thorac Oncol, 2019, 14(5): 844-856.
- 2. Warth A, Macher-Goeppinger S, Muley T, et al. Clonality of multifocal nonsmall cell lung cancer: Implications for staging and therapy. Eur Respir J, 2012, 39(6): 1437-1442.
- 3. Hsu HH, Ko KH, Chou YC, et al. SUVmax and tumor size predict surgical outcome of synchronous multiple primary lung cancers. Medicine (Baltimore), 2016, 95(6): e2351.
- 4. Mascalchi M, Comin CE, Bertelli E, et al. Screen-detected multiple primary lung cancers in the ITALUNG trial. J Thorac Dis, 2018, 10(2): 1058-1066.
- 5. Chou TY, Dacic S, Wistuba I, et al. Differentiating separate primary lung adenocarcinomas from intrapulmonary metastases with emphasis on pathological and molecular considerations: Recommendations from the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol, 2025, 20(3): 311-330.
- 6. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg, 1975, 70(4): 606-612.
- 7. Girard N, Deshpande C, Lau C, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol, 2009, 33(12): 1752-1764.
- 8. Chansky K, Detterbeck FC, Nicholson AG, et al. The IASLC Lung Cancer Staging Project: External validation of the revision of the TNM stage groupings in the eighth edition of the TNM classification of lung cancer. J Thorac Oncol, 2017, 12(7): 1109-1121.
- 9. Detterbeck FC, Bolejack V, Arenberg DA, et al. The IASLC Lung Cancer Staging Project: Background data and proposals for the classification of lung cancer with separate tumor nodules in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol, 2016, 11(5): 681-692.
- 10. Detterbeck FC, Franklin WA, Nicholson AG, et al. The IASLC Lung Cancer Staging Project: Background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol, 2016, 11(5): 651-665.
- 11. Detterbeck FC, Marom EM, Arenberg DA, et al. The IASLC Lung Cancer Staging Project: Background data and proposals for the application of TNM staging rules to lung cancer presenting as multiple nodules with ground glass or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol, 2016, 11(5): 666-680.
- 12. Suh YJ, Lee HJ, Sung P, et al. A novel algorithm to differentiate between multiple primary lung cancers and intrapulmonary metastasis in multiple lung cancers with multiple pulmonary sites of involvement. J Thorac Oncol, 2020, 15(2): 203-215.
- 13. Chang JC, Alex D, Bott M, et al. Comprehensive next-generation sequencing unambiguously distinguishes separate primary lung carcinomas from intrapulmonary metastases: Comparison with standard histopathologic approach. Clin Cancer Res, 2019, 25(23): 7113-7125.
- 14. Miyamoto A, Kurosaki A, Fujii T, et al. HRCT features of surgically resected invasive mucinous adenocarcinoma associated with interstitial pneumonia. Respirology, 2017, 22(4): 735-743.
- 15. Serın G, Savaş P, İşgör İŞ, et al. Prognostic impact of mitosis and necrosis in non-mucinous lung adenocarcinomas and correlation with IASLC grading system. Histol Histopathol, 2024, 39(6): 703-714.
- 16. Yang SR, Chang JC, Leduc C, et al. Invasive mucinous adenocarcinomas with spatially separate lung lesions: Analysis of clonal relationship by comparative molecular profiling. J Thorac Oncol, 2021, 16(7): 1188-1199.
- 17. Kim M, Hwang J, Kim KA, et al. Genomic characteristics of invasive mucinous adenocarcinoma of the lung with multiple pulmonary sites of involvement. Mod Pathol, 2022, 35(2): 202-209.
- 18. Shim HS, Kenudson M, Zheng Z, et al. Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung. J Thorac Oncol, 2015, 10(8): 1156-1162.
- 19. Chang JC, Offin M, Falcon C, et al. Comprehensive molecular and clinicopathologic analysis of 200 pulmonary invasive mucinous adenocarcinomas identifies distinct characteristics of molecular subtypes. Clin Cancer Res, 2021, 27(14): 4066-4076.
- 20. Lee HY, Cha MJ, Lee KS, et al. Prognosis in resected invasive mucinous adenocarcinomas of the lung: Related factors and comparison with resected nonmucinous adenocarcinomas. J Thorac Oncol, 2016, 11(7): 1064-1073.
- 21. Matsui T, Sakakura N, Koyama S, et al. Comparison of surgical outcomes between invasive mucinous and non-mucinous lung adenocarcinoma. Ann Thorac Surg, 2021, 112(4): 1118-1126.
- 22. Detterbeck FC, Boffa DJ, Kim AW, et al. The eighth edition lung cancer stage classification. Chest, 2017, 151(1): 193-203.
- 23. Shao J, Wang C, Li J, et al. A comprehensive algorithm to distinguish between MPLC and IPM in multiple lung tumors patients. Ann Transl Med, 2020, 8(18): 1137.
- 24. Kakinuma R, Noguchi M, Ashizawa K, et al. Natural history of pulmonary subsolid nodules: A prospective multicenter study. J Thorac Oncol, 2016, 11(7): 1012-1028.
- 25. Rami-Porta R, Nishimura KK, Giroux DJ, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for revision of the TNM stage groups in the forthcoming (ninth) edition of the TNM classification for lung cancer. J Thorac Oncol, 2024, 19(7): 1007-1027.
- 26. Lee HW, Jin KN, Lee JK, et al. Long-term follow-up of ground-glass nodules after 5 years of stability. J Thorac Oncol, 2019, 14(8): 1370-1377.
- 27. Aokage K, Ishii G, Yoshida J, et al. Histological progression of small intrapulmonary metastatic tumor from primary lung adenocarcinoma. Pathol Int, 2010, 60(12): 765-773.
- 28. Nicholson AG, Torkko K, Viola P, et al. Interobserver variation among pathologists and refinement of criteria in distinguishing separate primary tumors from intrapulmonary metastases in lung. J Thorac Oncol, 2018, 13(2): 205-217.
- 29. Dacic S, Ionescu DN, Finkelstein S, et al. Patterns of allelic loss of synchronous adenocarcinomas of the lung. Am J Surg Pathol, 2005, 29(7): 897-902.
- 30. Shen C, Xu H, Liu L, et al. "Unique trend" and "contradictory trend" in discrimination of primary synchronous lung cancer and metastatic lung cancer. BMC Cancer, 2013, 13: 467.
- 31. Shimizu S, Yatabe Y, Koshikawa T, et al. High frequency of clonally related tumors in cases of multiple synchronous lung cancers as revealed by molecular diagnosis. Clin Cancer Res, 2000, 6(10): 3994-3999.
- 32. Sorscher S, Lopiccolo J, Heald B, et al. Rate of pathogenic germline variants in patients with lung cancer. JCO Precis Oncol, 2023, 7: e2300190.
- 33. Costa JL, Meijer G, Ylstra B, et al. Array comparative genomic hybridization copy number profiling: A new tool for translational research in solid malignancies. Semin Radiat Oncol, 2008, 18(2).
- 34. Murphy SJ, Harris FR, Kosari F, et al. Using genomics to differentiate multiple primaries from metastatic lung cancer. J Thorac Oncol, 2019, 14(9): 1567-1582.
- 35. Murphy SJ, Aubry MC, Harris FR, et al. Identification of independent primary tumors and intrapulmonary metastases using DNA rearrangements in non-small-cell lung cancer. J Clin Oncol, 2014, 32(36): 4050-4058.
- 36. Sherwood J, Dearden S, Ratcliffe M, et al. Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: A literature review. J Exp Clin Cancer Res, 2015, 34(1): 92.
- 37. Yatabe Y, Matsuo K, Mitsudomi T. Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma. J Clin Oncol, 2011, 29(22): 2972-2977.
- 38. Chen H, Huang D, Lin G, et al. The prevalence and real-world therapeutic analysis of Chinese patients with KRAS-Mutant Non-Small Cell lung cancer. Cancer Med, 2022, 11(19): 3581-3592.
- 39. Melosky B, Kambartel K, Häntschel M, et al. Worldwide prevalence of epidermal growth factor receptor mutations in non-small cell lung cancer: A meta-analysis. Mol Diagn Ther, 2022, 26(1): 7-18.
- 40. Ning B, Su Z, Mei N, et al. Toxicogenomics and cancer susceptibility: Advances with next-generation sequencing. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev, 2014, 32(2): 121-158.
- 41. Curtius K, Wright NA, Graham TA. An evolutionary perspective on field cancerization. Nat Rev Cancer, 2018, 18(1): 19-32.
- 42. Asmar R, Sonett JR, Singh G, et al. Use of oncogenic driver mutations in staging of multiple primary lung carcinomas: A single-center experience. J Thorac Oncol, 2017, 12(10): 1524-1535.
- 43. Yang CY, Yeh YC, Wang LC, et al. Genomic profiling with large-scale next-generation sequencing panels distinguishes separate primary lung adenocarcinomas from intrapulmonary metastases. Mod Pathol, 2023, 36(3): 100047.
- 44. Jasper K, Stiles B, Mcdonald F, et al. Practical management of oligometastatic non-small-cell lung cancer. J Clin Oncol, 2022, 40(6): 635-641.
- 45. Wu TC, Luterstein E, Neilsen BK, et al. Accelerated hypofractionated chemoradiation followed by stereotactic ablative radiotherapy boost for locally advanced, unresectable non-small cell lung cancer: A nonrandomized controlled trial. JAMA Oncol, 2024, 10(3): 352-359.
- 46. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med, 2020, 383(18): 1711-1723.
- 47. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage ⅠB-ⅢA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet, 2021, 398(10308): 1344-1357.
- 48. Hu C, Zhao L, Liu W, et al. Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers. J Immunother Cancer, 2021, 9(12): e003773.
- 49. Goodwin D, Rathi V, Conron M, et al. Genomic and clinical significance of multiple primary lung cancers as determined by next-generation sequencing. J Thorac Oncol, 2021, 16(7): 1166-1175.
- 50. Cortiula F, Reymen B, Peters S, et al. Immunotherapy in unresectable stageⅢ non-small-cell lung cancer: State of the art and novel therapeutic approaches. Ann Oncol, 2022, 33(9): 893-908.
- 51. Stinchcombe TE, Wang X, Damman B, et al. Secondary analysis of the rate of second primary lung cancer from Cancer and Leukemia Group B 140503 (Alliance) trial of lobar versus sublobar resection for T1aN0 non-small-cell lung cancer. J Clin Oncol, 2024, 42(10): 1110-1113.
- 52. Burr R, Leshchiner I, Costantino CL, et al. Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors. Nat Cancer, 2024, 5(11): 1681-1696.
- 53. Li M, Hao B, Zhang M, et al. Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development. Signal Transduct Target Ther, 2021, 6(1): 330.
- 54. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med, 2023, 389(6): 491-503.
- 55. Sutera PA, Shetty AC, Hakansson A, et al. Transcriptomic and clinical heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer. Ann Oncol, 2023, 34(7): 605-614.
- 56. Finley DJ, Yoshizawa A, Travis W, et al. Predictors of outcomes after surgical treatment of synchronous primary lung cancers. J Thorac Oncol, 2010, 5(2): 197-205.
- 57. Zhang Z, Gao S, Mao Y, et al. Surgical outcomes of synchronous multiple primary non-small cell lung cancers. Sci Rep, 2016, 6: 23252.
- 58. Tanvetyanon T, Finley DJ, Fabian T, et al. Prognostic factors for survival after complete resections of synchronous lung cancers in multiple lobes: Pooled analysis based on individual patient data. Ann Oncol, 2013, 24(4): 889-894.
- 59. Jiang L, He J, Shi X, et al. Prognosis of synchronous and metachronous multiple primary lung cancers: Systematic review and meta-analysis. Lung Cancer, 2015, 87(3): 303-310.