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Abstract
ABSTRACT
Targeted therapy is the standard treatment for driver‐mutated lung cancer, but its efficacy in multiple primary lung cancers (MPLCs) remains limited due to significant inter‐lesional molecular heterogeneity. We present a case of synchronous MPLC with 34 bilateral pulmonary nodules. The dominant right upper lobe lesion was an
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Introduction
The widespread implementation of thin-slice computed tomography (CT) screening has led to increased detection of multiple lung cancers (MLCs), presenting significant diagnostic and therapeutic challenges in clinical practice [1]. MLCs encompass multiple primary lung cancers (MPLCs) and intrapulmonary metastases (IPM). Previous studies report that MPLCs constitute 3.72%–5.56% of screen-detected lung malignancies, with superior surgical outcomes compared to IPM [2, 3]. Accurate discrimination between MPLC and IPM is clinically imperative due to their divergent biological behaviors and prognostic implications. Traditional diagnostic criteria have primarily relied on clinical and pathological features, but the latest consensus indicates that diagnostic criteria integrating clinical, imaging, pathological, and molecular evaluations can more accurately distinguish MPLC from IPM [4].
MPLC is categorized as synchronous (sMPLC) and metachronous (mMPLC), with the key distinction being whether additional primary tumors are identified within a 2-year interval from initial diagnosis [3]. Histologically, adenocarcinoma within non-small cell lung cancer (NSCLC) represents the major tissue type in MPLCs, frequently accompanied by epidermal growth factor receptor (EGFR) mutations [5]. Targeted therapy has been successfully and widely applied in the treatment of lung cancers with driver gene mutations, yet significant intertumoral heterogeneity exists among MPLCs, and the presence of driver mutations in one lesion does not necessarily reflect the molecular profile of all lesions, thereby complicating therapeutic decision-making for MPLCs [6].
Here, we report a case of sMPLC in which the EGFR-mutated lesion showed good response to osimertinib while other lesions showed progression. Subsequent chemoimmunotherapy-induced tumor regression enabled definitive surgical resection, and significant genomic discrepancies in post-operative lesions confirmed the diagnosis of MPLC. This case reveals the significant heterogeneity among different lesions in MPLC and highlights the limitations of single-agent targeted therapy in the treatment of MPLC.
Case Presentation
A 75-year-old male heavy smoker with a 50-year history of smoking was found to have 34 bilateral pulmonary nodules on chest CT at baseline (Figure 1 and Table 1). Positron emission tomography/X-ray computed tomography (PET/CT) identified the right upper lobe (RUL) anterior segment nodule (P1, 30.1 × 19.6 mm, SUVmax 4.6), RUL posterior segment nodule (P2, 26.6 × 20.0 mm, SUVmax 11.8), and left upper lobe (LUL) anterior segment nodule (P3, 9.2 × 7.8 mm, SUVmax 3.1), with right hilar lymph node metastasis. Cranial magnetic resonance imaging (MRI) revealed no metastases, clinically staged as cT3N1M0 IIIA. CT-guided biopsy of P1 nodule revealed lung adenocarcinoma with PD-L1 negative. Next-generation sequencing (NGS) detected an EGFR L858R mutation. Neoadjuvant osimertinib targeted therapy was initiated 1 month after baseline, with a treatment course of 12 weeks. Two-month follow-up CT after baseline showed shrinkage of the P1 nodule (30.1 × 19.6 mm to 14.75 × 11.25 mm) but progression of the P2 nodule (26.6 × 20.0 mm to 29 × 18 mm) and P3 nodule (9.2 × 7.8 mm to 23 × 17 mm), along with mediastinal lymphadenopathy and bilateral pleural thickening. Serum carcinoembryonic antigen (CEA) was 27.27 ng/mL. Four-month follow-up CT after baseline showed stable P1 and P3 nodules but further enlargement of the P2 nodule (29 × 18 mm to 31 × 24 mm), with CEA rising to 153.17 ng/mL, indicating a mixed response.
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TABLE 1 Summary of multiple pulmonary nodules at baseline.
| Location | Characterization | Size | |
| Nodule 1 | RUL apical segment | Mass | 30*21 mm |
| Nodule 2 | RUL apical segment | Solid nodule | 25*19 mm |
| Nodule 3 | RUL anterior segment | Solid nodule | 20*18 mm |
| Nodule 4 | LUL apicoposterior segment | Ground glass nodule | 13*11 mm |
| Nodule 5 | RLL posterior segment | Ground glass nodule | 16*11 mm |
| Nodule 6 | RUL anterior segment | Ground glass nodule | 15*13 mm |
| Nodule 7 | LUL apicoposterior segment | Part-solid nodule | 21*12 mm |
| Nodule 8 | RLL posterior segment | Ground glass nodule | 26*20 mm |
| Nodule 9 | LUL superior lingular segment | Ground glass nodule | 20*12 mm |
| Nodule 10 | RUL apical segment | Ground glass nodule | 12*9 mm |
| Nodule 11 | LUL apicoposterior segment | Solid nodule | 2*2 mm |
| Nodule 12 | RUL posterior segment | Solid nodule | 3*2 mm |
| Nodule 13 | LUL apicoposterior segment | Solid nodule | 12*8 mm |
| Nodule 14 | LUL anterior segment | Solid nodule | 2*2 mm |
| Nodule 15 | RUL anterior segment | Ground glass nodule | 5*3 mm |
| Nodule 16 | RLL superior segment | Solid nodule | 12*7 mm |
| Nodule 17 | LUL apicoposterior segment | Solid nodule | 10*8 mm |
| Nodule 18 | LUL superior lingular segment | Ground glass nodule | 7*5 mm |
| Nodule 19 | LLL superior segment | Ground glass nodule | 10*8 mm |
| Nodule 20 | RLL posterior basal segment | Ground glass nodule | 13*8 mm |
| Nodule 21 | RML lateral segment | Ground glass nodule | 9*8 mm |
| Nodule 22 | RLL anterior basal segment | Ground glass nodule | 9*8 mm |
| Nodule 23 | LLL anteromedial basal segment | Solid nodule | 6*6 mm |
| Nodule 24 | RLL lateral basal segment | Ground glass nodule | 13*9 mm |
| Nodule 25 | RLL medial basal segment | Ground glass nodule | 14*12 mm |
| Nodule 26 | RLL anterior basal segment | Ground glass nodule | 4*2 mm |
| Nodule 27 | RML medial segment | Solid nodule | 7*4 mm |
| Nodule 28 | RLL anterior basal segment | Solid nodule | 4*4 mm |
| Nodule 29 | RLL posterior basal segment | Ground glass nodule | 5*4 mm |
| Nodule 30 | RUL apical segment | Ground glass nodule | 5*4 mm |
| Nodule 31 | RUL apical segment | Ground glass nodule | 5*3 mm |
| Nodule 32 | RUL anterior segment | Solid nodule | 7*5 mm |
| Nodule 33 | LUL apicoposterior segment | Ground glass nodule | 5*4 mm |
| Nodule 34 | RLL posterior segment | Solid nodule | 3*3 mm |
After multi-disciplinary treatment (MDT) discussion, the patient received two cycles of neoadjuvant chemoimmunotherapy (nab-paclitaxel + carboplatin + nivolumab). Six-month follow-up CT after baseline demonstrated regression of all measurable lesions and mediastinal lymph nodes. Subsequently, the patient underwent video-assisted thoracoscopic surgery for right upper lobectomy. P2 nodule confirmed adenocarcinoma with PD-L1 negative and NGS revealed no driver mutations. The lesions exhibited distinct molecular profiles, confirming the diagnosis of MPLC.
Postoperative treatment included one cycle of adjuvant chemoimmunotherapy (nab-paclitaxel + carboplatin + nivolumab) followed by nivolumab maintenance. Five months postoperatively, follow-up CT showed regression of the P3 nodule and stable mediastinal nodes. CEA was 26 ng/mL. However, 7-month postoperative evaluation revealed PET/CT evidence of recurrence in the surgical bed (16 × 11 mm, SUVmax 5.8) and suspected metastatic involvement of multiple nodal stations (1L, 1R, 4L, 4R, 10R, 11-14R). Cranial MRI showed no metastases, and restaging as rT1bN3M0 IIIB. CEA had risen to 73 ng/mL. Bronchoscopy with 4R lymph node TBNA confirmed metastatic non-small cell lung carcinoma-not otherwise specified (NSCLC-NOS), with PD-L1 negative and no detectable driver mutations on NGS. After MDT discussion, local radiotherapy was recommended. The patient underwent radiotherapy but subsequently developed widespread metastatic disease. At last follow-up, the patient had a PS score of 3, along with multiple metastases and a large volume of pleural effusion. The patient ultimately died within less than half a year after radiotherapy. Detailed diagnosis information and a treatment flow chart are shown (Figure 2).
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Discussion
We report a case of sMPLC with EGFR mutation, which showed a mixed response to single-agent targeted therapy. After switching to systemic chemo-immunotherapy, all visible lesions shrank, enabling surgical resection. Genomic analysis revealed independent molecular profiles among different lesions, explaining the efficacy limitations of single-agent targeted therapy. The rapid growth and dedifferentiation features of driver gene-negative lesions highlight that these lesions may also exhibit high malignancy and invasiveness, confirming the advantages of chemotherapy-based systemic treatment strategies in addressing the molecular heterogeneity of MPLC.
MPLC frequently occurs with driver gene mutations, with EGFR being the most common mutation type [5]. Studies have reported that EGFR-mutated lesions treated with EGFR TKIs exhibit significantly improved prognosis and overall survival [7]. Notably, a striking 70%–92.9% discordance rate in driver mutations exists among MPLC lesions, indicating that a mutation in one lesion does not represent all lesions [6]. In this case, osimertinib treatment showed a mixed response due to the molecular heterogeneity of different lesions in MPLC, which is consistent with observational data that the objective response rate of ground-glass nodules after EGFR-TKI therapy in MPLC is only 14.9%, highlighting the limited efficacy of lesion-specific single-targeted therapy [8].
The highly aggressive behavior of driver gene-negative lesions, which showed rapid enlargement after single-agent targeted therapy, challenges the conventional notion that most driver gene-negative lesions are indolent [9]. Additionally, the post-surgical recurrent lesions were diagnosed as NSCLC-NOS without driver gene mutations, indicating tumor progression through dedifferentiation—where the original histological features and differentiation phenotype gradually vanish, leading to a significant increase in malignancy [10]. These findings confirm the possibility that driver gene-negative lesions can also exhibit high malignancy and strong invasiveness, highlighting the importance of early biopsy to clarify the unique molecular profiling of each lesion for clinical treatment guidance.
Localized therapy including surgery and/or radiation is the preferred treatment for MPLC, with drug therapy providing more options when such local approaches are infeasible [11]. Disease progression occurred during single-agent targeted therapy, and following MDT, a prompt switch to chemo-immunotherapy combination led to synchronous regression of all measurable lesions and lymph nodes, enabling surgical resection. This outcome highlights the critical role of multidisciplinary decision-making and individualized regimens in MPLC treatment. It also reveals the advantages of systemic combination therapy based on chemotherapy in addressing inter-lesional molecular heterogeneity of MPLC when early multi-site biopsy for clarifying the molecular profiling of each lesion is unavailable.
Conclusion
This case highlights the significant heterogeneity in the treatment of MPLC and emphasizes the importance of early multi-site biopsies to clarify the molecular profiles of different lesions. In MPLC cases with driver gene mutations, the mutation of one lesion does not represent all lesions, so the efficacy of single-agent targeted therapy may be suboptimal. Therefore, we advocate that for MPLCs, regardless of whether the detected lesions have driver mutations, a chemotherapy-based combination treatment strategy including immunotherapy and targeted therapy may bring greater benefits.
Author Contributions
Zi-Rui Ren: conceptualization, methodology, software, investigation, formal analysis, writing – original draft. Lv Wu: conceptualization, methodology, software, investigation, formal analysis, writing – original draft. Chang Lu: data curation, writing – original draft, methodology. Fen Wang: investigation, writing – original draft, methodology. Ying-Long Peng: visualization, investigation. Dong-Xuan Cai: visualization, methodology. Li-Bo Tang: software, writing – review and editing. Jia-Ting Li: visualization, validation. Zhi Guo: visualization, writing – review and editing. Zhi-Hong Chen: resources, supervision. Yu Deng: resources, supervision. Lu Sun: formal analysis, software. Xue-Wu Wei: software, methodology. Qian-Lin Huang: software, validation. Chong-Rui Xu: conceptualization, funding acquisition, resources, supervision, writing – review and editing. Qing Zhou: conceptualization, funding acquisition, resources, supervision, writing – review and editing. All authors reviewed and agreed on the version of the article to be published, the journal to which the manuscript has been submitted, and agreed to be accountable for the contents of the article.
Funding
This work was supported by Guangzhou Science and Technology Program (Grant No. 2025A03J4506), the National Natural Science Foundation of China (Grant No. 82303643), MOE Changjiang Distinguished Professor Supporting Project (Grant No. KY0120240205), Guangdong Provincial Science and Technology Planning Project (Grant No. 2023B110009), and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120).
Ethics Statement
Informed consent was obtained from the family of the patient.
Consent
The family of the patient provided informed consent for the publication of this report.
Conflicts of Interest
The authors declare no conflicts of interest. The abstract of the relevant content had presented as a E-poster at the 26th World Congress on Lung Cancer in 2025, Barcelona, Spain, September 6–9, 2025.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
C. Li, S. Lei, L. Ding, et al., “Global Burden and Trends of Lung Cancer Incidence and Mortality,” Chinese Medical Journal 136, no. 13 (2023): 1583–1590.
N. Horeweg, E. T. Scholten, P. A. de Jong, et al., “Detection of Lung Cancer Through Low‐Dose CT Screening (NELSON): A Prespecified Analysis of Screening Test Performance and Interval Cancers,” Lancet Oncology 15, no. 12 (2014): 1342–1350.
Y. Shintani, J. Okami, H. Ito, et al., “Clinical Features and Outcomes of Patients With Stage I Multiple Primary Lung Cancers,” Cancer Science 112, no. 5 (2021): 1924–1935.
K. Chen, A. Liu, C. Wang, et al., “Multidisciplinary Expert Consensus on Diagnosis and Treatment of Multiple Lung Cancers,” Medicus 6, no. 4 (2025): 100643.
D. Zhu, D. Cao, M. Shen, and J. Lv, “Morphological and Genetic Heterogeneity of Synchronous Multifocal Lung Adenocarcinoma in a Chinese Cohort,” BMC Cancer 21 (2021): 1–10.
H. Cheng, Z. Guo, X. Zhang, et al., “Lack of Evolutionary Convergence in Multiple Primary Lung Cancer Suggests Insufficient Specificity of Personalized Therapy,” Journal of Genetics and Genomics 50, no. 5 (2023): 330–340.
K. Fu, F. Xie, F. Wang, and L. Fu, “Therapeutic Strategies for EGFR‐Mutated Non‐Small Cell Lung Cancer Patients With Osimertinib Resistance,” Journal of Hematology & Oncology 15, no. 1 (2022): 173.
B. Cheng, C. Li, Y. Zhao, et al., “The Impact of Postoperative EGFR‐TKIs Treatment on Residual GGO Lesions After Resection for Lung Cancer,” Signal Transduction and Targeted Therapy 6, no. 1 (2021): 73.
P.‐Y. Shen, C.‐Y. Chuang, C.‐H. Lin, et al., “Importance of Driver Gene Mutation Assessment and Targeted Therapy for Patients With Early‐Stage Non‐Small Cell Lung Cancer and Non‐R0 Resection,” Oncology Letters 29, no. 1 (2024): 35.
M. Fujii, S. Sekine, and T. Sato, “Decoding the Basis of Histological Variation in Human Cancer,” Nature Reviews Cancer 24, no. 2 (2024): 141–158.
J. Comeau, K. Beedupalli, and S. Jois, “Multiple Primary Lung Cancer Tumors With Diversified Genetic Mutations‐Complications in Choosing Therapeutic Options,” Clinical and Translational Discovery 2, no. 3 (2022): e123.
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