Diagnosis and selection of surgical approaches for synchronous multiple primary lung cancer: a narrative review

Abstract

Background and Objective

Synchronous multiple primary lung cancer (SMPLC) is a distinct clinical entity in lung cancer management. Because SMPLC differs substantially from intrapulmonary metastasis (IPM) in staging, treatment strategy, and prognosis, accurate assessment of the clonal relationship among multiple malignant pulmonary lesions is essential for treatment planning. This narrative review summarizes the diagnostic basis, preoperative assessment, and selection of surgical approaches for SMPLC and discusses bilateral surgery, residual ground-glass nodules, and future research directions.

Methods

PubMed was searched for English- or Chinese-language publications from 1 January 2000 to 18 August 2026 using terms related to SMPLC, IPM, molecular clonality, lobectomy, segmentectomy, wedge resection, bilateral surgery, subsolid nodules, and local therapy. An updated search was performed during revision to capture recent literature on molecular clonality, bilateral video-assisted thoracoscopic surgery (VATS), and residual ground-glass nodules. Relevant guidelines, reviews, cohort studies, systematic reviews, case series, and representative case reports were selected according to their relevance to the clinical scope of this review. No formal risk-of-bias assessment or quantitative synthesis was performed.

Key Content and Findings

Traditional diagnosis is based mainly on lesion distribution and histologic features, but morphology alone has limitations when lesions share similar histologic types. Comprehensive histologic assessment, thin-section computed tomography, and selective molecular testing provide complementary evidence for differentiating SMPLC from IPM. Surgery remains the principal treatment for resectable SMPLC. The choice among lobectomy, anatomical segmentectomy, wedge resection, and combined resection should consider the invasiveness of the dominant and secondary lesions, the number and distribution of lesions, laterality, nodal status, predicted postoperative pulmonary function, comorbidity, and cumulative loss of lung parenchyma. In carefully selected patients with early-stage disease, parenchyma-sparing strategies may provide acceptable oncologic outcomes; however, current evidence is derived mainly from retrospective studies and is limited by selection bias and heterogeneous diagnostic criteria.

Conclusions

Accurate multidisciplinary diagnosis and individualized surgical planning are central to SMPLC management. Prospective multicenter studies using standardized diagnostic criteria are needed to clarify the optimal extent of resection, timing of bilateral surgery, and management of residual low-risk ground-glass nodules.

Introduction

Synchronous multiple primary lung cancer (SMPLC) refers to the presence of two or more independent primary lung cancers diagnosed simultaneously or within a short interval, commonly defined as 6 months or less. With the widespread use of high-resolution computed tomography (HRCT) and positron emission tomography-computed tomography (PET-CT) in lung cancer screening and clinical evaluation, together with improved recognition of multiple primary lung cancers, the detection rate of SMPLC has increased steadily. However, SMPLC and intrapulmonary metastasis (IPM) differ substantially in biological behavior, treatment strategy, and prognosis. Correctly distinguishing between these entities is therefore critical for treatment selection and patient survival (1,2). Accurate diagnosis of SMPLC and the development of an appropriate individualized treatment plan have consequently become important topics in thoracic surgery.

No universally accepted treatment strategy has been established for SMPLC. Although conventional lobectomy may provide more complete oncologic clearance, extensive resection in patients with multiple lesions, particularly bilateral lesions, can substantially reduce postoperative functional reserve, making preservation of lung parenchyma an important planning consideration (3). With the increasing adoption of minimally invasive surgery, especially video-assisted thoracoscopic surgery (VATS), sublobar resection, including segmentectomy and wedge resection, has been increasingly used in SMPLC. Available studies have reported no statistically significant difference in overall survival between sublobar resection and standard lobectomy in selected patients with early-stage SMPLC (4,5). For bilateral disease, simultaneous bilateral VATS has been reported to be feasible in appropriately selected patients; earlier series also noted that more extensive bilateral combinations may increase postoperative pulmonary morbidity (6,7).

Advances in molecular pathology and minimally invasive surgery have created new opportunities for precise diagnosis and individualized surgical planning in SMPLC. The traditional Martini-Melamed criteria rely mainly on histologic type and lesion location, but distinguishing SMPLC from IPM remains difficult when lesions share the same histologic type (8). Comprehensive histologic assessment (CHA) and molecular methods such as next-generation sequencing (NGS) can assess clonal relationships by comparing mutational profiles across lesions and can improve classification in selected cases (9,10). At the same time, the maturation of minimally invasive techniques has supported the feasibility of simultaneous or staged bilateral VATS according to lesion distribution and patient functional reserve (7).

This review focuses on the diagnostic criteria and differential diagnosis of SMPLC, surgical indications, comparative outcomes of different surgical approaches, and future directions. It summarizes the limitations of current diagnostic standards and recent advances in NGS-based molecular assessment for distinguishing SMPLC from IPM (9). It also examines how the number and location of lesions, laterality, cardiopulmonary reserve, comorbidity, and nodal status affect surgical decision-making. Existing systematic reviews and meta-analyses have compared lobectomy with sublobar resection in multiple primary lung cancer, providing evidence relevant to balancing oncologic radicality and preservation of pulmonary function (4,5). Non-surgical and multimodal treatments, including stereotactic body radiotherapy (SBRT), radiofrequency ablation (RFA), targeted therapy, and immunotherapy, may also have roles in selected patients (9,11). We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-2146/rc).

Methods

A narrative literature search was conducted to identify publications relevant to the diagnosis, preoperative assessment, and surgical management of SMPLC. PubMed was searched for publications dated from 1 January 2000 to 18 August 2026. English- and Chinese-language articles were considered. Search terms included “multiple primary lung cancer”, “synchronous multiple primary lung cancer”, “intrapulmonary metastasis”, “molecular clonality”, “next-generation sequencing”, “lobectomy”, “segmentectomy”, “wedge resection”, “bilateral surgery”, “subsolid nodule”, “ground-glass nodule”, “stereotactic body radiotherapy”, and related combinations. An update search was performed during revision to identify recent studies on molecular clonality, one-stage versus staged bilateral VATS, and management of residual subsolid nodules. Reference lists of relevant reviews and clinically pertinent articles were also examined. Guidelines, narrative and systematic reviews, cohort studies, meta-analyses, case series, and representative case reports were selected according to their relevance to the clinical focus of this review. For Chinese-language publications, the authors used the original Chinese-language source when available and translated relevant findings into English for synthesis; wording was cross-checked against the source before inclusion. Because this was a narrative review, no exhaustive systematic screening, formal risk-of-bias assessment, or quantitative synthesis was performed. The search strategy is summarized in Table 1, and an example of the detailed PubMed search strategy is provided in Table S1. During revision, ChatGPT (OpenAI) was used as an editorial aid for language and organization. It was not used as a source of scientific evidence or to generate or analyze study data; the authors remain responsible for the final content. Technical details and prompts are provided in Appendix 1.

Table 1. The search strategy summary.

Items	Specification
Date of search	Initial search: 30 June 2026; updated search: 18 August 2026
Databases and other sources searched	PubMed; reference lists of relevant reviews and clinically pertinent articles
Search terms used	“multiple primary lung cancer”, “synchronous multiple primary lung cancer”, “intrapulmonary metastasis”, “molecular clonality”, “next-generation sequencing”, “lobectomy”, “segmentectomy”, “wedge resection”, “bilateral surgery”, “subsolid nodule”, “ground-glass nodule”, “stereotactic body radiotherapy”, and related combinations
Timeframe	1 January 2000 to 18 August 2026
Inclusion and exclusion criteria	English- or Chinese-language guidelines, reviews, cohort studies, systematic reviews/meta-analyses, case series, and representative case reports directly relevant to SMPLC diagnosis or surgical management were considered
	Publications with limited relevance to SMPLC or insufficiently accessible information were excluded
Selection process	One author conducted the search and initial selection according to relevance. The second author reviewed the final selection and clinical interpretation; uncertainties were resolved through discussion. During revision, the search was updated to identify recent literature specifically addressing molecular clonality, bilateral VATS, and management of residual subsolid nodules
Additional considerations	The search was intended to support transparent reporting of a narrative review and was not designed as an exhaustive systematic-review search. No formal risk-of-bias assessment or quantitative synthesis was undertaken. For Chinese-language publications, the original Chinese-language source was used when available and relevant findings were translated into English and cross-checked against the source before inclusion

The detailed PubMed search strategy is provided in Table S1. This table is included to improve transparency and does not indicate that the review was systematic. SMPLC, synchronous multiple primary lung cancer; VATS, video-assisted thoracoscopic surgery.

Diagnostic criteria and differential diagnosis of SMPLC

Pathologic diagnostic criteria and their limitations

The pathologic diagnosis of SMPLC has traditionally been based on the classic Martini-Melamed criteria. According to these criteria, lesions should be located in different lobes or in different segments of the same lobe and should either have different histologic types or, when histologically similar, meet additional conditions such as origin from carcinoma in situ, absence of metastasis to common lymphatic drainage regions, and absence of extrapulmonary metastasis (12,13). More recent practice incorporates CHA, which compares detailed morphologic patterns across tumors, and molecular profiling when morphology remains equivocal (14). Importantly, studies of multiple lung cancers have not used uniform diagnostic definitions: some rely mainly on classic clinicopathologic criteria, others use CHA, and more recent cohorts incorporate molecular clonality. This heterogeneity can alter classification and complicate direct comparison of treatment outcomes across studies (14,15). Even when multiple lesions share the same major histologic type, discordant driver-gene mutation profiles may support independent primary origins (10,16). For example, a case of synchronous triple primary lung cancer showed different EGFR mutations among the lesions, supporting a diagnosis of multiple primary tumors rather than intrapulmonary metastases (16). A limitation of conventional criteria is that lesions may display subclonal heterogeneity or overlapping biomarker patterns, which complicates classification (17). Therefore, when histologic subtypes are similar or biomarker profiles overlap, pathologic findings should be integrated with molecular data and clinical information (14,18).

Role of molecular diagnostic techniques

NGS plays an important role in the differential diagnosis of SMPLC. Simultaneous analysis of the mutational profiles of multiple lesions has demonstrated that lesions within the same patient may harbor discordant EGFR alterations, highlighting the value of combining molecular findings with pathologic assessment (19). One reported patient with bilateral SMPLC had an EGFR G719C mutation in the right-sided lesion and an EGFR exon 19 deletion in the left-sided lesion (20). Clonality analysis based on broader genomic profiles may also provide useful information by identifying shared alterations together with lesion-specific subclonal changes (17,18). In practice, multi-lesion molecular profiling should be considered when lesions have similar or indistinguishable histology, when pathologic and radiographic findings conflict, or when classification as separate primaries versus IPM would materially change TNM staging or treatment. When lesions have clearly different histologic types and the clinicopathologic context already strongly supports independent primary tumors, CHA may be sufficient and molecular testing may be less essential, although it can still be useful when uncertainty remains (14). Interpretation should not rely on a single driver alteration. Discordant driver mutations generally support separate primaries, but rare discordance can occur in truly clonal tumor pairs; conversely, a single shared hotspot alteration may occur coincidentally in non-clonal tumors. Broader NGS panels that assess multiple alterations reduce inconclusive classifications and provide stronger evidence when several concordant alterations are shared (21,22). Lesion-specific subclonal differences therefore do not, by themselves, exclude a common clonal origin. Circulating tumor DNA (ctDNA) has been used for mutation detection and resistance monitoring in non-small cell lung cancer (23), but its role in distinguishing interlesional clonality in SMPLC has not been established and should not substitute for multi-lesion tissue-based assessment (14,21,22). Accordingly, molecular results should be interpreted together with CHA, imaging, nodal pattern, and the overall clinical context in a multidisciplinary setting (14).

Application of imaging in differential diagnosis

Imaging, particularly HRCT and PET-CT, is central to the evaluation of SMPLC. PET-CT can assess metabolic activity and may help correlate the maximum standardized uptake value (SUVmax) with surgical outcome. Thin-section HRCT is important for detecting and characterizing multiple pulmonary nodules before surgery. Tumor size and SUVmax have been reported as prognostic indicators in SMPLC; in one study, patients with tumors no larger than 3 cm and an SUVmax of 3.1 or less achieved a 5-year survival rate of 100% (24). Artificial intelligence and deep-learning methods have been explored as adjuncts for the characterization of multiple pulmonary lesions, but they remain investigational and should not replace integrated pathologic and molecular assessment (25). Thin-section HRCT remains a key preoperative imaging modality for identifying multiple lesions and supporting clinical decision-making (26). Although imaging provides important clues, it should be interpreted together with pathologic and molecular findings when differentiating synchronous primary tumors from metastatic disease.

Preoperative assessment and optimization of surgical indications

Assessment of pulmonary function and cardiopulmonary reserve

Accurate preoperative assessment of pulmonary function and cardiopulmonary reserve is essential for selecting the surgical approach and estimating operative risk in SMPLC. Because multiple lesions may require resection of lung tissue at several sites, the risk of cumulative postoperative functional impairment is greater than that associated with a single limited resection. Baseline spirometry and DLCO should therefore be assessed, and predicted postoperative FEV1 (ppoFEV1) and predicted postoperative DLCO (ppoDLCO) should be estimated according to the planned extent of resection. The 2025 ERS/ESTS clinical practice guideline emphasizes pulmonary function tests, split-lung function, exercise testing, comorbidities, and multidisciplinary risk stratification when assessing fitness for curative-intent lung cancer treatment (3). Lower predicted postoperative reserve, previous lung resection, advanced age, smoking-related lung disease, cardiovascular disease, and frailty should increase the weight given to parenchyma-preserving or staged strategies rather than extensive bilateral resection. Pulmonary function tests are also associated with early postoperative complications after lung resection (27). Three-dimensional reconstruction may further assist in determining the anatomic suitability of segmentectomy or subsegmentectomy for ground-glass opacity-dominant clinical T1a-bN0 non-small cell lung cancer (28). Such detailed assessment is especially important when lesions are distributed across different lobes or both lungs.

Lesion burden, localization, and staging strategy

The number of lesions, laterality, lobar distribution, dominant lesion, and radiographic invasiveness of secondary lesions should be documented before surgery. Pure ground-glass or GGO-dominant lesions generally represent a different risk profile from solid-dominant lesions, and the size of the solid component has been associated with nodal metastasis in subsolid lung cancer (29,30). These features influence whether every lesion requires immediate resection, the amount of lung parenchyma that can be safely removed, and whether bilateral surgery should be performed simultaneously or in stages. For SMPLC presenting as multiple GGOs, accurate preoperative localization is also important for achieving complete resection and avoiding missed lesions. Some GGOs are difficult to identify by visual inspection or palpation during surgery, making intraoperative localization clinically relevant (31). Separately, for bronchoscopic tissue diagnosis, the blizzard sign and mixed blizzard sign on endobronchial ultrasonography with a guide sheath (EBUS-GS) have been described as imaging patterns that can support identification of GGO targets and are associated with successful diagnostic sampling (32,33). Because SMPLC may involve lymph-node metastasis, particularly when lesions contain substantial solid components, accurate preoperative N staging is important when determining whether systematic nodal dissection is required (29). Contrast-enhanced brain magnetic resonance imaging and abdominal computed tomography are commonly used to exclude distant metastases and support curative-intent treatment planning. Integrating lesion burden, localization, radiographic phenotype, and staging findings can facilitate more precise and individualized surgical strategies.

Classification and selection of surgical approaches

Lobectomy combined with sublobar resection

When the dominant lesion is centrally located or requires standard lobectomy, while smaller ground-glass lesions are present in the contralateral lung or another lobe of the same lung, lobectomy combined with sublobar resection is a commonly used parenchyma-preserving strategy. This approach aims to achieve oncologic control of the dominant lesion while preserving as much healthy lung tissue as possible. Reported series of synchronous multiple primary non-small cell lung cancer include combinations of lobectomy and limited resection according to lesion location and patient reserve (34,35). Studies have found no significant difference in 5-year overall survival between sublobar resection and lobectomy in selected patients with multiple primary lung cancer (4). With the development of minimally invasive surgery, simultaneous bilateral VATS may reduce cumulative hospitalization and avoid a second anesthetic exposure in carefully selected patients (7). This combined approach may be particularly suitable for lesions located in different lobes in patients with adequate cardiopulmonary reserve.

Bilateral lobectomy and pneumonectomy

Bilateral lobectomy or pneumonectomy should be used cautiously in SMPLC and reserved for situations in which complete treatment of clinically important disease cannot be achieved with a less extensive resection (36,37). The main concern is the cumulative loss of functional lung parenchyma, particularly in bilateral disease. Meta-analytic evidence in surgically treated SMPLC identifies pneumonectomy as an adverse prognostic factor and supports avoiding it whenever an oncologically appropriate parenchyma-preserving alternative is feasible (38). Any extensive bilateral strategy should therefore be preceded by careful assessment of predicted postoperative pulmonary reserve and comorbidity.

Sublobar resection alone

Limited resection may be considered for pure ground-glass or GGO-dominant adenocarcinomas when complete excision with an adequate margin can be achieved. In carefully selected patients with early-stage non-small cell lung cancer, sublobar resection may provide long-term outcomes comparable to lobectomy, particularly for small peripheral lesions (30,39). Thoracoscopic segmentectomy has shown favorable safety and oncologic outcomes in appropriately selected patients (40). Nodal assessment should be tailored to radiographic invasiveness and the estimated risk of nodal metastasis; the size of the solid component is an important predictor of nodal involvement in subsolid lung cancer (29). This strategy maximizes preservation of healthy lung tissue and is particularly relevant for patients with limited pulmonary reserve or multiple lesions.

Simultaneous versus staged bilateral VATS

For bilateral disease, the choice between simultaneous and staged VATS should be individualized rather than determined by laterality alone. A 2025 propensity score-matched analysis of 156 patients with bilateral multiple pulmonary nodules found no significant difference in overall complications or 3-year overall survival between one-stage and two-stage VATS after matching, whereas one-stage surgery was associated with a shorter total hospital stay and lower cost (41). These findings are consistent with earlier reports supporting the feasibility of simultaneous bilateral VATS in selected patients (7). Simultaneous bilateral surgery is most reasonable when both sides can be treated by limited minimally invasive resections, cardiopulmonary reserve is adequate, and the expected cumulative loss of lung parenchyma is acceptable. A staged approach may be preferable when one side requires a larger resection, ppoFEV1 or ppoDLCO is borderline, important comorbidities increase perioperative risk, postoperative recovery is uncertain, or the pathologic result from the first operation could alter management of the contralateral lesion. Because available comparisons remain retrospective and subject to selection bias, one-stage surgery should not be regarded as universally superior.

Management of residual GGNs and non-surgical local therapy

Residual small pure GGNs or GGO-dominant lesions do not always require immediate resection, particularly when removing every lesion would result in substantial cumulative loss of functional lung parenchyma. Contemporary expert consensus supports individualized surveillance of selected subsolid nodules with serial thin-section CT, with the intensity of follow-up determined by lesion size, density, and change over time (42). Intervention should be reconsidered when a residual lesion shows clinically meaningful growth, develops a new solid component, demonstrates enlargement of an existing solid component, or otherwise becomes more radiographically suspicious (30,31,42,43). For a secondary lesion that warrants local treatment but the patient is medically inoperable or at high surgical risk, SBRT can be considered as a non-surgical local option. Retrospective series of early-stage GGO-predominant lung cancers treated with SBRT have reported favorable local control, but these data are nonrandomized and are not specific to residual SMPLC lesions (44). Other image-guided ablative approaches may also be considered in selected non-surgical candidates, although evidence specific to SMPLC remains limited (11). Hybrid management combining surgery for the dominant lesion with SBRT for another lesion has been described, but current support is based mainly on limited observational evidence and case reports (45).

A practical diagnostic and surgical decision pathway is summarized in Figure 1. Table 2 provides a concise synthesis of preferred approaches by common clinical scenario; these are decision aids rather than prescriptive rules and should be adapted through multidisciplinary discussion.

Figure 1.

Integrated diagnostic and surgical decision pathway for SMPLC. The editable figure summarizes sequential assessment of clinicopathologic diagnosis, selective molecular clonality testing when classification remains uncertain, preoperative functional evaluation, surgical approach selection, residual ground-glass nodule management, and multidisciplinary reassessment. CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 second; GGNs, ground-glass nodules; GGO, ground-glass opacity; IPM, intrapulmonary metastasis; MDT, multidisciplinary team; NGS, next-generation sequencing; ppoDLCO, predicted postoperative diffusing capacity of the lung for carbon monoxide; ppoFEV1, predicted postoperative forced expiratory volume in 1 second; SBRT, stereotactic body radiotherapy; SMPLC, synchronous multiple primary lung cancer; VATS, video-assisted thoracoscopic surgery.

Table 2. Preferred management according to common clinical scenarios.

Clinical scenario	Preferred approach	Key considerations
Dominant invasive lesion plus smaller peripheral/GGO lesions	Anatomic resection of the dominant lesion with wedge resection or segmentectomy of selected secondary lesions	Aim for oncologic control of the dominant lesion while limiting cumulative parenchymal loss
Multiple peripheral GGO-dominant lesions	Selective wedge resection or anatomical segmentectomy; surveillance may be appropriate for residual low-risk GGNs	Prioritize complete treatment of the most suspicious lesions rather than automatic resection of every GGN
Bilateral limited lesions with good functional reserve	Consider simultaneous bilateral VATS	Most appropriate when both sides can be treated by limited minimally invasive resections and expected postoperative reserve is acceptable
Bilateral larger/asymmetric lesions or borderline functional reserve/comorbidity	Consider staged VATS	Allows recovery and reassessment between operations and may reduce cumulative physiologic stress
Similar histology with uncertain SMPLC versus IPM and management consequences	CHA plus selective multi-lesion NGS before final staging/treatment decision	Interpret molecular findings with histology, imaging, nodal pattern, and clinical context; a single mutation should not be used in isolation
Secondary lesion requiring treatment in a high surgical-risk patient	Consider SBRT or another local therapy after MDT review	Evidence specific to SMPLC is limited; treatment should account for lesion phenotype, location, and competing risks

GGO, ground-glass opacity; GGN, ground-glass nodule; IPM, intrapulmonary metastasis; MDT, multidisciplinary team; NGS, next-generation sequencing; SBRT, stereotactic body radiotherapy; SMPLC, synchronous multiple primary lung cancer; VATS, video-assisted thoracoscopic surgery.

Effects of surgical approach on prognosis and decisions regarding postoperative adjuvant therapy

Comparison of survival outcomes

Retrospective studies have reported 5-year overall survival rates of approximately 40% to 60% after curative-intent resection for SMPLC. In a retrospective series of 122 patients, the postoperative 5-year survival rate was 40.5% (35). A meta-analysis of 26 studies including 1,788 patients reported a pooled 5-year overall survival rate of 45% (38). These findings support an active surgical approach for appropriately selected patients with resectable SMPLC, while also underscoring the heterogeneity of the populations included in published series.

A meta-analysis of SMPLC found no statistically significant difference in overall survival between sublobar resection and lobectomy (hazard ratio, 1.29; P=0.159), suggesting broadly comparable long-term survival in selected patients (38). Another systematic review likewise found no significant survival difference between lobectomy and limited resection in multiple primary lung cancer (4). These retrospective comparisons should not be interpreted as proof of oncologic equivalence, because the choice of resection is strongly influenced by tumor size, peripheral location, GGO predominance, pulmonary reserve, and comorbidity. In one study of the dominant lesion, 5-year overall survival was 83.9% after sublobar resection and 86.7% after lobectomy (P=0.482), while 5-year disease-free survival was 87.7% and 67.6%, respectively (P=0.324) (46). The apparent similarity in survival therefore needs to be interpreted in the context of confounding by indication and selection bias.

Across surgical series, stage, lymph-node involvement, completeness of resection, and the overall extent of pulmonary resection have been associated with prognosis (12,35,38,47). Although lobectomy versus sublobar resection has not consistently emerged as an independent determinant of overall survival, meta-analytic evidence suggests that pneumonectomy is associated with increased mortality and should be avoided whenever oncologically feasible (38). The principal goal should therefore be complete treatment of clinically important lesions with an extent of surgery tailored to the characteristics of each lesion and the functional status of the patient.

Decisions regarding postoperative adjuvant therapy

For patients with pathologically confirmed nodal involvement or positive surgical margins, postoperative treatment should be individualized according to the overall pathologic stage, histology, molecular profile, resection status, and prevailing NSCLC treatment principles. Lymph-node metastasis is an adverse prognostic factor in SMPLC (38,47). Because evidence specific to adjuvant treatment of SMPLC is limited, decisions regarding chemotherapy, targeted therapy, immunotherapy, or radiotherapy should be made in a multidisciplinary setting rather than extrapolated from surgical extent alone.

Lesion-specific molecular profiling may have both diagnostic and therapeutic relevance, although evidence for adjuvant treatment specifically in SMPLC remains sparse. A recent postoperative SMPLC cohort characterized EGFR, TP53, and KRAS alterations and evaluated their associations with recurrence-related outcomes (47). For the diagnostic distinction between independent primaries and IPM, the most direct evidence comes from integrated histologic and broader molecular clonality assessment rather than from the mutation status of only one lesion (14,21,22). A case report also described a lesion-specific strategy in which a gefitinib-insensitive tumor was surgically resected while another gefitinib-sensitive lesion was treated medically (48). These observations support evaluating clinically relevant lesions separately when molecular findings are expected to affect management.

For patients whose clinically important lesions have been completely resected, evidence supporting routine adjuvant treatment specifically because multiple primary tumors are present is limited. In the SMPLC meta-analysis, adjuvant therapy was not associated with a significant overall-survival benefit (38). A recent single-center postoperative cohort found that, among stage IA patients, disease-free survival was associated with high-risk pathologic features and PD-L1 expression, whereas the number of primary lesions was not significantly associated with disease-free survival (47). Postoperative therapy should therefore be individualized according to the highest-risk lesion, pathologic stage, molecular findings, and standard NSCLC treatment principles rather than the number of primary tumors alone.

Multidisciplinary collaboration and future directions in individualized surgical decision-making

Role of the multidisciplinary team (MDT)

A MDT plays a central role in the diagnosis and treatment of SMPLC. Because the distinction between SMPLC and IPM and the selection of treatment involve several disciplines, decisions made by a single department may be limited (2). Integration of imaging, pathology, molecular findings, pulmonary function, predicted postoperative reserve, lesion distribution, and patient preferences can improve diagnostic confidence and facilitate individualized treatment planning. MDT review is particularly important when clonality remains indeterminate, bilateral procedures are being considered, or residual lesions may be managed with surveillance or non-surgical local therapy.

New tools for individualized surgical planning

A range of new tools is being explored to support individualized decision-making in SMPLC. Systematic reviews have evaluated the survival impact of lobectomy versus sublobar resection in multiple primary lung cancer (4). Artificial intelligence methods have also been investigated as diagnostic aids for multiple primary lung cancer (25). Their clinical role remains investigational, and they should be viewed as adjuncts rather than replacements for integrated pathologic, molecular, imaging, and multidisciplinary assessment.

Strengths and limitations of the current evidence

This review integrates clinicopathologic, molecular, surgical, and radiologic evidence and was updated during revision to include recent studies. Nevertheless, the underlying evidence has important limitations. First, diagnostic criteria are heterogeneous across studies, ranging from classic Martini-Melamed criteria to CHA and modern molecular clonality testing, which can change whether the same patient is classified as SMPLC or IPM and thereby reduce comparability across cohorts (14,15). Second, comparisons of lobectomy with sublobar resection are dominated by retrospective studies and are vulnerable to confounding by indication: patients with smaller, peripheral, GGO-dominant lesions or limited pulmonary reserve may preferentially receive limited resection, whereas larger or more invasive lesions are more likely to undergo lobectomy (4,38,46). Consequently, a non-significant survival difference should not be interpreted as proof that the procedures are equivalent for all patients. Third, because this is a narrative review, the initial literature search and selection were performed by one author with secondary review by another author; selection bias cannot be excluded, and no formal risk-of-bias assessment or quantitative synthesis was undertaken. Finally, Chinese-language sources were translated by the authors when used in the English synthesis, and differences in terminology and reporting style may still influence cross-language interpretation.

Future research directions

Future research in SMPLC should focus on generating higher-level clinical evidence and standardizing diagnostic definitions across surgical cohorts. Existing systematic reviews emphasize that the evidence comparing different extents of resection remains limited and that randomized or well-designed prospective studies are needed (4). Recent IASLC recommendations and NGS studies support integrated histologic and broader molecular profiling in diagnostically ambiguous cases, while also showing that small mutation panels can leave a substantial proportion of tumor pairs inconclusive (14,21,22). Updated bilateral VATS data similarly suggest that both one-stage and staged approaches can be feasible in selected patients, but prospective evidence remains limited (41). Further investigation of the immune microenvironment, including clonal expansion within the T-cell receptor repertoire and interlesional tumor heterogeneity, may deepen understanding of SMPLC biology (49). Integration of multi-omics data, AI-assisted diagnosis, and lesion-specific treatment strategies may promote more precise management of multiple primary lung cancer (50). Recent surgical cohorts also reinforce the need to revisit historical diagnostic frameworks in the context of contemporary pathology and molecular testing (15).

Conclusions

Accurate differentiation between SMPLC and IPM is fundamental to staging and treatment selection. Thin-section CT, CHA, and selective molecular clonality analysis provide complementary evidence, but no single diagnostic gold standard is applicable to all cases. When lesions have similar histologic features or atypical clinical presentations, multidisciplinary assessment is required, and uncertainty should be acknowledged when the available evidence remains inconclusive.

Surgery remains the main treatment for resectable SMPLC. The operative strategy should prioritize oncologic control of the dominant and other clinically significant lesions while accounting for the number and distribution of lesions, laterality, invasive potential, nodal status, predicted postoperative pulmonary function, comorbidity, and cumulative loss of lung parenchyma. Lobectomy combined with sublobar resection, multiple sublobar resections, and simultaneous or staged bilateral surgery may all be appropriate in selected patients. Residual low-risk GGNs may be managed with structured CT surveillance, whereas SBRT or another local therapy can be considered for selected lesions when additional surgery carries excessive risk. Because the current evidence is derived mainly from retrospective studies with heterogeneous diagnostic criteria and substantial selection bias, no single surgical approach can be recommended for all patients. Standardized diagnostic criteria and multicenter prospective studies are needed to clarify the long-term outcomes associated with different extents of resection, the timing of bilateral surgery, and management of residual lesions.

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