Occult Hilar and Intrapulmonary Nodal Metastasis in Non-Small Cell Lung Cancer After Anatomical Resection

Occult Hilar and Intrapulmonary Nodal Metastasis in Non-Small Cell Lung Cancer After Anatomical Resection | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Occult Hilar and Intrapulmonary Nodal Metastasis in Non-Small Cell Lung Cancer After Anatomical Resection Arda Sarıgül, Salih Duman, Berna Karataş, Adalet Demir, Murat Kara, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8965130/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Backround: Hilar and pulmonary lymph node metastases are key determinants of prognosis in primary lung cancer. Despite advances in imaging and staging, the prognostic implications of N1 disease undetected during preoperative assessment remain poorly defined. This study evaluates patients with pathologically confirmed but preoperatively occult N1 metastases, focusing on survival outcomes and clinicopathological features, and explores their potential implications for prognostic stratification and future staging refinement. Methods: Data retrieved from 94 patients who underwent anatomical surgical resection for primary lung carcinoma between 2008 and 2024 and clinically, N0 were found to have N1 lymph node metastases on final pathology. Preoperative workup included both non-invasive and invasive staging. Results: Among patients with single-station N1 involvement, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.2% and 59.7%, respectively — significantly better than those with multi-station disease (DFS: 17.8%, OS: 27.9%; p = p < 0.05 and p < 0.05). Stage IIA and IIB patients showed relatively favorable survival, while Stage IIIA patients had markedly poorer 5-year DFS and OS (p < 0.01). Univariate analysis confirmed that multi-station N1 involvement was associated with significantly worse prognosis, a finding that remained consistent in multivariate models as well. Conclusion: Multistation N1 involvement emerged as the strongest determinant of disease recurrence, while pleural invasion independently predicted overall survival. These findings indicate that unexpected N1 disease represents a biologically meaningful subgroup rather than a mere consequence of staging limitations and underscore the importance of detailed pathological nodal assessment for postoperative risk stratification and therapeutic decision-making. Occult Hilar and Intrapulmonary Nodal Metastasis in Non-Small Cell Lung Cancer After Resection Clinical trial number: not applicable. Hilar lymph nodes NSCLC Occult metastases Long-term survival Figures Figure 1 Figure 2 Introduction Lymph node involvement remains one of the cornerstones of staging and prognosis in non–small cell lung cancer (NSCLC), yet the clinical significance of N1 metastasis has received relatively limited attention ( 1 , 2 ). The TNM-9 classification, much like earlier editions, continues to emphasize all subgroups of N1 disease into a single category, despite the previous studies suggesting heterogenity and survival differences within this patient group ( 3 ). Also proposal studies for staging suggest a better understanding of characteristic variability may help redefine prognostic assessment and inform future revisions of the staging system ( 4 ). Invasive and imaging-based staging techniques have improved over the years but the preoperative evaluation of N1 lymph nodes shows considerable variability among published studies ( 5 – 7 ). As a result, some patients undergo surgery with completely negative radiologic or invasive findings but are later found to exhibit N1 metastasis on final pathology. This group matters clinically, since knowing about nodal disease beforehand could alter several aspects of management, such as how patients preoperative planing such as neo-adjuvant therapy requirement, the extent or approach of the operation, and the planning of postoperative adjuvant therapy ( 8 ). The biological and prognostic significance of unexpected N1 involvement remains insufficiently characterized ( 9 ). It is not clear whether these occult nodal metastases are only the result of the limited sensitivity towards certain micrometastases or whether they represent a separate pathological pattern with different survival outcomes ( 10 – 12 ). Assumably the usual prognostic patterns observed in the subgroups of N1-metastatic patients also apply to those with unexpected N1 metastasis remains unclear ( 12 ). In this study, we aimed to analyze the prognostic implications of N1 lymph node metastases that were not detected by preoperative radiological or invasive staging—designated as unexpected N1 disease ( 13 ). Specifically, we aimed to determine whether survival differed across the subgroup analyses within this unique cohort and to evaluate the impact of additional pathological features on long-term clinical outcomes. METHODS This retrospective cohort study included patients who underwent anatomical lung resection for primary lung carcinoma at the Department of Thoracic Surgery, Istanbul University, Istanbul Faculty of Medicine, between January 2018 and November 2024. Among a total of 1,134 patients who underwent anatomical pulmonary resection, 94 had complete clinical and pathological records, provided written informed consent for scientific use of their anonymized clinical data and fulfilled all eligibility criteria; these patients constituted the study population. The study had ethical approval from the Istanbul University Istanbul Faculty of Medicine Clinical Research Ethics Committee (Decision No: 3095252, 2024/1023). All procedures were conducted in accordance with the Declaration of Helsinki. All patients underwent standardized preoperative evaluation, including pulmonary function testing, cardiopulmonary assessment, and appropriate staging investigations, in accordance with international guidelines( 14 ). Operability and surgical candidacy were determined by a multidisciplinary thoracic oncology board before operative planning. We include the patients who underwent lobectomy, sleeve lobectomy, or pneumonectomy for suspected or histologically confirmed primary non–small cell lung cancer (NSCLC). All patients underwent preoperative evaluation with high-resolution computed tomography and FDG-PET/CT (18-F-fluorodeoxyglucose positron emission tomography). Lymph nodes at the hilar and mediastinal stations were considered clinically negative when the short-axis diameter was less than 10 mm on high-resolution CT and when no pathological FDG uptake was observed on FDG-PET/CT. Final pathological analysis was required to confirm N1 metastasis in stations 10–14 according to the IASLC lymph node map( 15 ). Uneligible patients (n: 1,040) were excluded according to predefined criteria. Patients who had received neoadjuvant therapy were excluded to ensure cohort homogeneity (n = 103). Additional exclusions included incomplete clinical, pathological, or survival data (n = 116); preoperative distant metastasis (M1a-b), benign pathology, previous lung malignancy, or metastasectomy for another primary tumor (n = 36); sublobar or non-anatomical resections (n = 12); and early non-informative postoperative mortality within 90 days (n = 3). Following pathological assessment, patients with pathological N0 disease (n = 732) or pathological N2 metastasis (n = 38) were also excluded to isolate cases of unexpected N1 involvement. Patients who were medically ineligible for guideline-recommended adjuvant therapy were excluded, as uniform receipt of standard postoperative treatment was required for inclusion ( 16 ). All patients in the final cohort received adjuvant therapy appropriate to their pathological stage ( 14 , 17 , 18 ). Surgical procedures were carried out either with video-assisted thoracoscopic surgery or with a standard open thoracotomy, depending on routine practice at our center. A systematic dissection of the hilar and intrapulmonary lymph nodes was done in all patients. According to the IASLC lymph node map, stations 10 and 11 were considered hilar–central N1, while stations 12 to 14 were accepted as peripheral N1. Patients with metastasis limited to only one of 10-11-12-13-14 stations were classified as single-station N1, and those with involvement of more than one were classified as multi-station N1( 15 ). Single-station lymph node involvement was stratified into two subgroups—hilar and peripheral—for subgroup anaylsis. Overall survival (OS) and disease-free survival (DFS) were subsequently evaluated and compared between these two groups. Statistical analyses were performed using SPSS version 31.0 (IBM Corporation, Chicago, IL, USA) and Microsoft Excel version 16.0 (Microsoft Corporation, Redmond, WA, USA). Normality of continuous variables was evaluated using histogram inspection and the Kolmogorov–Smirnov test. Continuous variables were summarized using means, medians, and standard deviations, whereas categorical variables were presented as counts and percentages. Survival curves were generated using the Kaplan–Meier method, and comparisons between groups were conducted with the log-rank test. Variables that demonstrated statistical significance at p < 0.05 in univariate analyses were entered into multivariate Cox proportional hazards modeling to assess independent predictors of survival. Continuous variables were compared using the Student’s t-test or the Mann–Whitney U test depending on distribution, and categorical variables were compared with the chi-square test. The median follow-up duration was 57 months, with a range of 6 to 208 months. No AI tools were used for data generation, statistical analysis, patient identification, or image interpretation. All clinical data extraction and statistical analyses were performed manually by the authors. RESULTS The median age of the cohort was 61 years (range, 44–77 years), and 87.2% were male. Smoking history was present in 90.4% of the cohort. Preoperative respiratory function tests revealed a mean FEV1 of 2404 ± 613 mL/min (83.9 ± 17.8% predicted), and a mean predicted DLCO of 83.7 ± 19.0% in the overall cohort. Radiological assessment demonstrated that 38 patients (40.4%) had right-sided tumors, 56 patients (59.6%) had left-sided lesions. Most frequently located in the left upper lobe (35.1%) and right upper lobe (26.6%). The distribution across other lobes was as follows: left lower lobe in 24.5%, right lower lobe in 10.6%, and right middle lobe in 3.2% of patients. Invasive mediastinal staging with cervical mediastinoscopy was undertaken in 19.1% of the cohort (n = 18). The most common surgical procedures were left upper lobectomy (20.2%), left pneumonectomy (17.0%), and right upper lobectomy (13.8%). Pneumonectomy was required in 16 left-sided cases (17.0%), whereas other procedures such as bilobectomy and right middle lobectomy constituted smaller proportions of the cohort. Systematic hilar and intrapulmonary lymphadenectomy yielded a median of 14 (6–28) nodes. The median number of dissected N1 lymph nodes was highest in patients undergoing right lower lobectomy (8 ± 5.5), followed by right pneumonectomy (7 ± 4.5). Most common postoperative complications were nosocomial pneumonia in 7.8% of patients and atrial fibrillation in 3.6%. Survival analysis demonstrated no significant effect of demographic variables, as patients aged ≤ 60 years showed a 5-year DFS of 42.60% and OS of 51.30%, compared with 48.00% and 56.30%, respectively, in older patients (p = 0.65 and p = 0.29). Sex similarly did not influence outcomes, with men achieving a 5-year DFS of 43.70% and OS of 52.40%, and women 57.10% and 63.50% (p = 0.62 and p = 0.94). Smoking exposure did not stratify survival, as patients with ≤ 43 pack-years had a 5-year DFS of 37.70% and OS of 47.60%, compared with 57.90% and 63.30% in heavier smokers (p = 0.48 and p = 0.52). Patinetns with FEV1 values above 2,404 mL demonstrated superior overall survival (p = 0.04). Operative factors did not significantly influence long-term outcomes. Patients undergoing pneumonectomy achieved a 5-year DFS of 43.50% and OS of 47.80%, similar to those receiving lesser resections (52.00% and 53.10%, p = 0.71 and p = 0.45). Extended resections performed for accomplish tumor-free origin related with lower 5-year DFS (24.20%) compared with standard procedures (48.50%), but without statistical significance (p = 0.15). Perioperative complications were also not prognostic, as patients with complications had DFS and OS rates of 41.70% and 51.70%, compared with 48.90% and 55.60% in uncomplicated cases (p = 0.85 and p = 0.79). The associations between clinicopathological variables and both disease-free survival (DFS) and overall survival (OS) are presented in Table 1. T-category showed a stepwise decline in prognosis, with 5-year DFS and OS of 100.00% / 100.00% in T1a, 57.10% / 70.70% in T1b, 48.90% / 50.80% in T2a, 40.30% / 44.50% in T2b, 21.00% / 34.40% in T3, and 0.00% / 20.00% in T4 disease respectively (p < 0.01). Pleural invasion was absent in 68.1% of patients, while PL1, PL2, and PL3 involvement was observed in 24.5%, 4.3%, and 3.2% of cases, respectively. Five-year DFS decreased progressively with increasing pleural invasion (51.3% for absent, 30.1% for PL1, 25.0% for PL2, and 0% for PL3; p = 0.02). Median survival was 68 months (95% CI: 45.4–90.6) in the absence of pleural invasion, compared with 45 months (95% CI: 21.6–68.4) for PL1 and 12 months (95% CI: 0.0–41.4) for PL2. Five-year OS similarly declined across pleural invasion categories (59.1%, 40.7%, 37.5%, and 0%, respectively; p = 0.02). Squamous cell carcinoma was the most frequent histological subtype (55.3%), followed by adenocarcinoma (36.2%), while adenosquamous carcinoma was rare (4.3%). Five-year disease-free survival (DFS) was similar between adenocarcinoma and squamous cell carcinoma (46.1% vs. 47.5%, respectively), although histological subtype was associated with DFS on overall comparison (p = 0.001). Median DFS was 79 months (95% CI, 51.8–106.2) for adenocarcinoma and 70 months (95% CI, 21.6–118.3) for squamous cell carcinoma. Five-year overall survival (OS) differed significantly according to histology (p < 0.01), with rates of 48.7% for adenocarcinoma, 61.5% for squamous cell carcinoma, and 75.0% for adenosquamous carcinoma. According to final TNM stage; patients stage IIA and IIB exhibited substantially more favorable long-term outcomes compared with those staged as IIIA. Five-year DFS rates were 68.6% for stage IIA and 55.6% for stage IIB, whereas stage IIIA patients demonstrated a markedly reduced DFS of 17.3%. A similar pattern was observed for OS, with five-year OS rates of 75.0% in stage IIA, 59.7% in stage IIB, and 37.2% in stage IIIA (p < 0.01). Kaplan–Meier estimates of disease-free and overall survival according to tumor-related determinants are presented in Table 2 and shown on Fig. 1. Considering the N1 metastasis; patients with single-station N1 disease had markedly better 5-year DFS and OS (53.20% and 59.70%) compared with those with multi-station involvement (17.80% and 27.90%, p = 0.01 and p = 0.05). In contrast, nodal zone had limited prognostic value, as hilar metastasis produced a 5-year DFS of 51.30% and OS of 56.00%, compared with 40.00% and 59.30% for peripheral involvement (p = 0.04 and p = 0.22) (Fig. 2). Single-station nodal involvement was observed in 75 patients (79.8%), whereas 19 patients (20.2%) demonstrated multi-station disease. Within the single-station subgroup, hilar involvement (N10–N11) accounted for 63 patients (84.0%), while peripheral involvement (N12–N14) was identified in 12 patients (16.0%). Regarding station-specific distribution in the overall cohort, N10 metastasis was present in 67 patients (71.3%) and absent in 27 (28.7%). N11 involvement was detected in 34 patients (36.2%) and was negative in 60 (63.8%). Peripheral station positivity was less frequent, with N12 involvement in 8 patients (8.5%) and negativity in 86 (91.5%), N13 involvement in 4 patients (4.3%) and negativity in 90 (95.7%), and N14 involvement in 1 patient (1.1%) and negativity in 93 (98.9%). Among the 19 patients with multi-station disease, 18 (94.7%) exhibited concomitant N10 and N11 involvement, and 1 patient (5.3%) demonstrated triple-station positivity involving N10, N11, and N12. Extent and anatomical distribution of N1 nodal metastasis were associated with different survival outcomes. Patients with single-station N1 involvement (n = 75, 79.8%) demonstrated significantly better prognosis than those with multi-station disease (n = 19, 20.2%), with higher 5-year DFS (52.3% vs 17.8%; p = 0.005) and 5-year OS (59.7% vs 27.9%; p = 0.045). Median survival was also longer in the single-station group (79 months, 62.9–95.1) compared with the multi-station group (40 months, 19.3–60.7). Among single-station cases, hilar involvement (N10–11; n = 63, 84.0%) was associated with inferior 5-year DFS compared with peripheral involvement (N12–14; n = 12, 16.0%) (40.0% vs 51.3%; p = 0.036) and a shorter median survival (28 months, 0.0–62.7 vs 74 months, 47.2–100.8). In contrast, 5-year OS did not differ significantly between hilar and peripheral subgroups (56.0% vs 59.3%; p = 0.224). In univariate Cox regression analysis, multiple tumor and nodal variables showed significant associations with survival. Visceral pleural invasion was one of a predictive of worse outcomes, increasing the risk of recurrence 2.83-fold (95% CI: 1.33–6.02, p = 0.007) and mortality 2.36-fold (95% CI: 1.33–4.18, p = 0.003). Advancing TNM stage also conferred progressively poorer prognosis, with stage IIIA exhibiting a 4.02-fold higher risk of recurrence (95% CI: 1.90–8.47, p < 0.001) and a 2.19-fold higher risk of mortality (95% CI: 1.28–3.74, p = 0.004) compared with stage IIB. Nodal burden was an important determinant of outcome; patients with multistation N1 metastasis had a 3.11-fold increased risk of recurrence (95% CI: 1.51–6.43, p = 0.002) and a borderline increase in mortality (HR 1.92, 95% CI: 1.00–3.70, p = 0.050). In contrast, neither T-category transitions (T2a→T2b→T3) nor nodal zone (hilar vs peripheral) achieved statistical significance for either DFS or OS. On multivariate analysis, only a limited subset of variables retained independent prognostic significance. TNM stage IIIA remained a strong predictor of both recurrence and mortality, demonstrating a 3.68-fold increased risk of recurrence (95% CI: 1.59–8.52, p = 0.002) and a 2.13-fold increased risk of death (95% CI: 1.26–3.58, p = 0.004) compared with stage IIB. Multistation N1 metastasis remained independently associated with worse DFS, conferring a 13.22-fold increased recurrence risk (95% CI: 1.08–161.17, p = 0.043), although its effect on OS did not meet statistical significance (HR 7.31, p = 0.095). Pleural invasion did not retain significance for DFS (HR 1.50, p = 0.09) but preserved independent prognostic value for OS (HR 1.45, 95% CI: 1.03–2.03, p = 0.034). Univariate and multivariable Cox proportional hazards regression analyses identifying factors associated with disease-free and overall survival are summarized in Table 3. DISCUSSION Unexpected N1 lymph node metastasis remains a relatively understudied aspect of lung cancer staging, positioned at the interface of tumor biology and the inherent limitations of current preoperative diagnostic methods ( 9 ). Inaccuracies in preoperative staging may result in the underrecognition of nodal disease, thereby increasing the likelihood that selected patients proceed directly to upfront surgical resection despite potential eligibility for neoadjuvant chemotherapy and/or immunotherapy under contemporary treatment algorithms ( 19 ). In this context, meticulous pathological examination of resected specimens plays a critical role in achieving accurate postoperative staging, thereby ensuring that patients receive appropriate adjuvant therapy aligned with their true pathological status ( 16 , 18 , 20 ). In patients with small, peripheral lung lesions, limitations in both invasive and imaging-based preoperative staging may result in nodal understaging and bias surgical decision-making toward segmentectomy ( 21 ). In the presence of occult intralobar N1 metastasis, this strategy may confer an increased risk of locoregional recurrence and may further delay or preclude appropriate adjuvant therapy due to false downstaging ( 22 ). Notably, in our cohort, a considerable number of patients with T1 and T2 tumors would have been eligible for segmentectomy under current criteria, highlighting the potential oncologic implications of preoperative nodal misclassification ( 23 ). Limitations in preoperative staging may contribute to clinically meaningful heterogenity among patients ultimately classified within the same pathological stage, thereby complicating postoperative risk stratification and the interpretation of survival outcomes ( 24 ). In this study, we evaluated a carefully selected cohort of patients who were clinically staged as N0, exhibited no radiologic or invasive evidence of nodal involvement, yet were subsequently found to have pathological N1 metastasis. Our findings, despite certain differences compared with previously published reports, may contribute to the expanding body of literature suggesting that occult N1 metastasis represents more than a simple limitation of preoperative staging. Rather, it constitutes a prognostically distinct subgroup with implications for clinical decision-making and future refinements of staging systems ( 25 ). Despite negative preoperative imaging and invasive assessments, prognostic stratification according to T category, overall TNM stage, and nodal burden remained consistently preserved, in line with previous literature describing the dominant prognostic role of pathological nodal status ( 14 , 26 ). Survival stratification in our cohort, with stepwise reductions in 5-year DFS and OS across increasing T category and overall stage, was consistent with patterns described in clinically recognized N1 populations. These findings indicate prognostic behaviour analogous to overt N1 disease, despite preoperative nodal underrecognition ( 27 , 28 ). For the cohort, the extent of surgical resection or postoperative complications did not exert a significant influence on long-term outcomes. Patients who underwent pneumonectomy had survival comparable to that achieved with lesser resections, and extended procedures performed for local invasion did not demonstrate a statistically meaningful decrement in disease-free or overall survival. Similarly, postoperative complications were not associated with inferior DFS or OS. These findings suggest that, when surgery is appropriately indicated and performed, perioperative morbidity and the need for more extensive resections do not independently compromise long-term prognosis in patients with unexpected N1 disease. Instead, oncologic outcomes appear to be primarily dictated by tumor-related factors, particularly nodal burden and pathologic stage, rather than by operative complexity or short-term postoperative events ( 29 ). In a single-centre cohort, researchers found that among cN0 patients upstaged to pN1, 52% of metastases resided in stations 12–14, locations typically beyond the reach of EBUS/EUS; overall, 23.1% of cN0 patients presented occult N1 or N2 disease, underscoring non-ignorable upstaging between clinical and pathological findings. Accordingly, to paper, 50% of patients with occult nodal metastasis had primary tumors ≤ 30 mm, indicating that tumor size alone is insufficient as a surrogate for nodal spread ( 30 ). These observations are concordant with our cohort, in which early-stage tumors (e.g., T1b–T2a) could still present with nodal burden. Although the adverse prognostic impact of increased nodal burden—particularly multistation N1 involvement—has been reported in several studies, this factor has not been systematically evaluated across cohorts, and its clinical relevance therefore requires confirmation through additional supporting evidence ( 31 , 32 ). A potential clarification may involve early lymphovascular dissemination facilitated by permissive tumor–microenvironment interactions; however, this remains speculative and would require further studies directly addressing these pathways ( 12 ). Despite the clear stepwise decline in survival across increasing T categories in our cohort, no meaningful relationship was observed between primary tumor size or local extension and the extent of N1 involvement. Tumors classified as T1b or T2a frequently exhibited multistation N1 metastasis, whereas several T3 lesions demonstrated only single-station disease, indicating that nodal burden in unexpected N1 cases does not follow a size-dependent gradient. This dissociation between T-category and intrathoracic nodal dissemination has been repeatedly emphasized in contemporary N1-focused literature, which suggests that occult N1 metastasis represents a biological phenotype driven more by early lymphovascular invasion and permissive tumor–microenvironmental characteristics than by the anatomical dimensions of the primary tumor. These findings reinforce the growing consensus that the anatomical descriptor of T-category alone is insufficient for anticipating the complexity of N1 disease and should be interpreted alongside detailed nodal mapping when prognosticating or planning management ( 30 ). Another important alignment between our results and the literature concerns the prognostic significance of nodal stations and the survival status. We found that multistation N1 involvement was strongly associated with poor long-term outcomes, conferring a 13-fold increase in recurrence risk and driving 5-year DFS down to 17.8%, compared with 53.2% in single-station disease. This observation also aligns with the previous evidence that the number of involved N1 stations is more prognostically informative than their specific anatomical location. Previous studies examining hilar versus peripheral involvement and single- versus multistation N1 disease have predominantly relied on pathological nodal status, frequently including patients with both clinically positive and clinically negative lymph nodes at presentation. In this context, accumulating evidence suggests that nodal metastases identified only after resection may demonstrate clinical behavior different from that of preoperatively detected nodal disease, particularly at the N2 level. Our findings suggest that a similar clinical consideration may apply to unexpected N1 disease, in which current preoperative staging cannot reliably distinguish limited nodal involvement from multistation metastasis. Although both patterns are clinically occult, they are associated with different postoperative prognostic outcomes ( 3 , 8 ). In contrast to the prognostic impact of multinodal involvement, hilar versus peripheral lymph node involvement demonstrated limited prognostic value in our cohort. Accordingly to our findings prognosis primarily dictated by the number of involved nodal stations rather than by peripheral or hilar location per se. This lack of prognostic discrimination supports the growing argument that anatomical distinctions within N1 disease should not be overemphasized unless they are anchored to quantifiable patterns of tumor dissemination ( 10 ). The prognostic significance of pleural invasion represented another important observation in our study. Visceral pleural involvement was strongly associated with both recurrence and mortality on univariate analysis and retained independent prognostic value for overall survival in multivariate modeling. This finding is consistent with prior reports demonstrating the adverse impact of pleural invasion irrespective of lymph node status. These results suggest that pleural involvement may interact with nodal disease in shaping long-term prognosis, warranting careful consideration in postoperative risk stratification ( 33 ). Although several variables demonstrated prognostic relevance on univariate analysis, only advanced pathologic stage, nodal burden, and pleural invasion retained independent significance after multivariable adjustment, reinforcing the hierarchical dominance of these factors in long-term disease control. The lack of prognostic impact from nodal zone, extent of resection, or postoperative complications further supports the concept that anatomical and technical considerations alone are insufficient to capture the heterogeneity of N1 disease. Collectively, these findings highlight the central role of detailed nodal assessment and refined biologic risk stratification in improving prognostication and may inform future efforts to optimize staging frameworks and postoperative management strategies for this distinct patient population. CONCLUSION Unexpected N1 metastasis in clinically node-negative NSCLC should not be viewed solely as a result of limitations in preoperative staging. In this study, occult N1 disease demonstrated clear prognostic heterogeneity, with multistation nodal involvement emerging as the strongest determinant of survival for this patient group, while pleural invasion independently predicted overall survival. Survival decreased progressively with advancing pathological stage, suggesting that postoperative outcomes in this setting are determined mainly by tumor biology and nodal burden rather than by resection extent or postoperative morbidity. These findings suggest that detailed pathological evaluation of N1 disease, particularly in terms of nodal burden, may enhance postoperative risk stratification and contribute to the refinement of future staging and treatment strategies in this distinct patient subgroup. Abbreviations AI – artificial intelligence cN – clinical nodal status CI – confidence interval CT – computed tomography DFS – disease-free survival DLCO – diffusing capacity of the lung for carbon monoxide EBUS/EUS – endobronchial ultrasound / endoscopic ultrasound FDG – fluorodeoxyglucose FEV1 – forced expiratory volume in 1 second HR – hazard ratio IASLC – International Association for the Study of Lung Cancer N0 – no regional lymph node metastasis N1 – ipsilateral peribronchial and/or hilar and intrapulmonary lymph node metastasis N2 –mediastinal and/or subcarinal lymph node metastasis NSCLC – non–small cell lung cancer OS – overall survival pN – pathological nodal status PET/CT – positron emission tomography/computed tomography PL – pleural invasion (PL0–PL3) SPSS – Statistical Package for the Social Sciences TNM-9 – Tumor–Node–Metastasis classification, 9th edition Declarations Ethics approval and consent to participate The study had ethical approval from the Istanbul University Istanbul Faculty of Medicine Clinical Research Ethics Committee (Decision No: 3095252, 2024/1023). Consent for publication Not applicable, as the manuscript does not contain any individual person’s data in any form. Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due to ethical and privacy considerations but are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author contributions: Conceptualization and study design: A.S., B.O., M.K.; Data collection and curation: A.S., B.K., B.O.; Statistical analysis and data interpretation: A.S., M.K., S.D.; Manuscript drafting: A.S., B.O.; Critical revision of the manuscript for important intellectual content: B.O., M.K., A.T.; Supervision and final approval: A.S., B.K., B.O. All authors read and approved the final version of the manuscript. 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Efficiency and safety of neoadjuvant PD-1 inhibitor (penpulimab) combined with chemotherapy in resectable N1/N2 nonsmall cell lung cancer: a prospective cohort study. (1743–9159 (Electronic)). John AO, Ramnath N. Neoadjuvant Versus Adjuvant Systemic Therapy for Early-Stage Non-Small Cell Lung Cancer: The Changing Landscape Due to Immunotherapy. (1549-490X (Electronic)). Abdallat M, Leo RT, Sugarbaker EA, McAllister M, Xie Y, Mazzola E et al. Segmentectomy vs Lobectomy for Occult N1 in Non-Small Cell Lung Cancer: Is Less More? LID - S0003-4975(25)00725-8 [pii] LID – 10.1016/j.athoracsur.2025.07.020 [doi]. (1552–6259 (Electronic)). Bowes KA-O, Jovanoski N, Brown AE, Di Maio D, Belleli R, Chadda S, Abogunrin S. Treatment patterns and survival of patients with locoregional recurrence in early-stage NSCLC: a literature review of real-world evidence. (1559-131X (Electronic)). Ryuko T, Okazaki M, Mitsuhashi T, Suzawa K, Shien K, Ueno T et al. Comparable Clinical Outcomes Between Segmentectomy and Lobectomy for NSCLC With Unsuspected N1/N2: A Multicenter Real-World Data Study. (1552–6259 (Electronic)). Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in Lung Cancer: Current Landscape and Future Directions. (1664–3224 (Electronic)). Kawamoto NA-O, Tsutani YA-O, Kamigaichi AA-O, Ohsawa M, Mimae TA-O, Miyata Y, Okada MA-O. Tumour location predicts occult N1 nodal metastasis in clinical stage I non-small-cell lung cancer. LID - ezac575 [pii] LID – 10.1093/ejcts/ezac575 [doi]. (1873-734X (Electronic)). Yoon DW, Kang D, Jeon YJ, Lee J, Shin S, Cho JH et al. Computed tomography characteristics of cN0 primary non-small cell lung cancer predict occult lymph node metastasis. (1432 – 1084 (Electronic)). Kurose Y, Azuma Y, Iyoda A, Tochigi N. Prognostic impact based on tumor diameter of pathological N1 lymph node metastases for non-small cell lung cancer. (2072 – 1439 (Print)). Yu L, Xu J, Qiao R, Han B, Zhong H, Zhong R. Pathological Stage N1 Limited-Stage Small-Cell Lung Cancer Patients Can Benefit From Surgical Resection. (1938 – 0690 (Electronic)). Bai GA-O, Chen X, Peng Y, Ji Y, Bie F, Liu Y et al. Surgery challenges and postoperative complications of lung cancer after neoadjuvant immunotherapy. (1759–7714 (Electronic)). Beyaz F, Verhoeven RLJ, Schuurbiers OCJ, Verhagen A, van der Heijden E. Occult lymph node metastases in clinical N0/N1 NSCLC; A single center in-depth analysis. (1872–8332 (Electronic)). Hegde P, Molina JC, Thivierge-Southidara M, Jain RV, Gowda A, Ferraro P, Liberman M. Combined Endosonographic Mediastinal Lymph Node Staging in Positron Emission Tomography and Computed Tomography Node-Negative Non-Small-Cell Lung Cancer in High-Risk Patients. (1532–9488 (Electronic)). Gao SJ, Kim AW, Puchalski JT, Bramley K, Detterbeck FC, Boffa DJ, Decker RH. Indications for invasive mediastinal staging in patients with early non-small cell lung cancer staged with PET-CT. (1872–8332 (Electronic)). Tanju S, Erus S, Selçukbiricik F, İliaz S, Kapdağlı M, Bulutay P et al. Level of pleural invasion effects on prognosis in lung cancer. (2038–2529 (Electronic)). Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 23 Apr, 2026 Reviewers agreed at journal 08 Apr, 2026 Reviewers invited by journal 05 Apr, 2026 Editor invited by journal 02 Apr, 2026 Editor assigned by journal 09 Mar, 2026 Submission checks completed at journal 09 Mar, 2026 First submitted to journal 09 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8965130","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":619587482,"identity":"c0e3c1b9-7d75-4d26-80f4-2a05085a2e2a","order_by":0,"name":"Arda Sarıgül","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIie3QsUrEMBzH8X8pOAVcI4fJEwgphePg5B7DOUVIlh4IwuHYScd7gA6+guWgc46s8eaCi7c4t4PQ0aQHHoLNrYL5Qmko/fCjBQiF/mgKYObuzF4xGZ68nyb4m6TDE3566Eiywh19hD697refjxjOS121UT6Xzzd6b1cW5Kr4nTAjmb60BO/EPY5quazeBLPkNp2qEQIC9IUlYBCzRC+rkjuisnqE0PXHgVCD0t4SmZSy9RJoBGw7S5hBU7fC6ST3r7DGrsAOo8ScrWZZLZOXSX6nOBv/FroWcdevrgkx8abp6jmlpdy07cOCjBFXjADQcOJuVx1+i7eo/7Fb+N8OhUKh/9cXZYpe/Cv9cKUAAAAASUVORK5CYII=","orcid":"","institution":"Istanbul University","correspondingAuthor":true,"prefix":"","firstName":"Arda","middleName":"","lastName":"Sarıgül","suffix":""},{"id":619587483,"identity":"4a1b65a1-ff2f-468c-bdec-fd7c1f3e661e","order_by":1,"name":"Salih Duman","email":"","orcid":"","institution":"Istanbul University","correspondingAuthor":false,"prefix":"","firstName":"Salih","middleName":"","lastName":"Duman","suffix":""},{"id":619587484,"identity":"f01dda4d-ff69-49c5-84d4-a8e2b1ac2910","order_by":2,"name":"Berna Karataş","email":"","orcid":"","institution":"Istanbul University","correspondingAuthor":false,"prefix":"","firstName":"Berna","middleName":"","lastName":"Karataş","suffix":""},{"id":619587485,"identity":"8076f7af-9c88-4bd0-93e6-017c2359beb8","order_by":3,"name":"Adalet Demir","email":"","orcid":"","institution":"Istanbul University","correspondingAuthor":false,"prefix":"","firstName":"Adalet","middleName":"","lastName":"Demir","suffix":""},{"id":619587486,"identity":"5a5f4034-fd61-4748-8cf9-3303e2df7439","order_by":4,"name":"Murat Kara","email":"","orcid":"","institution":"Istanbul University","correspondingAuthor":false,"prefix":"","firstName":"Murat","middleName":"","lastName":"Kara","suffix":""},{"id":619587487,"identity":"93062fc9-7ac7-47b1-8c52-1b4c2911a98e","order_by":5,"name":"Seyfi Alper Toker","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Seyfi","middleName":"Alper","lastName":"Toker","suffix":""},{"id":619587488,"identity":"ef31da0f-7dc1-4d79-b7cf-1a5f22dd5b08","order_by":6,"name":"Berker Özkan","email":"","orcid":"","institution":"Istanbul University","correspondingAuthor":false,"prefix":"","firstName":"Berker","middleName":"","lastName":"Özkan","suffix":""}],"badges":[],"createdAt":"2026-02-25 08:24:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8965130/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8965130/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106545418,"identity":"aadc8e94-bacb-4ff0-b515-65d2c70214f5","added_by":"auto","created_at":"2026-04-09 16:45:48","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":90814,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier overall survival and disease-free survival curves stratified by pathological stage in patients with unexpected N1 disease. (a) Overall survival curves according to pathological stage (IIA, IIB, and IIIA). (b) Disease-free survival curves according to pathological stage (IIA, IIB, and IIIA). Survival differences were assessed using the log-rank test.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8965130/v1/c9335d9987106fd101e660ba.jpg"},{"id":106724987,"identity":"bc4b0131-300b-4abe-a898-f88db5fc2323","added_by":"auto","created_at":"2026-04-12 18:30:53","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":87335,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier overall survival and disease-free survival curves comparing single-station and multistation N1 involvement in patients with unexpected N1 disease. (a) Overall survival curves according to nodal burden. (b) Disease-free survival curves according to nodal burden. Survival comparisons were performed using the log-rank test.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8965130/v1/cebcc783408e2d35beb8fcd1.jpg"},{"id":107705048,"identity":"2df98f2a-cf6b-409f-bff4-74bbc6ae5d6b","added_by":"auto","created_at":"2026-04-24 09:07:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":382618,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8965130/v1/a4cea6f8-807d-4ef6-895c-9f0eb93e8e29.pdf"},{"id":106725306,"identity":"229eb362-fb95-4b48-ac80-130d4e45b138","added_by":"auto","created_at":"2026-04-12 18:32:20","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22373,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8965130/v1/0aa89d51c9bfae8b5a81db5a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Occult Hilar and Intrapulmonary Nodal Metastasis in Non-Small Cell Lung Cancer After Anatomical Resection","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLymph node involvement remains one of the cornerstones of staging and prognosis in non\u0026ndash;small cell lung cancer (NSCLC), yet the clinical significance of N1 metastasis has received relatively limited attention (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The TNM-9 classification, much like earlier editions, continues to emphasize all subgroups of N1 disease into a single category, despite the previous studies suggesting heterogenity and survival differences within this patient group (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Also proposal studies for staging suggest a better understanding of characteristic variability may help redefine prognostic assessment and inform future revisions of the staging system (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInvasive and imaging-based staging techniques have improved over the years but the preoperative evaluation of N1 lymph nodes shows considerable variability among published studies (\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). As a result, some patients undergo surgery with completely negative radiologic or invasive findings but are later found to exhibit N1 metastasis on final pathology. This group matters clinically, since knowing about nodal disease beforehand could alter several aspects of management, such as how patients preoperative planing such as neo-adjuvant therapy requirement, the extent or approach of the operation, and the planning of postoperative adjuvant therapy (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe biological and prognostic significance of unexpected N1 involvement remains insufficiently characterized (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). It is not clear whether these occult nodal metastases are only the result of the limited sensitivity towards certain micrometastases or whether they represent a separate pathological pattern with different survival outcomes (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Assumably the usual prognostic patterns observed in the subgroups of N1-metastatic patients also apply to those with unexpected N1 metastasis remains unclear (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, we aimed to analyze the prognostic implications of N1 lymph node metastases that were not detected by preoperative radiological or invasive staging\u0026mdash;designated as unexpected N1 disease (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Specifically, we aimed to determine whether survival differed across the subgroup analyses within this unique cohort and to evaluate the impact of additional pathological features on long-term clinical outcomes.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis retrospective cohort study included patients who underwent anatomical lung resection for primary lung carcinoma at the Department of Thoracic Surgery, Istanbul University, Istanbul Faculty of Medicine, between January 2018 and November 2024. Among a total of 1,134 patients who underwent anatomical pulmonary resection, 94 had complete clinical and pathological records, provided written informed consent for scientific use of their anonymized clinical data and fulfilled all eligibility criteria; these patients constituted the study population. The study had ethical approval from the Istanbul University Istanbul Faculty of Medicine Clinical Research Ethics Committee (Decision No: 3095252, 2024/1023). All procedures were conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eAll patients underwent standardized preoperative evaluation, including pulmonary function testing, cardiopulmonary assessment, and appropriate staging investigations, in accordance with international guidelines(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Operability and surgical candidacy were determined by a multidisciplinary thoracic oncology board before operative planning.\u003c/p\u003e \u003cp\u003eWe include the patients who underwent lobectomy, sleeve lobectomy, or pneumonectomy for suspected or histologically confirmed primary non\u0026ndash;small cell lung cancer (NSCLC). All patients underwent preoperative evaluation with high-resolution computed tomography and FDG-PET/CT (18-F-fluorodeoxyglucose positron emission tomography). Lymph nodes at the hilar and mediastinal stations were considered clinically negative when the short-axis diameter was less than 10 mm on high-resolution CT and when no pathological FDG uptake was observed on FDG-PET/CT. Final pathological analysis was required to confirm N1 metastasis in stations 10\u0026ndash;14 according to the IASLC lymph node map(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Uneligible patients (n: 1,040) were excluded according to predefined criteria. Patients who had received neoadjuvant therapy were excluded to ensure cohort homogeneity (n\u0026thinsp;=\u0026thinsp;103). Additional exclusions included incomplete clinical, pathological, or survival data (n\u0026thinsp;=\u0026thinsp;116); preoperative distant metastasis (M1a-b), benign pathology, previous lung malignancy, or metastasectomy for another primary tumor (n\u0026thinsp;=\u0026thinsp;36); sublobar or non-anatomical resections (n\u0026thinsp;=\u0026thinsp;12); and early non-informative postoperative mortality within 90 days (n\u0026thinsp;=\u0026thinsp;3). Following pathological assessment, patients with pathological N0 disease (n\u0026thinsp;=\u0026thinsp;732) or pathological N2 metastasis (n\u0026thinsp;=\u0026thinsp;38) were also excluded to isolate cases of unexpected N1 involvement. Patients who were medically ineligible for guideline-recommended adjuvant therapy were excluded, as uniform receipt of standard postoperative treatment was required for inclusion (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). All patients in the final cohort received adjuvant therapy appropriate to their pathological stage (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSurgical procedures were carried out either with video-assisted thoracoscopic surgery or with a standard open thoracotomy, depending on routine practice at our center. A systematic dissection of the hilar and intrapulmonary lymph nodes was done in all patients. According to the IASLC lymph node map, stations 10 and 11 were considered hilar\u0026ndash;central N1, while stations 12 to 14 were accepted as peripheral N1. Patients with metastasis limited to only one of 10-11-12-13-14 stations were classified as single-station N1, and those with involvement of more than one were classified as multi-station N1(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Single-station lymph node involvement was stratified into two subgroups\u0026mdash;hilar and peripheral\u0026mdash;for subgroup anaylsis. Overall survival (OS) and disease-free survival (DFS) were subsequently evaluated and compared between these two groups.\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using SPSS version 31.0 (IBM Corporation, Chicago, IL, USA) and Microsoft Excel version 16.0 (Microsoft Corporation, Redmond, WA, USA). Normality of continuous variables was evaluated using histogram inspection and the Kolmogorov\u0026ndash;Smirnov test. Continuous variables were summarized using means, medians, and standard deviations, whereas categorical variables were presented as counts and percentages. Survival curves were generated using the Kaplan\u0026ndash;Meier method, and comparisons between groups were conducted with the log-rank test. Variables that demonstrated statistical significance at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in univariate analyses were entered into multivariate Cox proportional hazards modeling to assess independent predictors of survival. Continuous variables were compared using the Student\u0026rsquo;s t-test or the Mann\u0026ndash;Whitney U test depending on distribution, and categorical variables were compared with the chi-square test. The median follow-up duration was 57 months, with a range of 6 to 208 months.\u003c/p\u003e \u003cp\u003eNo AI tools were used for data generation, statistical analysis, patient identification, or image interpretation. All clinical data extraction and statistical analyses were performed manually by the authors.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe median age of the cohort was 61 years (range, 44–77 years), and 87.2% were male. Smoking history was present in 90.4% of the cohort. Preoperative respiratory function tests revealed a mean FEV1 of 2404 ± 613 mL/min (83.9 ± 17.8% predicted), and a mean predicted DLCO of 83.7 ± 19.0% in the overall cohort. Radiological assessment demonstrated that 38 patients (40.4%) had right-sided tumors, 56 patients (59.6%) had left-sided lesions. Most frequently located in the left upper lobe (35.1%) and right upper lobe (26.6%). The distribution across other lobes was as follows: left lower lobe in 24.5%, right lower lobe in 10.6%, and right middle lobe in 3.2% of patients. Invasive mediastinal staging with cervical mediastinoscopy was undertaken in 19.1% of the cohort (n = 18). The most common surgical procedures were left upper lobectomy (20.2%), left pneumonectomy (17.0%), and right upper lobectomy (13.8%). Pneumonectomy was required in 16 left-sided cases (17.0%), whereas other procedures such as bilobectomy and right middle lobectomy constituted smaller proportions of the cohort. Systematic hilar and intrapulmonary lymphadenectomy yielded a median of 14 (6–28) nodes. The median number of dissected N1 lymph nodes was highest in patients undergoing right lower lobectomy (8 ± 5.5), followed by right pneumonectomy (7 ± 4.5). Most common postoperative complications were nosocomial pneumonia in 7.8% of patients and atrial fibrillation in 3.6%. Survival analysis demonstrated no significant effect of demographic variables, as patients aged ≤ 60 years showed a 5-year DFS of 42.60% and OS of 51.30%, compared with 48.00% and 56.30%, respectively, in older patients (p = 0.65 and p = 0.29). Sex similarly did not influence outcomes, with men achieving a 5-year DFS of 43.70% and OS of 52.40%, and women 57.10% and 63.50% (p = 0.62 and p = 0.94). Smoking exposure did not stratify survival, as patients with ≤ 43 pack-years had a 5-year DFS of 37.70% and OS of 47.60%, compared with 57.90% and 63.30% in heavier smokers (p = 0.48 and p = 0.52). Patinetns with FEV1 values above 2,404 mL demonstrated superior overall survival (p = 0.04).\u003c/p\u003e\n\u003cp\u003eOperative factors did not significantly influence long-term outcomes. Patients undergoing pneumonectomy achieved a 5-year DFS of 43.50% and OS of 47.80%, similar to those receiving lesser resections (52.00% and 53.10%, p = 0.71 and p = 0.45). Extended resections performed for accomplish tumor-free origin related with lower 5-year DFS (24.20%) compared with standard procedures (48.50%), but without statistical significance (p = 0.15). Perioperative complications were also not prognostic, as patients with complications had DFS and OS rates of 41.70% and 51.70%, compared with 48.90% and 55.60% in uncomplicated cases (p = 0.85 and p = 0.79). The associations between clinicopathological variables and both disease-free survival (DFS) and overall survival (OS) are presented in Table 1.\u003c/p\u003e\n\u003cp\u003eT-category showed a stepwise decline in prognosis, with 5-year DFS and OS of 100.00% / 100.00% in T1a, 57.10% / 70.70% in T1b, 48.90% / 50.80% in T2a, 40.30% / 44.50% in T2b, 21.00% / 34.40% in T3, and 0.00% / 20.00% in T4 disease respectively (p \u0026lt; 0.01). Pleural invasion was absent in 68.1% of patients, while PL1, PL2, and PL3 involvement was observed in 24.5%, 4.3%, and 3.2% of cases, respectively. Five-year DFS decreased progressively with increasing pleural invasion (51.3% for absent, 30.1% for PL1, 25.0% for PL2, and 0% for PL3; p = 0.02). Median survival was 68 months (95% CI: 45.4–90.6) in the absence of pleural invasion, compared with 45 months (95% CI: 21.6–68.4) for PL1 and 12 months (95% CI: 0.0–41.4) for PL2. Five-year OS similarly declined across pleural invasion categories (59.1%, 40.7%, 37.5%, and 0%, respectively; p = 0.02).\u003c/p\u003e\n\u003cp\u003eSquamous cell carcinoma was the most frequent histological subtype (55.3%), followed by adenocarcinoma (36.2%), while adenosquamous carcinoma was rare (4.3%). Five-year disease-free survival (DFS) was similar between adenocarcinoma and squamous cell carcinoma (46.1% vs. 47.5%, respectively), although histological subtype was associated with DFS on overall comparison (p = 0.001). Median DFS was 79 months (95% CI, 51.8–106.2) for adenocarcinoma and 70 months (95% CI, 21.6–118.3) for squamous cell carcinoma. Five-year overall survival (OS) differed significantly according to histology (p \u0026lt; 0.01), with rates of 48.7% for adenocarcinoma, 61.5% for squamous cell carcinoma, and 75.0% for adenosquamous carcinoma.\u003c/p\u003e\n\u003cp\u003eAccording to final TNM stage; patients stage IIA and IIB exhibited substantially more favorable long-term outcomes compared with those staged as IIIA. Five-year DFS rates were 68.6% for stage IIA and 55.6% for stage IIB, whereas stage IIIA patients demonstrated a markedly reduced DFS of 17.3%. A similar pattern was observed for OS, with five-year OS rates of 75.0% in stage IIA, 59.7% in stage IIB, and 37.2% in stage IIIA (p \u0026lt; 0.01). Kaplan–Meier estimates of disease-free and overall survival according to tumor-related determinants are presented in Table 2 and shown on Fig. 1.\u003c/p\u003e\n\u003cp\u003eConsidering the N1 metastasis; patients with single-station N1 disease had markedly better 5-year DFS and OS (53.20% and 59.70%) compared with those with multi-station involvement (17.80% and 27.90%, p = 0.01 and p = 0.05). In contrast, nodal zone had limited prognostic value, as hilar metastasis produced a 5-year DFS of 51.30% and OS of 56.00%, compared with 40.00% and 59.30% for peripheral involvement (p = 0.04 and p = 0.22) (Fig.\u0026nbsp;2). Single-station nodal involvement was observed in 75 patients (79.8%), whereas 19 patients (20.2%) demonstrated multi-station disease. Within the single-station subgroup, hilar involvement (N10–N11) accounted for 63 patients (84.0%), while peripheral involvement (N12–N14) was identified in 12 patients (16.0%). Regarding station-specific distribution in the overall cohort, N10 metastasis was present in 67 patients (71.3%) and absent in 27 (28.7%). N11 involvement was detected in 34 patients (36.2%) and was negative in 60 (63.8%). Peripheral station positivity was less frequent, with N12 involvement in 8 patients (8.5%) and negativity in 86 (91.5%), N13 involvement in 4 patients (4.3%) and negativity in 90 (95.7%), and N14 involvement in 1 patient (1.1%) and negativity in 93 (98.9%). Among the 19 patients with multi-station disease, 18 (94.7%) exhibited concomitant N10 and N11 involvement, and 1 patient (5.3%) demonstrated triple-station positivity involving N10, N11, and N12.\u003c/p\u003e\n\u003cp\u003eExtent and anatomical distribution of N1 nodal metastasis were associated with different survival outcomes. Patients with single-station N1 involvement (n = 75, 79.8%) demonstrated significantly better prognosis than those with multi-station disease (n = 19, 20.2%), with higher 5-year DFS (52.3% vs 17.8%; p = 0.005) and 5-year OS (59.7% vs 27.9%; p = 0.045). Median survival was also longer in the single-station group (79 months, 62.9–95.1) compared with the multi-station group (40 months, 19.3–60.7). Among single-station cases, hilar involvement (N10–11; n = 63, 84.0%) was associated with inferior 5-year DFS compared with peripheral involvement (N12–14; n = 12, 16.0%) (40.0% vs 51.3%; p = 0.036) and a shorter median survival (28 months, 0.0–62.7 vs 74 months, 47.2–100.8). In contrast, 5-year OS did not differ significantly between hilar and peripheral subgroups (56.0% vs 59.3%; p = 0.224).\u003c/p\u003e\n\u003cp\u003eIn univariate Cox regression analysis, multiple tumor and nodal variables showed significant associations with survival. Visceral pleural invasion was one of a predictive of worse outcomes, increasing the risk of recurrence 2.83-fold (95% CI: 1.33–6.02, p = 0.007) and mortality 2.36-fold (95% CI: 1.33–4.18, p = 0.003). Advancing TNM stage also conferred progressively poorer prognosis, with stage IIIA exhibiting a 4.02-fold higher risk of recurrence (95% CI: 1.90–8.47, p \u0026lt; 0.001) and a 2.19-fold higher risk of mortality (95% CI: 1.28–3.74, p = 0.004) compared with stage IIB. Nodal burden was an important determinant of outcome; patients with multistation N1 metastasis had a 3.11-fold increased risk of recurrence (95% CI: 1.51–6.43, p = 0.002) and a borderline increase in mortality (HR 1.92, 95% CI: 1.00–3.70, p = 0.050). In contrast, neither T-category transitions (T2a→T2b→T3) nor nodal zone (hilar vs peripheral) achieved statistical significance for either DFS or OS.\u003c/p\u003e\n\u003cp\u003eOn multivariate analysis, only a limited subset of variables retained independent prognostic significance. TNM stage IIIA remained a strong predictor of both recurrence and mortality, demonstrating a 3.68-fold increased risk of recurrence (95% CI: 1.59–8.52, p = 0.002) and a 2.13-fold increased risk of death (95% CI: 1.26–3.58, p = 0.004) compared with stage IIB. Multistation N1 metastasis remained independently associated with worse DFS, conferring a 13.22-fold increased recurrence risk (95% CI: 1.08–161.17, p = 0.043), although its effect on OS did not meet statistical significance (HR 7.31, p = 0.095). Pleural invasion did not retain significance for DFS (HR 1.50, p = 0.09) but preserved independent prognostic value for OS (HR 1.45, 95% CI: 1.03–2.03, p = 0.034). Univariate and multivariable Cox proportional hazards regression analyses identifying factors associated with disease-free and overall survival are summarized in Table 3.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eUnexpected N1 lymph node metastasis remains a relatively understudied aspect of lung cancer staging, positioned at the interface of tumor biology and the inherent limitations of current preoperative diagnostic methods (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Inaccuracies in preoperative staging may result in the underrecognition of nodal disease, thereby increasing the likelihood that selected patients proceed directly to upfront surgical resection despite potential eligibility for neoadjuvant chemotherapy and/or immunotherapy under contemporary treatment algorithms (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In this context, meticulous pathological examination of resected specimens plays a critical role in achieving accurate postoperative staging, thereby ensuring that patients receive appropriate adjuvant therapy aligned with their true pathological status (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn patients with small, peripheral lung lesions, limitations in both invasive and imaging-based preoperative staging may result in nodal understaging and bias surgical decision-making toward segmentectomy (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In the presence of occult intralobar N1 metastasis, this strategy may confer an increased risk of locoregional recurrence and may further delay or preclude appropriate adjuvant therapy due to false downstaging (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Notably, in our cohort, a considerable number of patients with T1 and T2 tumors would have been eligible for segmentectomy under current criteria, highlighting the potential oncologic implications of preoperative nodal misclassification (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Limitations in preoperative staging may contribute to clinically meaningful heterogenity among patients ultimately classified within the same pathological stage, thereby complicating postoperative risk stratification and the interpretation of survival outcomes (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, we evaluated a carefully selected cohort of patients who were clinically staged as N0, exhibited no radiologic or invasive evidence of nodal involvement, yet were subsequently found to have pathological N1 metastasis. Our findings, despite certain differences compared with previously published reports, may contribute to the expanding body of literature suggesting that occult N1 metastasis represents more than a simple limitation of preoperative staging. Rather, it constitutes a prognostically distinct subgroup with implications for clinical decision-making and future refinements of staging systems (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Despite negative preoperative imaging and invasive assessments, prognostic stratification according to T category, overall TNM stage, and nodal burden remained consistently preserved, in line with previous literature describing the dominant prognostic role of pathological nodal status (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Survival stratification in our cohort, with stepwise reductions in 5-year DFS and OS across increasing T category and overall stage, was consistent with patterns described in clinically recognized N1 populations. These findings indicate prognostic behaviour analogous to overt N1 disease, despite preoperative nodal underrecognition (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor the cohort, the extent of surgical resection or postoperative complications did not exert a significant influence on long-term outcomes. Patients who underwent pneumonectomy had survival comparable to that achieved with lesser resections, and extended procedures performed for local invasion did not demonstrate a statistically meaningful decrement in disease-free or overall survival. Similarly, postoperative complications were not associated with inferior DFS or OS. These findings suggest that, when surgery is appropriately indicated and performed, perioperative morbidity and the need for more extensive resections do not independently compromise long-term prognosis in patients with unexpected N1 disease. Instead, oncologic outcomes appear to be primarily dictated by tumor-related factors, particularly nodal burden and pathologic stage, rather than by operative complexity or short-term postoperative events (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn a single-centre cohort, researchers found that among cN0 patients upstaged to pN1, 52% of metastases resided in stations 12\u0026ndash;14, locations typically beyond the reach of EBUS/EUS; overall, 23.1% of cN0 patients presented occult N1 or N2 disease, underscoring non-ignorable upstaging between clinical and pathological findings. Accordingly, to paper, 50% of patients with occult nodal metastasis had primary tumors\u0026thinsp;\u0026le;\u0026thinsp;30 mm, indicating that tumor size alone is insufficient as a surrogate for nodal spread (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). These observations are concordant with our cohort, in which early-stage tumors (e.g., T1b\u0026ndash;T2a) could still present with nodal burden. Although the adverse prognostic impact of increased nodal burden\u0026mdash;particularly multistation N1 involvement\u0026mdash;has been reported in several studies, this factor has not been systematically evaluated across cohorts, and its clinical relevance therefore requires confirmation through additional supporting evidence (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). A potential clarification may involve early lymphovascular dissemination facilitated by permissive tumor\u0026ndash;microenvironment interactions; however, this remains speculative and would require further studies directly addressing these pathways (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite the clear stepwise decline in survival across increasing T categories in our cohort, no meaningful relationship was observed between primary tumor size or local extension and the extent of N1 involvement. Tumors classified as T1b or T2a frequently exhibited multistation N1 metastasis, whereas several T3 lesions demonstrated only single-station disease, indicating that nodal burden in unexpected N1 cases does not follow a size-dependent gradient. This dissociation between T-category and intrathoracic nodal dissemination has been repeatedly emphasized in contemporary N1-focused literature, which suggests that occult N1 metastasis represents a biological phenotype driven more by early lymphovascular invasion and permissive tumor\u0026ndash;microenvironmental characteristics than by the anatomical dimensions of the primary tumor. These findings reinforce the growing consensus that the anatomical descriptor of T-category alone is insufficient for anticipating the complexity of N1 disease and should be interpreted alongside detailed nodal mapping when prognosticating or planning management (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnother important alignment between our results and the literature concerns the prognostic significance of nodal stations and the survival status. We found that multistation N1 involvement was strongly associated with poor long-term outcomes, conferring a 13-fold increase in recurrence risk and driving 5-year DFS down to 17.8%, compared with 53.2% in single-station disease. This observation also aligns with the previous evidence that the number of involved N1 stations is more prognostically informative than their specific anatomical location. Previous studies examining hilar versus peripheral involvement and single- versus multistation N1 disease have predominantly relied on pathological nodal status, frequently including patients with both clinically positive and clinically negative lymph nodes at presentation. In this context, accumulating evidence suggests that nodal metastases identified only after resection may demonstrate clinical behavior different from that of preoperatively detected nodal disease, particularly at the N2 level. Our findings suggest that a similar clinical consideration may apply to unexpected N1 disease, in which current preoperative staging cannot reliably distinguish limited nodal involvement from multistation metastasis. Although both patterns are clinically occult, they are associated with different postoperative prognostic outcomes (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn contrast to the prognostic impact of multinodal involvement, hilar versus peripheral lymph node involvement demonstrated limited prognostic value in our cohort. Accordingly to our findings prognosis primarily dictated by the number of involved nodal stations rather than by peripheral or hilar location per se. This lack of prognostic discrimination supports the growing argument that anatomical distinctions within N1 disease should not be overemphasized unless they are anchored to quantifiable patterns of tumor dissemination (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe prognostic significance of pleural invasion represented another important observation in our study. Visceral pleural involvement was strongly associated with both recurrence and mortality on univariate analysis and retained independent prognostic value for overall survival in multivariate modeling. This finding is consistent with prior reports demonstrating the adverse impact of pleural invasion irrespective of lymph node status. These results suggest that pleural involvement may interact with nodal disease in shaping long-term prognosis, warranting careful consideration in postoperative risk stratification (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough several variables demonstrated prognostic relevance on univariate analysis, only advanced pathologic stage, nodal burden, and pleural invasion retained independent significance after multivariable adjustment, reinforcing the hierarchical dominance of these factors in long-term disease control. The lack of prognostic impact from nodal zone, extent of resection, or postoperative complications further supports the concept that anatomical and technical considerations alone are insufficient to capture the heterogeneity of N1 disease. Collectively, these findings highlight the central role of detailed nodal assessment and refined biologic risk stratification in improving prognostication and may inform future efforts to optimize staging frameworks and postoperative management strategies for this distinct patient population.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eUnexpected N1 metastasis in clinically node-negative NSCLC should not be viewed solely as a result of limitations in preoperative staging. In this study, occult N1 disease demonstrated clear prognostic heterogeneity, with multistation nodal involvement emerging as the strongest determinant of survival for this patient group, while pleural invasion independently predicted overall survival. Survival decreased progressively with advancing pathological stage, suggesting that postoperative outcomes in this setting are determined mainly by tumor biology and nodal burden rather than by resection extent or postoperative morbidity. These findings suggest that detailed pathological evaluation of N1 disease, particularly in terms of nodal burden, may enhance postoperative risk stratification and contribute to the refinement of future staging and treatment strategies in this distinct patient subgroup.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAI \u0026ndash; artificial intelligence\u003c/p\u003e\n\u003cp\u003ecN \u0026ndash; clinical nodal status\u003c/p\u003e\n\u003cp\u003eCI \u0026ndash; confidence interval\u003c/p\u003e\n\u003cp\u003eCT \u0026ndash; computed tomography\u003c/p\u003e\n\u003cp\u003eDFS \u0026ndash; disease-free survival\u003c/p\u003e\n\u003cp\u003eDLCO \u0026ndash; diffusing capacity of the lung for carbon monoxide\u003c/p\u003e\n\u003cp\u003eEBUS/EUS \u0026ndash; endobronchial ultrasound / endoscopic ultrasound\u003c/p\u003e\n\u003cp\u003eFDG \u0026ndash; fluorodeoxyglucose\u003c/p\u003e\n\u003cp\u003eFEV1 \u0026ndash; forced expiratory volume in 1 second\u003c/p\u003e\n\u003cp\u003eHR \u0026ndash; hazard ratio\u003c/p\u003e\n\u003cp\u003eIASLC \u0026ndash; International Association for the Study of Lung Cancer\u003c/p\u003e\n\u003cp\u003eN0 \u0026ndash; no regional lymph node metastasis\u003c/p\u003e\n\u003cp\u003eN1 \u0026ndash; ipsilateral peribronchial and/or hilar and intrapulmonary lymph node metastasis\u003c/p\u003e\n\u003cp\u003eN2 \u0026ndash;mediastinal and/or subcarinal lymph node metastasis\u003c/p\u003e\n\u003cp\u003eNSCLC \u0026ndash; non\u0026ndash;small cell lung cancer\u003c/p\u003e\n\u003cp\u003eOS \u0026ndash; overall survival\u003c/p\u003e\n\u003cp\u003epN \u0026ndash; pathological nodal status\u003c/p\u003e\n\u003cp\u003ePET/CT \u0026ndash; positron emission tomography/computed tomography\u003c/p\u003e\n\u003cp\u003ePL \u0026ndash; pleural invasion (PL0\u0026ndash;PL3)\u003c/p\u003e\n\u003cp\u003eSPSS \u0026ndash; Statistical Package for the Social Sciences\u003c/p\u003e\n\u003cp\u003eTNM-9 \u0026ndash; Tumor\u0026ndash;Node\u0026ndash;Metastasis classification, 9th edition\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study had ethical approval from the Istanbul University Istanbul Faculty of Medicine Clinical Research Ethics Committee (Decision No: 3095252, 2024/1023). \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable, as the manuscript does not contain any individual person\u0026rsquo;s data in any form.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to ethical and privacy considerations but are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization and study design: A.S., B.O., M.K.;\u003c/p\u003e\n\u003cp\u003eData collection and curation: A.S., B.K., B.O.;\u003c/p\u003e\n\u003cp\u003eStatistical analysis and data interpretation: A.S., M.K., S.D.;\u003c/p\u003e\n\u003cp\u003eManuscript drafting: A.S., B.O.;\u003c/p\u003e\n\u003cp\u003eCritical revision of the manuscript for important intellectual content: B.O., M.K., A.T.;\u003c/p\u003e\n\u003cp\u003eSupervision and final approval: A.S., B.K., B.O.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final version of the manuscript.\u003c/p\u003e\n\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the staff of the Department of Thoracic Surgery, Istanbul University Istanbul Faculty of Medicine, for their support in patient management and data collection.\u003cbr clear=\"all\"\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDetterbeck FC, Woodard GA, Bader AS, Dacic S, Grant MJ, Park HS, Tanoue LT. 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(2038\u0026ndash;2529 (Electronic)).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hilar lymph nodes, NSCLC, Occult metastases, Long-term survival","lastPublishedDoi":"10.21203/rs.3.rs-8965130/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8965130/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackround:\u003c/p\u003e\n\u003cp\u003eHilar and pulmonary lymph node metastases are key determinants of prognosis in primary lung cancer. Despite advances in imaging and staging, the prognostic implications of N1 disease undetected during preoperative assessment remain poorly defined. This study evaluates patients with pathologically confirmed but preoperatively occult N1 metastases, focusing on survival outcomes and clinicopathological features, and explores their potential implications for prognostic stratification and future staging refinement.\u003c/p\u003e\n\u003cp\u003eMethods:\u003c/p\u003e\n\u003cp\u003eData retrieved from 94 patients who underwent anatomical surgical resection for primary lung carcinoma between 2008 and 2024 and clinically, N0 were found to have N1 lymph node metastases on final pathology. Preoperative workup included both non-invasive and invasive staging.\u003c/p\u003e\n\u003cp\u003eResults:\u003c/p\u003e\n\u003cp\u003eAmong patients with single-station N1 involvement, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.2% and 59.7%, respectively — significantly better than those with multi-station disease (DFS: 17.8%, OS: 27.9%; p = p \u0026lt; 0.05 and p \u0026lt; 0.05). Stage IIA and IIB patients showed relatively favorable survival, while Stage IIIA patients had markedly poorer 5-year DFS and OS (p \u0026lt; 0.01). Univariate analysis confirmed that multi-station N1 involvement was associated with significantly worse prognosis, a finding that remained consistent in multivariate models as well.\u003c/p\u003e\n\u003cp\u003eConclusion:\u003c/p\u003e\n\u003cp\u003eMultistation N1 involvement emerged as the strongest determinant of disease recurrence, while pleural invasion independently predicted overall survival. These findings indicate that unexpected N1 disease represents a biologically meaningful subgroup rather than a mere consequence of staging limitations and underscore the importance of detailed pathological nodal assessment for postoperative risk stratification and therapeutic decision-making.\u003c/p\u003e\n\u003cp\u003eOccult Hilar and Intrapulmonary Nodal Metastasis in Non-Small Cell Lung Cancer After Resection\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable.\u003c/p\u003e","manuscriptTitle":"Occult Hilar and Intrapulmonary Nodal Metastasis in Non-Small Cell Lung Cancer After Anatomical Resection","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-09 16:45:38","doi":"10.21203/rs.3.rs-8965130/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-23T13:48:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93731251639135619758696927695726469091","date":"2026-04-08T09:29:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-05T20:17:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-02T21:04:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-09T10:47:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-09T08:27:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2026-03-09T07:53:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e5fbb512-16a8-48de-9f9e-4f5b8082bffe","owner":[],"postedDate":"April 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-09T16:45:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-09 16:45:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8965130","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8965130","identity":"rs-8965130","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}