The Potential of NTR Value in Primary Lung Cancer to Predict Lymphovascular Invasion: A Retrospective Study

The Potential of NTR Value in Primary Lung Cancer to Predict Lymphovascular Invasion: A Retrospective Study | 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 The Potential of NTR Value in Primary Lung Cancer to Predict Lymphovascular Invasion: A Retrospective Study MERAL MERVE URUNGA This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8353396/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim This retrospective study aims to improve preoperative conventional imaging and assessment criteria for non-small cell lung cancer cases eligible for surgery and to enhance the surgical and clinical approach to patients through reliable preoperative staging. Materials and Methods A group of 574 patients who attended the Thoracic Surgery outpatient clinic at Cukurova University Balcalı Training and Research Hospital between 2012 and 2022 and were investigated for suspected lung cancer or diagnosed with lung cancer were retrospectively examined. T SUVmax (primary tumour SUVmax), N SUVmax (mediastinal lymph node SUVmax) and NTR (node to tumor SUVmax ratio), correlated with clinical Tumor (T)-Node (N)-Metastasis (M) staging, were recorded and compared with histopathological findings of lymphovascular invasion of the tumour. Results In the 574 NSCLC patients included in the study, the ratio of the SUVmax value of the lymph node with the highest metabolic activity detected in the mediastinum to the SUVmax value of the primary lesion (node-to-tumour SUVmax, NTR) was examined, and this ratio was found to have significant potential for predicting lymphovascular invasion (AUC: 73.1 and 71% sensitivity, 74% specificity for a cut-off value of 0.79). Conclusion The NTR value from metabolic parameters in F-18 FDG PET/CT can be used to evaluate the primary lesion for lymphovascular invasion in the preoperative period in NSCLC. Nuclear Medicine & Medical Imaging Oncology NSCLC F-18 FDG PET-CT lymphovascular invasion NTR Figures Figure 1 INTRODUCTION Among conventional imaging systems, low-dose CT is the first-line diagnostic method for pulmonary nodule screening in guidelines for the early detection of primary lung cancer ( 1 ). Confirming and evaluating lesions suspected of cancer using PET-based imaging yields more reliable results in terms of diagnosis and staging. ( 2 ) In addition, it is a strong determinant in nodal staging and treatment management ( 3 ). Surgery is the primary treatment in the group of patients with small-stage disease ( 4 ). Demonstration of N2 disease with preoperative F-18 FDG PET/CT scanning requires confirmation with more invasive methods and identifies the group of patients eligible for neoadjuvant therapy ( 5 ). The SUVmax value, a metabolic parameter in F-18 FDG PET/CT, shows a positive correlation with malignancy potential in the diagnosis of lung cancer ( 6 ). FDG uptake via the tumour's GLUT-1 pathway is also related to histological grade ( 7 ). Cerfolio et. al ( 8 ), stage-specific T SUVmax analyses revealed that stage IB and stage II NSCLC cases with T SUVmax values higher than the median value had lower 4-year survival.This information indicated that the tumour-specific SUVmax value was a stronger potential prognostic factor than the TNM staging system in terms of recurrence and survival. Nambu et. al, ( 9 ) examined the relationship between lymph node metastases and pathological subtypes of lung cancer and they found that lymph node metastasis was significantly more frequent in the group with high primary lesion SUVmax values in lung cancer. MATERIALS AND METHODS Study Design Patients, study population, and inclusion criteria Data were obtained from the computer system of Cukurova University Training and Research Hospital for cases with suspected primary lung cancer diagnosed for diagnostic purposes or by an invasive technique (bronchoscopic biopsy, transthoracic fine needle aspiration biopsy, thoracotomy). Patients who had undergone PET/CT scanning due to suspected malignancy in the lung and/or had primary lung malignancy confirmed by any invasive method, who had not yet started treatment, and who were classified as stage I, II, and selected stage III (IIIA, IIB) according to the TNM classification were included in the study. Measurement of SUV and NTR Reconstructed images were examined. SUVmax was calculated based on tissue concentration (MBq/ml)/activity dose administered (MBq)/patient weight (g) using the voxel values provided by the automatic reconstruction system, which showed the maximum concentration. The metabolic activities of the primary lesions were compared to the metabolic activity of the lymph nodes with the highest metabolic activity detected in the mediastinum, and NTR (node-to-tumor SUVmax ratio) values were obtained for the SCC and adenocarcinoma groups. Statistical Analysis After the data were transferred to Microsoft Excel, statistical analysis was performed using IBM SPSS Statistics software. Following data control, suitability, and normality testing, the required descriptive and advanced statistical analyses were presented in tables and graphs. Patient characteristics and values were presented as frequency, percentage, and min.-max. for categorical variables, chi-square test and kappa; for continuous variables, as they did not conform to the normal distribution assumption according to the histogram and Kolmogorov-Smirnov results, non-parametric methods were used in the analysis of the variables: Mann-Whitney U test, Wilcoxon signed rank test, and Kruskal-Wallis test for differences between three groups. The significance of differences in subgroups was analysed using Dunn's post hoc test. The diagnostic decision-making properties of T SUVmax, N SUVmax, and NTR values in predicting lymphovascular invasion were examined using Receiver Operating Characteristics (ROC) curve analysis. Where meaningful cut-off values existed, the sensitivity, specificity, cut-off point, and area under the curve were calculated. In the evaluation of the area under the curve, cases with a type 1 error level below 5% were interpreted as having a statistically significant diagnostic value. Variables found to be significant in univariate analyses for the detection of lymphovascular invasion, along with age, gender, stage, and tumour type variables, were included in the logistic regression analysis as independent potential factors. The Hosmer-Lemeshow goodness-of-fit test was used for model fit. The most meaningful model was identified. The criterion for statistical significance was set at p<0.05. Patient demographic and baseline characteristics The case group consisted of 574 patients, 508 (88.5%) male and 66 (11.5%) female, with a mean age of 60.5 ± 7.1. When the subgroups were examined according to the clinical TNM staging system, the number of stage I patients was 94 (16.4%), stage II patients numbered 90 (15.7%), and stage III patients numbered 390 (67.9%). Primary lesion evaluation Primary lesion sizes (longest diameter) in SCC and adenocarcinoma cases were measured from the CT images of PET/CT. According to the primary tumour localisations evaluated in accordance with tomographic methodology guidelines, 54.7% of cases (n=314) were peripheral and 45.3% (n=260) were centrally located. 87.8% of lesions (n=504) were extra-hilar, while 12.2% (n=70) were hilar. In terms of morphological features, 45.8% of cases (n=263) contained spiculation, 4.2% (n=24) contained cavitation, and 12.4% (n=71) contained necrosis. Additionally, pleural thickening was observed in 26.5% (n=152), atelectasis in 9.9% (n=57), and advanced invasion findings (invasion of hilar structures, main bronchus, large vessels, pericardium, or carina) in 1.2% (n=7). According to histopathological subtypes (squamous cell carcinoma, adenocarcinoma and its subtypes), 42.0% of cases (n=241) were diagnosed with squamous cell carcinoma. The adenocarcinoma group was further divided according to pathological subtypes (solid, acinar, invasive mucinous, bronchoalveolar, papillary, pleomorphic, lepidic, and minimally invasive types). Among these, solid (12%, n=69) and acinar types (14.3%, n=82) were the most common, while minimally invasive adenocarcinoma was the least common (0.7%, n=4). Mediastinal lymph node evaluation If the SUVmax value of the mediastinal lymph node with the highest activity detected was lower than the mediastinal blood pool, it was considered N0. Mediastinal lymph nodes were classified as N0, N1, N2, or N3 according to their clinical location within the current TNM staging system. The clinical stages of the sample group were determined according to the current staging table. Mediastinal SUVmax values according to clinical N stages showed different distributions in each N stage. In pairwise comparisons, N1 SUVmax and N2 SUVmax values showed different distributions. NTR rates were found to show different distributions according to each clinical N stage (p<0.001). In pairwise comparisons, the NTR ratio showed a different distribution for the N0 group compared to all N stages. N1 SUVmax showed a different distribution from N2 and N3 SUVmax; N2 SUVmax showed a different distribution from N3 SUVmax (p<0.05). Evaluation in terms of lymphovascular invasion When the lymphovascular invasion present group was taken as the endpoint; when the cut-off point for T SUVmax was set at 13.0, sensitivity was 66.0 and specificity was 72.5, determining a reliable cut-off point. For N , when the cut-off point for SUVmax was set at 7.05, sensitivity was 82.9% and specificity was 75.0%, establishing a reliable cut-off point. When the cut-off point for NTR was set at 0.79, sensitivity was 71.8% and specificity was 74, a reliable cut-off point was determined. RESULTS The presence of lymphovascular invasion increases the incidence of local recurrence, and adjuvant therapy is indicated in cases where lymphovascular invasion is detected after surgery (10). Furthermore, in a study correlating lymphovascular invasion with survival, multivariate analysis results revealed its prognostic value for short disease-free and overall survival (12). According to this study, even in the absence of lymph node metastasis, lymphovascular invasion should be investigated due to micrometastases within the lymph vessels for physiopathological reasons (12). Another study emphasised the need to investigate the presence of lymphovascular invasion, which causes the spread of tumour cells, based on the metabolic activity of enlarged lymph nodes in the mediastinum. The study results showed a positive correlation between high N SUVmax values and lymphovascular invasion (13). In our study, the sensitivity of N SUVmax values for lymphovascular invasion was 82.9% and the specificity was 75% (AUC=81.2) in all cases. Furthermore, in the adenocarcinoma group (AUC=81.7), the performance of the N SUVmax value in detecting lymphovascular invasion was found to be higher than in the SCC group (AUC=61.7). In a study based on logistic regression analysis results, which established a reference standard in the literature, it was noted that the N SUVmax ratio was higher in adenocarcinoma with histopathologically detected lymphovascular invasion than in SCC (14). When the cut-off point for N SUVmax was set at 7.05, the ability to accurately predict lymphovascular invasion was significant according to both univariate and multivariate logistic regression analysis (p<0.05). This result suggests that N SUVmax (cut-off 7.05) may be a prognostic parameter for lymphovascular invasion. In lung cancer, adjuvant chemotherapy is considered in the treatment approach when lymphovascular invasion based on micrometastases formed during the vascular perfusion process is present (10). In our study, when the NTR cut-off point was determined as 0.79, it had a sensitivity of 71.8% and a specificity of 74% in demonstrating lymphovascular invasion in all cases (AUC=73.1). This result, based on the information from the study by Lee et al. (11), may serve as evidence for the presence of lymphovascular invasion based on micrometastases formed during the vascular perfusion process, as well as the predictive potential of the normalised SUV-R value with the aortic arch selected as background activity. Further studies are needed to increase the sensitivity of PET/CT for lymphovascular invasion in the literature. DISCUSSION In NSCLC, the metabolic activity of the primary lesion is based on the tumour's aggressive biological processes and has been reported to correlate not only with grade but also with stage and pathological subtype ( 15 ). Furthermore, high metabolic activity increases the likelihood of bronchovascular invasion and consequently significantly raises the probability of local recurrence and metastasis ( 16 ). There are many factors that determine prognosis in lung cancer. Several studies have reported the prognostic role of SUVmax, a metabolic parameter, in primary lung cancer ( 15 , 16 , 17 ). A significant issue with SUVmax is that it reflects the highest metabolic pixels within the tumour; however, it does not always represent the overall metabolic status of the tumour ( 18 ). Especially when tumour FDG uptake is highly heterogeneous, metabolic activities unrelated to the lesion negatively affect PET reliability ( 18 , 19 ). NTR, a proportional parameter for lymphovascular invasion, was found to be associated with an indication for adjuvant therapy (p < 0.05). As a result of our study, NTR may help predict the lymphovascular invasion characteristic of the primary tumour in the preoperative period. However, the retrospective design of the study, heterogeneity in the imaging protocol, and the lack of histological subtype differentiation are among the significant limitations. Therefore, prospective, multicentre studies involving homogeneous patient groups are needed to more robustly establish the prognostic value of proportional parameters and continuous variables. Declarations Ethical approval and consent to participate: Local Ethics Committee of the Cukurova University approved the study protocol (Approval date: 06-September-2024, no: 147/37). Ethical approval and consent to participate: This study was conducted in accordance with the principles of the Helsinki Declaration.In this study, patient consent cannot be obtained as it is a retrospective design in accordance with the regulations prepared by the reference to the relevant legislation. Availability of data and materials: Due to the anonymity of the study and its retrospective design, the dataset associated with the study cannot be shared. Conflicts of interest: There is no conflict of interest in this study. Funding: No funding support was provided for the study. Authors' contributions: The author(s) prepared the scientific results by conducting data screening, statistical analysis, and comparing the findings and interpretations with the medical literature. References Silvestri GA, Gonzalez AV, Jantz MA, Margolis ML, Gould MK, Tanoue LT, Harris LJ, Detterbeck FC. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e211S-e250S. doi: 10.1378/chest.12-2355. PMID: 23649440. Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review. Lancet Oncol. 2004 Sep;5(9):531-40. doi: 10.1016/S1470-2045(04)01564-5. PMID: 15337482 Harders SW, Madsen HH, Hjorthaug K, Arveschoug AK, Rasmussen TR, Meldgaard P, Hoejbjerg JA, Pilegaard HK, Hager H, Rehling M, Rasmussen F. Mediastinal staging in Non-Small-Cell Lung Carcinoma: computed tomography versus F-18-fluorodeoxyglucose positron-emission tomography and computed tomography. Cancer Imaging. 3 June 2014;14(1):23. doi: 10.1186/1470-7330-14-23. PMID: 25608616; PMCID: PMC4331828. Mortman, Keith D., and Bitana Saintilma. "Surgical Interventions and Care for Lung Cancer Control." Lung Cancer Navigation and Care: A Comprehensive Guide for Navigators and Allied Health Professionals . Cham: Springer Nature Switzerland, 2025. pp. 163–173. Vansteenkiste, J. F., et al. "Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa–N2 non-small-cell lung cancer: A prospective pilot study." Annals of oncology 9.11 (1998): 1193–1198. Schuurbiers, Olga CJ, et al. "Glucose metabolism in NSCLC is histology-specific and diverges the prognostic potential of 18FDG-PET for adenocarcinoma and squamous cell carcinoma." Journal of Thoracic Oncology 9.10 (2014): 1485-1493 Patching, Simon G. "Roles of facilitative glucose transporter GLUT1 in [18F] FDG positron emission tomography (PET) imaging of human diseases." J Diagn Imaging Ther 2.1 (2015): 30-102. Cerfolio, Robert James, et al. "The maximum standardised uptake values on positron emission tomography of a non-small cell lung cancer predict stage, recurrence, and survival." The Journal of Thoracic and Cardiovascular Surgery 130.1 (2005): 151-159. Nambu, Atsushi, et al. "Relationship between maximum standardised uptake value (SUVmax) of lung cancer and lymph node metastasis on FDG-PET." Annals of Nuclear Medicine 23 (2009): 269–275. Wang, Shuyuan, et al. "Adjuvant chemotherapy may improve prognosis after resection of stage I lung cancer with lymphovascular invasion." The Journal of Thoracic and Cardiovascular Surgery 156.5 (2018): 2006-2015. Lee, Paul C., et al. "Risk factors for occult mediastinal metastases in clinical stage I non-small cell lung cancer." The Annals of Thoracic Surgery 84.1 (2007): 177-181. Mollberg, Nathan M., et al. "Lymphovascular invasion as a prognostic indicator in stage I non-small cell lung cancer: a systematic review and meta-analysis." The Annals of Thoracic Surgery 97.3 (2014): 965-971. Bryant, Ayesha S., et al. "Maximum standard uptake value of mediastinal lymph nodes on integrated FDG-PET-CT predicts pathology in patients with non-small cell lung cancer." The Annals of Thoracic Surgery 82.2 (2006): 417-423. Noda, Yoshifumi, et al. "F-18 FDG uptake on positron emission tomography as a predictor for lymphovascular invasion in patients with lung adenocarcinoma." Annals of Nuclear Medicine 30.1 (2016): 11-17. Bar-Shalom R, Kagna O, Israel O, Guralnik L. Non-invasive diagnosis of solitary pulmonary lesions in cancer patients based on 2-fluoro-2-deoxy-D-glucose avidity on positron emission tomography/computed tomography. Cancer 2008; 113: 3213-21. Takeda, Atsuya, et al. "The maximum standardised uptake value (SUVmax) on FDG-PET is a strong predictor of local recurrence for localised non-small-cell lung cancer after stereotactic body radiotherapy (SBRT)." Radiotherapy and Oncology 101.2 (2011): 291-297. Kwon, Woocheol, et al. "FDG uptake on positron emission tomography correlates with survival and time to recurrence in patients with stage I non–small-cell lung cancer." Journal of Thoracic Oncology 10.6 (2015): 897-902. Schaarschmidt, Benedikt Michael, et al. "Correlation of the apparent diffusion coefficient (ADC) with the standardised uptake value (SUV) in lymph node metastases of non-small cell lung cancer (NSCLC) patients using hybrid 18F-FDG PET/MRI." PLoS One 10.1 (2015): e0116277. Clausen, Malene M., et al. "Multiple Testing, Cut-Point Optimisation, and Signs of Publication Bias in Prognostic FDG–PET Imaging Studies of Head and Neck and Lung Cancer: A Review and Meta-Analysis." Diagnostics 10.12 (2020): 1030. Tables Tables 1 to 6 are available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. Supplementary Files Tables.docx Tables (1-6) Cite Share Download PDF Status: Posted Version 1 posted 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. 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Study\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAmong conventional imaging systems, low-dose CT is the first-line diagnostic method for pulmonary nodule screening in guidelines for the early detection of primary lung cancer (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Confirming and evaluating lesions suspected of cancer using PET-based imaging yields more reliable results in terms of diagnosis and staging. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) In addition, it is a strong determinant in nodal staging and treatment management (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Surgery is the primary treatment in the group of patients with small-stage disease (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Demonstration of N2 disease with preoperative F-18 FDG PET/CT scanning requires confirmation with more invasive methods and identifies the group of patients eligible for neoadjuvant therapy (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe SUVmax value, a metabolic parameter in F-18 FDG PET/CT, shows a positive correlation with malignancy potential in the diagnosis of lung cancer (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). FDG uptake via the tumour's GLUT-1 pathway is also related to histological grade (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Cerfolio et. al (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), stage-specific T SUVmax analyses revealed that stage IB and stage II NSCLC cases with T SUVmax values higher than the median value had lower 4-year survival.This information indicated that the tumour-specific SUVmax value was a stronger potential prognostic factor than the TNM staging system in terms of recurrence and survival. Nambu et. al, (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) examined the relationship between lymph node metastases and pathological subtypes of lung cancer and they found that lymph node metastasis was significantly more frequent in the group with high primary lesion SUVmax values in lung cancer.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eStudy Design \u003c/p\u003e\n\u003cp\u003ePatients, study population, and inclusion criteria \u003c/p\u003e\n\u003cp\u003eData were obtained from the computer system of Cukurova University Training and Research Hospital for cases with suspected primary lung cancer diagnosed for diagnostic purposes or by an invasive technique (bronchoscopic biopsy, transthoracic fine needle aspiration biopsy, thoracotomy). \u003c/p\u003e\n\u003cp\u003ePatients who had undergone PET/CT scanning due to suspected malignancy in the lung and/or had primary lung malignancy confirmed by any invasive method, who had not yet started treatment, and who were classified as stage I, II, and selected stage III (IIIA, IIB) according to the TNM classification were included in the study. \u003c/p\u003e\n\u003cp\u003eMeasurement of SUV and NTR\u003c/p\u003e\n\u003cp\u003eReconstructed images were examined. SUVmax was calculated based on tissue concentration (MBq/ml)/activity dose administered (MBq)/patient weight (g) using the voxel values provided by the automatic reconstruction system, which showed the maximum concentration. The metabolic activities of the primary lesions were compared to the metabolic activity of the lymph nodes with the highest metabolic activity detected in the mediastinum, and NTR (node-to-tumor SUVmax ratio) values were obtained for the SCC and adenocarcinoma groups. \u003c/p\u003e\n\u003cp\u003eStatistical Analysis \u003c/p\u003e\n\u003cp\u003eAfter the data were transferred to Microsoft Excel, statistical analysis was performed using IBM SPSS Statistics software. Following data control, suitability, and normality testing, the required descriptive and advanced statistical analyses were presented in tables and graphs.\u003c/p\u003e\n\u003cp\u003ePatient characteristics and values were presented as frequency, percentage, and min.-max. for categorical variables, chi-square test and kappa; for continuous variables, as they did not conform to the normal distribution assumption according to the histogram and Kolmogorov-Smirnov results, non-parametric methods were used in the analysis of the variables: Mann-Whitney U test, Wilcoxon signed rank test, and Kruskal-Wallis test for differences between three groups. The significance of differences in subgroups was analysed using Dunn's post hoc test. \u003c/p\u003e\n\u003cp\u003eThe diagnostic decision-making properties of T SUVmax, N SUVmax, and NTR values in predicting lymphovascular invasion were examined using Receiver Operating Characteristics (ROC) curve analysis. Where meaningful cut-off values existed, the sensitivity, specificity, cut-off point, and area under the curve were calculated. In the evaluation of the area under the curve, cases with a type 1 error level below 5% were interpreted as having a statistically significant diagnostic value. Variables found to be significant in univariate analyses for the detection of lymphovascular invasion, along with age, gender, stage, and tumour type variables, were included in the logistic regression analysis as independent potential factors. The Hosmer-Lemeshow goodness-of-fit test was used for model fit. The most meaningful model was identified. The criterion for statistical significance was set at p\u0026lt;0.05. \u003c/p\u003e\n\u003cp\u003ePatient demographic and baseline characteristics \u003c/p\u003e\n\u003cp\u003eThe case group consisted of 574 patients, 508 (88.5%) male and 66 (11.5%) female, with a mean age of 60.5 ± 7.1. When the subgroups were examined according to the clinical TNM staging system, the number of stage I patients was 94 (16.4%), stage II patients numbered 90 (15.7%), and stage III patients numbered 390 (67.9%).\u003c/p\u003e\n\u003cp\u003ePrimary lesion evaluation \u003c/p\u003e\n\u003cp\u003ePrimary lesion sizes (longest diameter) in SCC and adenocarcinoma cases were measured from the CT images of PET/CT. According to the primary tumour localisations evaluated in accordance with tomographic methodology guidelines, 54.7% of cases (n=314) were peripheral and 45.3% (n=260) were centrally located. 87.8% of lesions (n=504) were extra-hilar, while 12.2% (n=70) were hilar. In terms of morphological features, 45.8% of cases (n=263) contained spiculation, 4.2% (n=24) contained cavitation, and 12.4% (n=71) contained necrosis. Additionally, pleural thickening was observed in 26.5% (n=152), atelectasis in 9.9% (n=57), and advanced invasion findings (invasion of hilar structures, main bronchus, large vessels, pericardium, or carina) in 1.2% (n=7).\u003c/p\u003e\n\u003cp\u003eAccording to histopathological subtypes (squamous cell carcinoma, adenocarcinoma and its subtypes), 42.0% of cases (n=241) were diagnosed with squamous cell carcinoma. The adenocarcinoma group was further divided according to pathological subtypes (solid, acinar, invasive mucinous, bronchoalveolar, papillary, pleomorphic, lepidic, and minimally invasive types). Among these, solid (12%, n=69) and acinar types (14.3%, n=82) were the most common, while minimally invasive adenocarcinoma was the least common (0.7%, n=4). \u003c/p\u003e\n\u003cp\u003eMediastinal lymph node evaluation \u003c/p\u003e\n\u003cp\u003eIf the SUVmax value of the mediastinal lymph node with the highest activity detected was lower than the mediastinal blood pool, it was considered N0. Mediastinal lymph nodes were classified as N0, N1, N2, or N3 according to their clinical location within the current TNM staging system. The clinical stages of the sample group were determined according to the current staging table.\u003c/p\u003e\n\u003cp\u003eMediastinal SUVmax values according to clinical N stages showed different distributions in each N stage. In pairwise comparisons, N1 SUVmax and N2 SUVmax values showed different distributions. NTR rates were found to show different distributions according to each clinical N stage (p\u0026lt;0.001). In pairwise comparisons, the NTR ratio showed a different distribution for the N0 group compared to all N stages. N1 SUVmax showed a different distribution from N2 and N3 SUVmax; N2 SUVmax showed a different distribution from N3 SUVmax (p\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003eEvaluation in terms of lymphovascular invasion\u003c/p\u003e\n\u003cp\u003eWhen the lymphovascular invasion present group was taken as the endpoint; when the cut-off point for T SUVmax was set at 13.0, sensitivity was 66.0 and specificity was 72.5, determining a reliable cut-off point. For N , when the cut-off point for SUVmax was set at 7.05, sensitivity was 82.9% and specificity was 75.0%, establishing a reliable cut-off point. When the cut-off point for NTR was set at 0.79, sensitivity was 71.8% and specificity was 74, a reliable cut-off point was determined. \u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe presence of lymphovascular invasion increases the incidence of local recurrence, and adjuvant therapy is indicated in cases where lymphovascular invasion is detected after surgery (10). Furthermore, in a study correlating lymphovascular invasion with survival, multivariate analysis results revealed its prognostic value for short disease-free and overall survival (12). \u0026nbsp;According to this study, even in the absence of lymph node metastasis, lymphovascular invasion should be investigated due to micrometastases within the lymph vessels for physiopathological reasons (12). Another study emphasised the need to investigate the presence of lymphovascular invasion, which causes the spread of tumour cells, based on the metabolic activity of enlarged lymph nodes in the mediastinum. The study results showed a positive correlation between high N SUVmax values and lymphovascular invasion (13). In our study, the sensitivity of N SUVmax values for lymphovascular invasion was 82.9% and the specificity was 75% (AUC=81.2) in all cases. Furthermore, in the adenocarcinoma group (AUC=81.7), the performance of the N SUVmax value in detecting lymphovascular invasion was found to be higher than in the SCC group (AUC=61.7). In a study based on logistic regression analysis results, which established a reference standard in the literature, it was noted that the N SUVmax ratio was higher in adenocarcinoma with histopathologically detected lymphovascular invasion than in SCC (14). \u0026nbsp;When the cut-off point for N SUVmax was set at 7.05, the ability to accurately predict lymphovascular invasion was significant according to both univariate and multivariate logistic regression analysis (p\u0026lt;0.05). This result suggests that N SUVmax (cut-off 7.05) may be a prognostic parameter for lymphovascular invasion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn lung cancer, adjuvant chemotherapy is considered in the treatment approach when lymphovascular invasion based on micrometastases formed during the vascular perfusion process is present (10). In our study, when the NTR cut-off point was determined as 0.79, it had a sensitivity of 71.8% and a specificity of 74% in demonstrating lymphovascular invasion in all cases (AUC=73.1). This result, based on the information from the study by Lee et al. (11), may serve as evidence for the presence of lymphovascular invasion based on micrometastases formed during the vascular perfusion process, as well as the predictive potential of the normalised SUV-R value with the aortic arch selected as background activity. Further studies are needed to increase the sensitivity of PET/CT for lymphovascular invasion in the literature.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn NSCLC, the metabolic activity of the primary lesion is based on the tumour's aggressive biological processes and has been reported to correlate not only with grade but also with stage and pathological subtype (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Furthermore, high metabolic activity increases the likelihood of bronchovascular invasion and consequently significantly raises the probability of local recurrence and metastasis (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere are many factors that determine prognosis in lung cancer. Several studies have reported the prognostic role of SUVmax, a metabolic parameter, in primary lung cancer (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). A significant issue with SUVmax is that it reflects the highest metabolic pixels within the tumour; however, it does not always represent the overall metabolic status of the tumour (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Especially when tumour FDG uptake is highly heterogeneous, metabolic activities unrelated to the lesion negatively affect PET reliability (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNTR, a proportional parameter for lymphovascular invasion, was found to be associated with an indication for adjuvant therapy (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). As a result of our study, NTR may help predict the lymphovascular invasion characteristic of the primary tumour in the preoperative period. However, the retrospective design of the study, heterogeneity in the imaging protocol, and the lack of histological subtype differentiation are among the significant limitations. Therefore, prospective, multicentre studies involving homogeneous patient groups are needed to more robustly establish the prognostic value of proportional parameters and continuous variables.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical approval and consent to participate: Local Ethics Committee of the Cukurova University approved the study protocol (Approval date: 06-September-2024, no: 147/37).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate: \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the principles of the Helsinki Declaration.In this study, patient consent cannot be obtained as it is a retrospective design in accordance with the regulations prepared by the\u0026nbsp;\u0026nbsp;reference to the relevant legislation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the anonymity of the study and its retrospective design, the dataset associated with the study cannot be shared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no conflict of interest in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding support was provided for the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) prepared the scientific results by conducting data screening, statistical analysis, and comparing the findings and interpretations with the medical literature.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSilvestri GA, Gonzalez AV, Jantz MA, Margolis ML, Gould MK, Tanoue LT, Harris LJ, Detterbeck FC. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e211S-e250S. doi: 10.1378/chest.12-2355. PMID: 23649440.\u003c/li\u003e\n\u003cli\u003eVansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review. Lancet Oncol. 2004 Sep;5(9):531-40. doi: 10.1016/S1470-2045(04)01564-5. PMID: 15337482\u003c/li\u003e\n\u003cli\u003eHarders SW, Madsen HH, Hjorthaug K, Arveschoug AK, Rasmussen TR, Meldgaard P, Hoejbjerg JA, Pilegaard HK, Hager H, Rehling M, Rasmussen F. Mediastinal staging in Non-Small-Cell Lung Carcinoma: computed tomography versus F-18-fluorodeoxyglucose positron-emission tomography and computed tomography. Cancer Imaging. 3 June 2014;14(1):23. doi: 10.1186/1470-7330-14-23. PMID: 25608616; PMCID: PMC4331828.\u003c/li\u003e\n\u003cli\u003eMortman, Keith D., and Bitana Saintilma. \u0026quot;Surgical Interventions and Care for Lung Cancer Control.\u0026quot; \u003cem\u003eLung Cancer Navigation and Care: A Comprehensive Guide for Navigators and Allied Health Professionals\u003c/em\u003e. Cham: Springer Nature Switzerland, 2025. pp. 163\u0026ndash;173.\u003c/li\u003e\n\u003cli\u003eVansteenkiste, J. F., et al. \u0026quot;Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa\u0026ndash;N2 non-small-cell lung cancer: A prospective pilot study.\u0026quot; \u003cem\u003eAnnals of oncology\u003c/em\u003e 9.11 (1998): 1193\u0026ndash;1198.\u003c/li\u003e\n\u003cli\u003eSchuurbiers, Olga CJ, et al. \u0026quot;Glucose metabolism in NSCLC is histology-specific and diverges the prognostic potential of 18FDG-PET for adenocarcinoma and squamous cell carcinoma.\u0026quot; \u003cem\u003eJournal of Thoracic Oncology\u003c/em\u003e 9.10 (2014): 1485-1493\u003c/li\u003e\n\u003cli\u003ePatching, Simon G. \u0026quot;Roles of facilitative glucose transporter GLUT1 in [18F] FDG positron emission tomography (PET) imaging of human diseases.\u0026quot; \u003cem\u003eJ Diagn Imaging Ther\u003c/em\u003e 2.1 (2015): 30-102.\u003c/li\u003e\n\u003cli\u003eCerfolio, Robert James, et al. \u0026quot;The maximum standardised uptake values on positron emission tomography of a non-small cell lung cancer predict stage, recurrence, and survival.\u0026quot; \u003cem\u003eThe Journal of Thoracic and Cardiovascular Surgery\u003c/em\u003e 130.1 (2005): 151-159.\u003c/li\u003e\n\u003cli\u003eNambu, Atsushi, et al. \u0026quot;Relationship between maximum standardised uptake value (SUVmax) of lung cancer and lymph node metastasis on FDG-PET.\u0026quot; \u003cem\u003eAnnals of Nuclear Medicine\u003c/em\u003e 23 (2009): 269\u0026ndash;275.\u003c/li\u003e\n\u003cli\u003eWang, Shuyuan, et al. \u0026quot;Adjuvant chemotherapy may improve prognosis after resection of stage I lung cancer with lymphovascular invasion.\u0026quot; \u003cem\u003eThe Journal of Thoracic and Cardiovascular Surgery\u003c/em\u003e 156.5 (2018): 2006-2015.\u003c/li\u003e\n\u003cli\u003eLee, Paul C., et al. \u0026quot;Risk factors for occult mediastinal metastases in clinical stage I non-small cell lung cancer.\u0026quot; \u003cem\u003eThe Annals of Thoracic Surgery\u003c/em\u003e 84.1 (2007): 177-181.\u003c/li\u003e\n\u003cli\u003eMollberg, Nathan M., et al. \u0026quot;Lymphovascular invasion as a prognostic indicator in stage I non-small cell lung cancer: a systematic review and meta-analysis.\u0026quot; \u003cem\u003eThe Annals of Thoracic Surgery\u003c/em\u003e 97.3 (2014): 965-971.\u003c/li\u003e\n\u003cli\u003eBryant, Ayesha S., et al. \u0026quot;Maximum standard uptake value of mediastinal lymph nodes on integrated FDG-PET-CT predicts pathology in patients with non-small cell lung cancer.\u0026quot; \u003cem\u003eThe Annals of Thoracic Surgery\u003c/em\u003e 82.2 (2006): 417-423.\u003c/li\u003e\n\u003cli\u003eNoda, Yoshifumi, et al. \u0026quot;F-18 FDG uptake on positron emission tomography as a predictor for lymphovascular invasion in patients with lung adenocarcinoma.\u0026quot; \u003cem\u003eAnnals of Nuclear Medicine\u003c/em\u003e 30.1 (2016): 11-17.\u003c/li\u003e\n\u003cli\u003eBar-Shalom R, Kagna O, Israel O, Guralnik L. Non-invasive diagnosis of solitary pulmonary lesions in cancer patients based on 2-fluoro-2-deoxy-D-glucose avidity on positron emission tomography/computed tomography. Cancer 2008; 113: 3213-21.\u003c/li\u003e\n\u003cli\u003eTakeda, Atsuya, et al. \u0026quot;The maximum standardised uptake value (SUVmax) on FDG-PET is a strong predictor of local recurrence for localised non-small-cell lung cancer after stereotactic body radiotherapy (SBRT).\u0026quot; \u003cem\u003eRadiotherapy and Oncology\u003c/em\u003e 101.2 (2011): 291-297.\u003c/li\u003e\n\u003cli\u003eKwon, Woocheol, et al. \u0026quot;FDG uptake on positron emission tomography correlates with survival and time to recurrence in patients with stage I non\u0026ndash;small-cell lung cancer.\u0026quot; \u003cem\u003eJournal of Thoracic Oncology\u003c/em\u003e 10.6 (2015): 897-902.\u003c/li\u003e\n\u003cli\u003eSchaarschmidt, Benedikt Michael, et al. \u0026quot;Correlation of the apparent diffusion coefficient (ADC) with the standardised uptake value (SUV) in lymph node metastases of non-small cell lung cancer (NSCLC) patients using hybrid 18F-FDG PET/MRI.\u0026quot; \u003cem\u003ePLoS One\u003c/em\u003e 10.1 (2015): e0116277.\u003c/li\u003e\n\u003cli\u003eClausen, Malene M., et al. \u0026quot;Multiple Testing, Cut-Point Optimisation, and Signs of Publication Bias in Prognostic FDG\u0026ndash;PET Imaging Studies of Head and Neck and Lung Cancer: A Review and Meta-Analysis.\u0026quot; \u003cem\u003eDiagnostics\u003c/em\u003e 10.12 (2020): 1030.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Cukurova University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"NSCLC, F-18 FDG PET-CT, lymphovascular invasion, NTR","lastPublishedDoi":"10.21203/rs.3.rs-8353396/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8353396/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study aims to improve preoperative conventional imaging and assessment criteria for non-small cell lung cancer cases eligible for surgery and to enhance the surgical and clinical approach to patients through reliable preoperative staging.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA group of 574 patients who attended the Thoracic Surgery outpatient clinic at Cukurova University Balcalı Training and Research Hospital between 2012 and 2022 and were investigated for suspected lung cancer or diagnosed with lung cancer were retrospectively examined. T SUVmax (primary tumour SUVmax), N SUVmax (mediastinal lymph node SUVmax) and NTR (node to tumor SUVmax ratio), correlated with clinical Tumor (T)-Node (N)-Metastasis (M) staging, were recorded and compared with histopathological findings of lymphovascular invasion of the tumour.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the 574 NSCLC patients included in the study, the ratio of the SUVmax value of the lymph node with the highest metabolic activity detected in the mediastinum to the SUVmax value of the primary lesion (node-to-tumour SUVmax, NTR) was examined, and this ratio was found to have significant potential for predicting lymphovascular invasion (AUC: 73.1 and 71% sensitivity, 74% specificity for a cut-off value of 0.79).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NTR value from metabolic parameters in F-18 FDG PET/CT can be used to evaluate the primary lesion for lymphovascular invasion in the preoperative period in NSCLC.\u003c/p\u003e","manuscriptTitle":"The Potential of NTR Value in Primary Lung Cancer to Predict Lymphovascular Invasion: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-17 09:04:48","doi":"10.21203/rs.3.rs-8353396/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"339b4aef-f93f-40ad-8488-2c5382152f3c","owner":[],"postedDate":"December 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59604099,"name":"Nuclear Medicine \u0026 Medical Imaging"},{"id":59604100,"name":"Oncology"}],"tags":[],"updatedAt":"2025-12-17T09:04:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-17 09:04:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8353396","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8353396","identity":"rs-8353396","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}