The impact of PET/CT and brain MRI for metastasis detection among patients with clinical T1-category lung cancer: Findings from a large-scale cohort study

Purpose [18F]-FDG PET/CT and brain MRI are common approaches to detect metastasis in patients of lung cancer. Current guidelines for the use of PET/CT and MRI in clinical T1-category lung cancer lack risk-based stratification and require optimization. This study stratified patients based on metastatic risk in terms of the lesions' size and morphological characteristics. Methods The detection rate of metastasis was measured in different sizes and morphological characteristics (solid and sub-solid) of tumors. To confirm the cut-off value for discriminating metastasis and overall survival (OS) prediction, the receiver operating characteristic (ROC) analysis was performed based on PET/CT metabolic parameters (SUVmax/SUVmean/SULpeak/MTV/TLG), followed by Kaplan–Meier analysis for survival in post-operation patients with and without PET/CT plus MRI. Results 2,298 patients were included. No metastasis was observed in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm. The cut-off of PET/CT metabolic parameters on discriminating metastasis were 1.09 (SUVmax), 0.26 (SUVmean), 0.31 (SULpeak), 0.55 (MTV), and 0.81 (TLG), respectively. Patients undergoing PET/CT plus MRI exhibited longer OS compared to those who did not receive it in solid nodules ≥ 8.0 mm & sub-solid nodules ≥ 10.0 mm (HR, 0.44; p < 0.001); in solid nodules ≥ 8.0 mm (HR, 0.12; p<0.001) and in sub-solid nodules ≥ 10.0 mm (HR; 0.61; p=0.075), respectively. Compared to patients with metabolic parameters lower than cut-off values, patients with higher metabolic parameters displayed shorter OS: SUVmax (HR, 12.94; p < 0.001), SUVmean (HR, 11.33; p <0.001), SULpeak (HR, 9.65; p < 0.001), MTV (HR, 9.16; p = 0.031), and TLG (HR, 12.06; p < 0.001). Conclusion The necessity of PET/CT and MRI should be cautiously evaluated in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm, however, these examinations remained essential and beneficial for patients with solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm. Supplementary Information The online version contains supplementary material available at 10.1007/s00259-024-06740-8.


Introduction
Lung cancer remains the predominant cause of cancerrelated mortality worldwide and ranks the most common cancer globally [1].The advent of widespread lung cancer screening has markedly elevated the detection rates of early-stage lung cancer [2,3].Early-stage lung cancer typically manifests as pulmonary nodules on computed tomography (CT) scan, appearing as small size (≤30 mm), focal and discrete radiographic density surrounded by lung parenchyma [4].
[ 18 F]-fluorodeoxyglucose ([ 18 F]-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) is a common approach in the metastases detection and staging of lung cancer, and provides useful data for the characterization of morphologically indeterminate pulmonary nodules and has been widely adopted in clinical practice [5].The deficiency of PET/CT in cerebral imaging necessitates the complementary use of contrast-enhanced brain MRI for thorough assessment of potential brain metastases.According to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines, PET/CT is recommended in all confirmed cases of lung cancer (category 2A recommendation), irrespective of tumor size [6,7].The European Society of Medical Oncology (ESMO) Clinical Practice Guidelines endorses preoperative PET/CT in lung cancer to rule out mediastinal lymph node metastasis, though it stops short of specifying a nodule size threshold for this recommendation [8].MRI is recommended for all lung cancer patients except those with stage IA peripheral non-small cell lung cancer (NSCLC) [6,7].Previous studies have shown that the metastatic potential of lung cancer correlates with its invasiveness and varies across tumors of different sizes and compositions (solid or ground glass nodules) [4,9].Consequently, in early-stage lung cancer patients harboring low-invasive lesions of small size or ground-glass opacity (GGO), the utilization of PET/CT and MRI could be exempted due to their weak metastatic risk.Therefore, a more definite recommendation involved in lesions' diameter and density for PET/ CT and MRI examinations in these early-stage lung cancer patients is warranted [10,11].
In this study, we aimed to stratify patients based on metastatic risk and optimize existing guidelines for the application of PET/CT and MRI in the management of clinical T1-category lung cancer patients manifesting as solid and sub-solid nodules.

Material and methods
This was a single-center, retrospective study utilizing a large-scale prospectively maintained cohort.Approval was obtained from institutional review board, and the requirement for informed consent was waived, considering its retrospective nature.

Study design and participants
Clinical-pathological data and survival information were retrieved from the database of our hospital.All pathologically diagnosed (via surgery or biopsy) lung cancer patients who underwent both PET/CT and contrast-enhanced brain MRI examinations were included between January 2009 and July 2022.Exclusion criteria were as follows: (1) patients with incomplete clinical information; (2) accompanied with other system malignancies history; (3) clinical T2, T3, or T4-categories lung cancers; (4) multiple primary lung cancer (MPLC); and (5) those who received anti-cancer therapy prior to the PET/CT plus MRI examination.

Image acquisition protocol
Scanning procedures were performed using a GE Discovery ST 8 scanner (GE Healthcare Lunar, Wisconsin, USA), employing [ 18 F]-FDG as the radiotracer with excellent chemical identity and purity (> 95%).The patients adhered to a 6-h fasting period prior to data acquisition.Height and weight measurements, along with fasting blood glucose levels were obtained, and maintained at < 8.0 mmol/L.Patients received an intravenous injection of 3.7 MBq/ kg (0.1 mCi/kg) [ 18 F]-FDG via the dorsal hand vein in a resting state.PET/CT imaging commenced 60-90 min post-injection, with patients resting in a dimly lit room to reduce external stimuli.The patients were prepared for the PET/CT examination in a supine position.A multislice spiral CT scan was performed first, covering a wide range from the head to the feet.The following scan parameters were utilized: tube voltage of 140 kV, tube current of 150 mA, pitch of 0.875, field of view (FOV) of 50 cm, slice thickness of 3.75 mm and a matrix 512 × 512.The PET scanning was performed in the same scanning range, using 2D acquisition mode and matrix of 128 × 128.The acquisition time was 3 min/bed position, and 6-7 bed position were collected.Bayesian penalized likelihood reconstruction algorithms were applied to reconstruct PET/ CT images in 3D, optimizing image resolution and quality.Simultaneous acquisition and fusion of PET and CT images were performed automatically, utilizing CT image data for attenuation correction of PET images.A thin-slice CT scan was conducted during a breath-hold on all lung nodules with a slice thickness of 1.25 mm, ensuring optimal reconstruction and reducing the impact of respiratory motion artifacts on PET image quality.

Image analysis
PET/CT images were independently evaluated by two experienced nuclear medicine physicians, who were apprised of the initial clinical data but remained blinded to the histologic outcomes and MRI findings.Any diagnostic discrepancies were resolved through a consensus approach.The analysis focused on semi-quantitative parameters of all discernible lesions.Utilizing a 3D regional growth algorithm, lesions were automatically segmented and delineated on axial, coronal, and sagittal planes to ensure precise and objective assessment.Metabolic parameters such as maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), standardized uptake values corrected for lean body mass (SULpeak), metabolic tumor volume (MTV), total lesion glycolysis (TLG = SUVmean×MTV) were calculated in same mode.We used a fixed threshold of 40% SUVmax for tumor delineation.

Outcomes
Clinical data encompassed variates such as gender, age, nodule diameter, location, histologic findings, and the presence of epidermal growth factor receptor (EGFR) mutations.Included patients (lesions) were assessed radiologically based on the maximum dimensions and classified as solid and sub-solid [12].The staging of lymph node and distant metastases were clinically performed and involved collaboration between a thoracic radiologist (X.Y.H., with a decade of experience in cardiopulmonary imaging) and a medical student (B.C., with five years of experience in pulmonary imaging diagnostics), who reached an in accordance with the 8th edition of the Tumor Node Metastasis (TNM) staging system [13].The detection rate of metastasis was herein defined as the percentage of clinical T1-category lung cancer patients who developed metastases.The diameter cut-off that corresponded to 0% detection rates of metastasis were observed.
The survival of enrolled patients who received surgical resection of tumor was analyzed, and a cohort of clinical T1-category post-operation patients who underwent CT only (or plus MRI) was set as control group, and the inclusion and exclusion criteria were the same for the PET/CT plus MRI.The primary objective was to compare the 5-year overall survival (OS, time from pathological diagnosis to death from lung cancer) in patients without baseline metastasis between those who received PET/CT plus MRI and those who underwent CT only (or plus MRI), furthermore, OS among PET/ CT plus MRI, CT plus MRI, and CT only were compared.

Statistical analysis
Patient demographics and tumor characteristics, including age and nodule diameter, were quantitatively summarized using median values and interquartile ranges (IQR).Categorical variables such as gender, lesion locations, histologic findings, and the presence of EGFR mutations were reported as percentages.Group comparisons were conducted using the Chi-square test, Fisher's exact test, or Mann-Whitney U test, as appropriate.Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic efficacy of PET/CT based on the binary variable as 5-year OS, and areas under the ROC curve (AUC) were calculated to confirm the optimal cut-off of PET/CT metabolic parameters that maximize specificity for metastasis detection (corresponding to the cut-off of 0% detection rate of metastasis) and OS prediction based on Youden's index.The OS was estimated using the Kaplan-Meier (K-M) methodology, and data for patients who were alive or lost to follow-up were censored at their last known contact (time cut-off: April 20, 2023).The stratified log-rank test was used to assess differences in OS between groups.For the assessment of hazard ratios (HRs) and their corresponding two-sided 95% confidence intervals (CIs), we employed the Cox proportional hazards model, incorporating Efron's method for tie-handling [14].Finally, the propensity-score matching (PSM) procedure was applied to balance baseline covariates and minimize potential confounding factors between these groups in post-operation [15], matching covariates encompassed the following factors: gender, age, nodule diameter, location, pathologic risk factors (pleural invasion, vascular cancer embolus, spread through air spaces, nerve invasion, bronchial invasion, and vascular invasion) and histologic findings.All matching covariates were matched at a ratio of 1:1 and a caliper of 0.02.Statistical significance was set at a p-value of less than 0.05, and all analyses were performed using Microsoft Excel (Version 2016) and R Studio (version 4.2.2).

Metastatic State
No metastases (0%) were observed in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm (Supplement Table 1).Metastases were found in 29.9% (686/2,298) of the patients, with a notably higher incidence among those with solid nodules (46.1%, 301/653) compared to those with sub-solid nodules (23.4%, 385/1,645).Furthermore, the overall detection rate of metastasis was consistently higher in solid nodules compared to sub-solid nodules within the same diameter range (Fig. 2A).As the diameter of both solid   and sub-solid nodules increased, so did in the detection rates of metastasis.This trend was consistent across overall metastasis, lymph node metastasis, and distant metastasis for both nodules (Fig. 2B-C).
Compared with distant metastasis, a higher detection rate of lymph node metastasis was observed within the same diameter of nodules (Fig. 3A and Supplement Table 1).This pattern persisted in both solid and sub-solid nodule groups (Fig. 3B-C).The detection rates of N1 and N2 lymph node metastases were comparable and exceeded that of N3 lymph node metastasis (Supplement Fig. 1A and Supplement Table 2).This trend remained consistent across solid and sub-solid nodules (Supplement Fig. 1B-C).Additionally, with increasing nodule diameter, the differences in distant metastasis rates (M1a-M1c) became more pronounced (Supplement Fig. 2A and Supplement Table 3), this trend was also observed in both solid and sub-solid nodules (Supplement Fig. 2B-C).In metastasis sites, ipsilateral hilar lymph nodes and bone were the most frequent sites for lymph node and distant metastases, respectively, with 300 cases of ipsilateral hilar lymph node metastasis and 217 cases of bone metastasis recorded.We also calculated the detection rates of metastasis diagnosed by PET/CT plus brain MRI separately, as shown in Supplement Fig. 3-7.
When the cohort undergoing CT only (or plus MRI) was subdivided into those receiving CT plus MRI and those receiving CT only, difference in OS was observed among groups in solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm (PET/CT plus MRI versus CT plus MRI versus CT only, p = 0.001) (Fig. 4D), and no difference in OS was observed in solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm (p = 0.923) (Fig. 5D).After the PSM procedure, all baseline variates were balanced (p > 0.05), and the demographic and clinical-pathological features can be found in Supplement Table 4.The differences in OS of those who underwent PET/CT plus MRI after PSM were consistent with that before PSM (Supplement Fig. 9-10).In clinical T1-category lung cancer patients who underwent PET/ CT plus MRI, metabolic parameters could be the predictors for poor prognosis, compared with metabolic parameters lower than cut-off value, patients with higher than cut-off had shorter OS: SUVmax (HR, 12.94; 95%CI, 2.98-56.09;p < 0.001), SUVmean (HR, 11.33; 95%CI, 2.61-49.13;p < 0.001), SULpeak (HR, 9.65; 95%CI, 3.47-26.83;p < 0.001), MTV (HR, 9.16, 95%CI, 1.22-68.73;p = 0.031), and TLG (HR, 12.06; 95%CI, 2.78-53.25;p < 0.001)(Supplement Fig. 11-15).Histologically, lung adenocarcinoma predominated, accounting for 82.3% (1,892/2,298) of the cases.The detection rate of metastasis in lung adenocarcinoma can be found in Supplement Table 5-7, while the detection rate of metastasis in lung non-adenocarcinoma were recorded in Supplement Table 8-10.Correspondingly, the results compared with lung non-adenocarcinoma were shown in Supplement Fig. 16-19.Lung adenocarcinoma accounted for 91.4% (3,496/3,826) of the cases included in the prognosis analysis and was further classified into atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA).Significant survival differences were observed among these groups (p < 0.001) (Supplement Fig. 20A).Furthermore, no significant differences in survival rates were detected among the AAH, AIS, and MIA subtypes when assessed using PET/CT combined with MRI (p = 0.126) (Supplement Fig. 20B), significant survival differences were found in IA with or without high-grade patterns (p = 0.014 and p = 0.013, respectively) (Supplement Fig. 20C-D).EGFR mutation testing was performed in 1490 patients, and the detection rates of metastasis for EGFR mutant and EGFR wild-type patients was detailed in Supplement

Discussion
PET/CT and brain MRI are widely recognized as effective methods for detecting metastases and staging of lung cancer, offering significant advantages over contrast-enhanced CT and other radiological techniques [16,17].PET/CT could intricately delineate viable tumor tissue and metastasis by analyzing tumor metabolism, provide clinically precise lymph node staging [6], and avert unnecessary treatments intended for cure [18].Complementarily, MRI serves as an efficacious adjunctive tool, particularly adept at detecting brain metastases in lung cancer patients [17].In our study, we have stratified metastasis risk in clinical T1-category lung cancer patients by lesion type and diameter, enabling us to ascertain critical diameter thresholds for detecting metastases using PET/CT plus MRI, thereby seeking to refine existing clinical guidelines.
This study reveals a direct correlation between the increased detection rate of metastasis and the diameter for both solid and sub-solid nodules.Notably, solid nodules presented a heightened risk at comparable diameters.Additionally, we observed similar detection rates for lymph node involvement at N1 and N2 stations, which were significantly higher than those at N3 stations within the same diameter range.The incidence of M1a metastasis outstripped that of M1b and M1c metastases, aligning with outcomes reported in previous research [2,12,13,19].Demographically, our findings indicate that lung cancer patients with metastasis are predominantly male and tend to have larger nodule diameters, and variations in detection rates of metastasis may be related to the locations of the nodules and their histologic findings.
Our research delineates clear thresholds for metastasis detection based on lesions' diameters and nodules types: solid nodules measuring 8 mm and sub-solid nodules measuring 10 mm exhibited detection rates of metastasis of 0%.Further, no significant differences in OS were observed among patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm.Therefore, patients with smaller nodules demonstrated a lower propensity for metastasis, suggesting that PET/CT plus MRI might be superfluous in their cases.These examinations were still essential for clinical T1-category lung cancer patients with solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm; for these patients, CT alone or plus MRI was insufficient for detecting the potential metastases after surgery and might led to poor prognosis.
Previous research indicated that metabolic parameters could be prognostic predictors [20][21][22][23].Moon [22,23].The findings of this study confirm that these metabolic parameters can be effectively used as prognostic predictors for T1-category lung cancer.
In this study, we cautiously propose that PET/CT and MRI examinations may not be necessary for clinical T1-category lung cancer patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm.This recommendation is based on the 0% detection rate of metastasis in these groups and lack of significant differences in OS between patients with and without PET/CT plus MRI examinations.Furthermore, our findings suggest that lower detection rate of metastasis in sub-solid nodules in comparable diameter, possibly attributable to their lower metastatic capability compared to solid nodules.This is supported by Ye et al., who reported a lower prevalence of lymph node metastasis in patients with part-solid nodules (2.2%) compared to those with pure solid nodules (27%) [24].Similarly, Choi et al. observed a significant difference in the prevalence of lymph node metastasis between pure-solid nodules and mixed ground-glass nodules [25], with additional studies corroborating these findings [26][27][28].GGO-predominant lung cancers are generally characterized by less active metabolism and immune microenvironment than solid nodules, which may underlie their more indolent clinical course and less aggressive invasiveness [29].Moreover, the variance in gene mutations (e.g., TP53) between solid and sub-solid lesions may contribute to their differing metastatic potentials [29,30].Upon examining baseline data for prognostic analysis, it was observed that the cohort undergoing PET/CT plus MRI, typically of advanced age, presented larger and more aggressive nodular characteristics.Notwithstanding these factors, this group demonstrated an unexpectedly superior prognosis, even after the matching variates were propensity-score matched.This may be attributed to the enhanced diagnostic accuracy of PET/ CT combined with MRI in excluding metastasis, thereby informing, and potentially altering subsequent therapeutic strategies.
To the best of our knowledge, this study represents the inaugural effort to represent the detection rate of metastasis of PET/CT plus MRI in clinical T1-category lung cancer, specifically addressing the variations across solid and subsolid nodules of different diameters.While the NCCN guidelines advocate for PET/CT in all lung cancer cases, there remains a lack of relative data.Meanwhile, MRI is recommended for all NSCLC patients except for those with peripheral stage IA NSCLC [6,7].The use of brain MRI in early-stage lung cancer is controversial, about a quarter of patients with stage IA NSCLC receive brain imaging at diagnosis, despite national recommendations against the practice [31].Nam et al. [32] found that no difference was observed between patients with clinical stage IA NSCLC who underwent brain MRI and those who did not in terms of OS.However, relevant studies did not stratify the metastatic risk of lung cancer based on lesions' size and morphological characteristics simultaneously, therefore, for clinical T1-category lung cancer patients, the conclusions may be incomplete and imprecise.Our study stratifies patients based on metastatic risk in terms of the lesions' size and morphological characteristics in clinical T1-category lung cancer patients.There was a difference in OS between clinical T1-category lung cancer patients with solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm who underwent brain MRI and those who did not, but the difference was not statistically significant.Significantly, our study suggests an economic advantage for clinical T1-category lung cancer patients with smaller nodules (solid nodules <8 mm and sub-solid nodules <10 mm), proposing that they could be exempted from PET/CT plus MRI examinations.This recommendation could reduce unnecessary medical interventions, thereby saving costs and facilitating the healthcare resources allocation [33].
It is crucial to consider the local medical and economic circumstances when deciding whether to utilize or forgo combined PET/CT and MRI.Additionally, although the sensitivity of PET/CT in lung cancer is generally recognized, 2D mode image acquisitions used in this study is below the state of the art, besides, the specificity is limited [34].More accurate methods/tools for metastasis detection, like molecular biomarkers and artificial intelligence (AI)-based diagnosis, particularly in clinical T1-category lung cancer patients [17,[35][36][37][38] This study presents several limitations.Firstly, the nature of retrospective studies inherently introduces potential biases in patient selection and evaluation.These biases may stem from factors, including the non-randomized selection of participants and reliance on existing records.Our findings necessitate further validation through a prospective multi-center study.Secondly, the genetic profiling in our study was predominantly focused on EGFR mutations, with only a subset of patients being assessed for other driver gene mutations.Thirdly, all the PET scanning was performed by using 2D mode, which is below the state of the art and may reduce sensitivity.Image acquisition using 3D mode is warrant to validified our findings.
In conclusion, our findings indicate that PET/CT plus MRI may not be necessary for clinical T1-category lung cancer patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm, considering their lower metastatic potency.Conversely, these imaging modalities are recommended for patients with solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm, where the risk of metastasis is comparatively higher.

Fig. 1
Fig. 1 Flowcharts depicting criteria for inclusion and exclusion of study participants

Fig. 2
Fig. 2 Comparison of Metastasis in Solid and Sub-solid Nodules in T1-Category Lung Cancer.Panels A-C depict nodule diameters (5-30 mm) on the X-axis versus detection rates of metastasis on the

Fig. 3
Fig. 3 Detection Rates of Metastasis in T1-Category Lung Cancer with Solid and Sub-solid Nodules.Panels A-C depict nodule diameters (5-30 mm) on the X-axis versus detection rates of metastasis on the Y-axis: A represents all nodules, B indicates solid nodules, and

Fig. 4
Fig. 4 Overall Survival in T1-Category Lung Cancer Patients with Solid (≥ 8 mm) and Sub-Solid (≥ 10 mm) Nodules, Analyzed by PET/CT plus MRI, CT plus MRI, and CT only.Panel A-D displays the patient's overall survival time (in months) on the X-axis, with the Y-axis showing the overall survival rate of post-surgical tumor resection.A: solid nodule ≥ 8 mm & sub-solid nodule ≥ 10 mm; B: solid nodule ≥ 8 mm; C: sub-solid nodule ≥ 10 mm and D: solid nodule ≥ 8 mm & sub-solid nodule ≥ 10 mm among PET/CT plus MRI, CT plus MRI, and CT only.The overall survival was estimated using

Fig. 5
Fig. 5 Overall Survival in T1-Category Lung Cancer Patients with Solid (< 8 mm) and Sub-Solid (< 10 mm) Nodules, Analyzed by PET/CT plus MRI, CT plus MRI, and CT only.Panel A-D displays the patient's overall survival time (in months) on the X-axis, with the Y-axis showing the overall survival rate of post-surgical tumor resection.A: solid nodule < 8 mm & sub-solid nodule < 10 mm; B: solid nodule < 8 mm; C: sub-solid nodule < 10 mm and D: solid nodule < 8 mm & sub-solid nodule < 10 mm among PET/CT plus MRI, CT plus MRI, and CT only.The overall survival was estimated using

Table 1
The demographic and clinical-pathological features of T1-category lung cancer patients with pulmonary nodules lobe, LLL Left lower lobe, RUL Right upper lobe, RML Right middle lobe, RLL Right lower lobe, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, SCLC small cell lung cancer, NA not available.EGFR, epidermal growth factor receptor; SUVmax, maximum standardized uptake value; SUVmean, mean standardized uptake value; SULpeak, standardized uptake values corrected for lean body mass; MTV, metabolic tumor volume; TLG, total lesion glycolysis * LUL Left upper
et al. found that SUVmax is an independent prognostic indicator capable of significantly improving risk stratification, Kurtipek et al. indicated that SUVmean and MTV had a significant impact on prognosis [21], Ling et al. and Lee et al. pointed out that MTV and TLG may have predictive value