Evaluation of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET in grading non-functioning pancreatic neuroendocrine neoplasms <20 mm without metastasis

Introduction

Pancreatic neuroendocrine neoplasms (panNENs) are a unique group of tumors that originate from neuroendocrine cells. Relevant epidemiological studies in China have shown that panNENs account for about 30% of all gastrointestinal-panNENs, and their incidence is still increasing, possibly due to advances in diagnostic methods and increased awareness among health care professionals (1). Currently, the overall incidence of panNENs is estimated at approximately 1.5 cases per 100,000 individuals each year (2).

panNENs comprise well-differentiated panNENs and poorly differentiated pancreatic neuroendocrine carcinomas. According to the World Health Organization classification, panNENs are further stratified into three grades based on mitotic count and Ki67 index: namely, Grade 1 (G1), G2, and G3 (3). In G1 tumors, the mitotic count is <2 cells/2 mm², and the Ki67 index is <3%; in G2 tumors, the mitotic count is 2–20 cells/2 mm², and the Ki67 index is 3–20%; and in G3 tumors, the mitotic count is >20 cells/2 mm², and the Ki67 index is >20% (4). The clinical management of small (<20 mm) panNENs remains challenging. The latest National Comprehensive Cancer Network guidelines recommend that for nonfunctional, nonmetastatic panNENs smaller than 20 mm, G2 tumors warrant active surgical resection, while G1 lesions may be managed through surveillance strategies to avoid surgical complications (5). Some real-world data studies have also shown that active surveillance or endoscopic ultrasonography-guided ablation are safe alternative strategies to surgical resection for patients with nonfunctional, nonmetastatic G1 panNENs smaller than 20 mm (6-8). This distinction underscores the critical importance of accurate pathological grading in guiding treatment decisions. Currently, tumor grading primarily relies on localized biopsy specimens. However, significant intratumoral heterogeneity in panNENs can lead to histological grade variations within individual lesions. Consequently, limited biopsy sampling may underestimate or overestimate the true tumor grade; both could be problematic in management (9).

Imaging plays an essential role in managing neuroendocrine neoplasms (NENs). While conventional modalities including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) form the diagnostic foundation (10), they offer limited accuracy in predicting pathological tumor grade (11). The development of ⁶⁸Ga-labeled somatostatin analog, such as ⁶⁸Ga-DOTA⁰-Tyr³-octreotate (⁶⁸Ga-DOTATATE), has advanced the clinical use of positron emission tomography (PET) in NENs management, with current evidence confirming its superior sensitivity over conventional imaging for NENs (12). ⁶⁸Ga-DOTATATE is now established as the gold standard for evaluating well-differentiated NENs classified as G1 or G2, which typically exhibit high somatostatin receptor density (13). Additionally, PET with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) has been proposed as a tool for assessing the aggressiveness of NENs, particularly moderate- to high-grade (G2 or G3) advanced tumors (14). Although G1 NENs are generally considered indolent tumors with low growth rates, some cases may progress rapidly and respond poorly to medical treatment. A previous study suggested that ¹⁸F-FDG PET can be useful in the evaluation of G1 NENs to identify patients at greater risk for an unfavorable disease course (15).

The maximum standardized uptake value (SUV) on PET imaging correlates with the pathological grade of NENs (16). Low-grade NENs are typically ⁶⁸Ga-DOTATATE positive and ¹⁸F-FDG negative, whereas high-grade tumors show the opposite pattern, illustrating an inverse relationship known as the “flip-flop” phenomenon. However, the ability to differentiate the grade of NENs on the basis of the SUV from PET remains controversial (11,17,18). Importantly, most of these studies included mixed populations, comprising patients with tumors larger than 20 mm, functional, metastases, and tumor grade assessments on the basis of biopsy findings.

Thus, we aimed to evaluate the effectiveness of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET in the pretreatment grading of nonfunctional panNENs without metastasis and with lesions smaller than 20 mm to identify patients suitable for surveillance or surgical resection. Additionally, we assessed the discriminative performance of visual assessment methods for clinical applicability. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2457/rc).

Methods

Study populations

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of West China Hospital (No. 2023–954), and individual consent for this retrospective analysis was waived. We consecutively included patients with NENs who underwent ⁶⁸Ga-DOTATATE PET imaging at West China Hospital between January 2019 and January 2025. The inclusion criteria were as follows: (I) patients with panNENs confirmed by postoperative pathology; (II) clear histopathological grade from postoperative pathology; (III) lesion diameter <20 mm on conventional imaging (CT, MRI or ultrasound); (IV) no function; and (V) no evidence of metastasis. The exclusion criteria were as follows: (I) history of antitumor treatment prior to imaging; (II) history of other malignant tumors; (III) not surgically resected. For patients who also underwent ¹⁸F-FDG PET, we analyzed the parameters from both examinations. The workflow of patient selection is shown in Figure 1.

Figure 1 Workflow of patient selection. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ⁶⁸Ga-DOTATATE PET/CT, ⁶⁸Ga-DOTA⁰-Tyr³-octreotate positron emission tomography/computed tomography; NENs, neuroendocrine neoplasms; panNENs, pancreatic neuroendocrine neoplasms.

Imaging protocol

⁶⁸Ga-DOTATATE and ¹⁸F-FDG were synthesized in the Nuclear Medicine Department of West China Hospital on separate days within a one-week period. PET/CT scans were performed on either the United Imaging uMI780 system (United Imaging Healthcare, Shanghai, China) or the Gemini GXL16 system (Philips, Eindhoven, the Netherlands). To reduce inter-scanner variability, both systems underwent routine quality control and cross-calibration using the same dose calibrator according to institutional protocols and European Association of Nuclear Medicine (EANM) guidelines (19). Acquisition and reconstruction parameters were harmonized as far as feasible between the two scanners, and scanner-specific reconstruction algorithms recommended by the manufacturers were applied. For ⁶⁸Ga-DOTATATE PET, patients underwent imaging without prior fasting or blood glucose testing. After intravenous injection of the tracer (1.85 MBq/kg), PET data acquisition commenced at approximately 60 minutes post-injection. In contrast, ¹⁸F-FDG PET required at least 6 hours of fasting prior to tracer administration (5.18 MBq/kg), with confirmed blood glucose levels below 11 mmol/L in all patients. Image acquisition for ¹⁸F-FDG PET started 60 minutes after injection. Both protocols employed three-dimensional PET acquisition with 2.5 minutes per bed position.

Imaging analysis

Following standard iterative reconstruction, ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET images were independently evaluated by two blinded nuclear medicine physicians. Discrepant interpretations were resolved by a third board-certified specialist. Surgically resected lesion locations were verified against operative records. Two physicians manually delineated slice-by-slice tumor boundaries to define the region of interest (ROI). For ⁶⁸Ga-DOTATATE-positive/¹⁸F-FDG-negative cases, ROIs were transposed from ⁶⁸Ga-DOTATATE to ¹⁸F-FDG images. Maximum SUVs (G-SUV for ⁶⁸Ga-DOTATATE; F-SUV for ¹⁸F-FDG) were calculated as [maximum tracer concentration (kBq/mL)]/[decay-corrected injected dose (kBq)/body weight]. The G-SUV/F-SUV ratio was analyzed given its established grading relevance (18). We also investigated whether visual assessment could differentiate G1 from G2 tumors, thereby triaging panNENs patients for qualitative diagnosis. Positive ⁶⁸Ga-DOTATATE uptake was defined as activity exceeding splenic background; ¹⁸F-FDG positivity required uptake above the physiological level of the liver (Figure 2).

Figure 2 The above images demonstrate tumor samples with different uptake on PET. (A,E) The lesion (thin arrow) with uptake higher than that of the spleen on ⁶⁸Ga-DOTATATE PET; (B,F) the lesion (thin arrow) with uptake higher than that of the liver on ¹⁸F-FDG PET; (C,G) the lesion (thick lesion) with uptake no higher than that of the spleen on ⁶⁸Ga-DOTATATE PET; (D,H) the lesion (thick lesion) with uptake no higher than that of the liver on ¹⁸F-FDG PET (hepatic focus was confirmed to be infection finally). ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTA⁰-Tyr³-octreotate; PET, positron emission tomography.

Statistical analysis

Continuous variables are presented as the median [25th percentile, 75th percentile], or mean ± standard deviation, whereas categorical data are expressed as counts (percentages). Normality was assessed via the Kolmogorov-Smirnov test. Continuous variables were analyzed using the Student’s t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data, while categorical variables were assessed with the Chi-squared test. The Spearman correlation coefficient was applied to assess the strength and direction of bivariate relationships. Receiver operating characteristic (ROC) analysis was performed to determine optimal cutoff values using Youden’s J-index [maximizing (sensitivity + specificity − 1)] for differentiating between groups. Diagnostic performance was expressed in terms of sensitivity and specificity. The Bonferroni correction was used to control for type I error, and the adjusted P value was eventually shown. All the statistical analyses were performed via SPSS 27.0 (Chicago, IL, USA), with a significance threshold set at P<0.05. The GraphPad Prism 10.4.2 (San Diego, CA, USA) was used to plot the results.

Results

Patient characteristics

The study enrolled 34 patients with nonfunctional panNENs smaller than 20 mm and without lymph node or distant metastasis. Among them, 28 patients were scanned using United Imaging equipment, and 6 patients were scanned using Philips equipment. The cohort comprised 15 women (44%) and 19 men (56%), aged 14–71 years (mean: 48 years). All patients underwent ⁶⁸Ga-DOTATATE PET/CT imaging with a median tracer activity of 125 MBq [interquartile range (IQR), 121–150 MBq]. Among the 34 patients, 6 (18%) had multiple lesions, with each lesion analyzed as a separate entity; all lesions within the same patient showed consistent grades. A total of 41 lesions were detected by ⁶⁸Ga-DOTATATE PET, including 15 G1 and 26 G2 tumors. No significant differences were observed in clinical characteristics (gender, age, tumor location) between G1 and G2 patients, nor in lesion size between G1 and G2 tumors (Table 1). A subgroup of 19 patients with 24 lesions concurrently underwent ¹⁸F-FDG PET (median activity: 348 MBq; IQR, 323–388 MBq), comprising 9 G1 and 15 G2 tumors. All dual-imaging patients used a single scanner.

Comparison of SUVs in G1 and G2 panNENs

On ⁶⁸Ga-DOTATATE PET, there was no significant difference in the G-SUV between G1 and G2 tumors [34.6 (19.1, 38.5) vs. 47.2 (18.6, 73.3), P=0.355]. Conversely, on ¹⁸F-FDG PET, the F-SUV of G1 tumors was significantly lower than that of G2 tumors [2.2 (2.1, 2.4) vs. 3.4 (2.5, 7.5), P=0.003]. The G-SUV/F-SUV ratio showed no significant difference between G1 and G2 tumors [11.8 (8.9, 15.8) vs. 11.4 (6.3, 19.8), P=0.861] (Table 2, Figure 3, results are based on lesion acquisition).

Figure 3 Comparison of G-SUV (A), F-SUV (B) and G-SUV/F-SUV (C) in panNENs by grade. ns, not significant, P>0.05; **, P<0.01. F-SUV, SUV on ¹⁸F-FDG; G-SUV, maximum standardized uptake values on ⁶⁸Ga-DOTATATE.

To address inter-scanner variability, we also evaluated SUV differentials for grading within the same machine, yielding consistent results (Table 2). A total of 28 patients with 35 lesions (13 G1, 22 G2) underwent ⁶⁸Ga-DOTATATE PET/CT on United Imaging systems, among whom 14 patients with 19 lesions (7 G1, 12 G2) also underwent ¹⁸F-FDG PET/CT on the same systems.

The results based on patient-level analysis were similar to the aforementioned lesion-level analysis (Table S1).

Comparison of SUV cutoff values and diagnostic performance in G1 and G2 panNENs

For G2 tumors, while an F-SUV >2.5 provided effective discrimination [area under the curve (AUC) 0.85, sensitivity 73%, specificity 89%], both the G-SUV and the G-SUV/F-SUV ratio failed to reliably distinguish G1 and G2 panNENs. A G-SUV cutoff of <41.0 yielded an AUC of only 0.59 (sensitivity 54%, specificity 80%), indicating very limited diagnostic utility. Similarly, the G-SUV/F-SUV ratio with a cutoff of 7.8 showed no meaningful discriminative capacity, achieving an AUC of just 0.53 (sensitivity 47%, specificity 78%) (Figure 4, Table 3, results are based on lesion acquisition). Similar results were observed in patient-level and lesion-level analyses (Table S2).

Figure 4 Receiver operating characteristic curves of various imaging parameters for discriminating between G1 and G2 panNENs. G, grade; F-SUV, SUV on ¹⁸F-FDG; G-SUV, maximum standardized uptake values on ⁶⁸Ga-DOTATATE; panNENs, pancreatic neuroendocrine neoplasms.

The correlation of SUVs with tumor size

In this study, no significant correlations were observed between tumor diameter and either G-SUV or F-SUV (P=0.960 and P=0.423, respectively). However, a moderate negative correlation was found between maximum tumor diameter and the G-SUV/F-SUV ratio (r=−0.532, P=0.007) (Figure 5). These findings indicate that in semiquantitative imaging analysis, tumor size shows some association with the G-SUV/F-SUV ratio but demonstrates little relationship with individual G-SUV or F-SUV values.

Figure 5 Correlation analysis of G-SUV (A), F-SUV (B) and G-SUV/F-SUV (C) with tumor diameter. F-SUV, SUV on ¹⁸F-FDG; G-SUV, maximum standardized uptake values on ⁶⁸Ga-DOTATATE.

Evaluating visual assessment for discriminating G1 from G2 panNENs

On ⁶⁸Ga-DOTATATE PET, 43% (6/14) of tumors with uptake level no higher than that of the spleen were G1 and 57% (8/14) were G2; 33% (9/27) of tumors with uptake level higher than that of the spleen were G1 and 67% (18/27) were G2 (P=0.548). On ¹⁸F-FDG PET, 53% (8/15) of tumors with uptake level no higher than background were G1 and 47% (7/15) were G2. Conversely, only 11% (1/9) of tumors with uptake level higher than the background on ¹⁸F-FDG PET were G1, but 89% (8/9) were G2 tumors (P=0.102), resulting in a high positive predictive value (PPV, 89%) for G2 (Table 4, results are based on lesion acquisition). The emphasis on PPV was intended to explore the potential clinical utility of PET-based grading rather than to substitute for statistical significance testing. Therefore, these findings should be regarded as exploratory, and further validation in larger, prospective studies is required. Patient-level analyses yielded results comparable to those obtained from lesion-level analyses (Table S3).

Discussion

In this study, we assessed the ability of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT imaging parameters to differentiate the grade of nonfunctional panNENs smaller than 20 mm without metastasis. Our results indicated that the F-SUV, as opposed to the G-SUV and the G-SUV/F-SUV ratio, could effectively distinguish G1 from G2 panNENs. Additionally, though failed to differentiate the grade status, visual assessment from ¹⁸F-FDG PET demonstrated high PPV for G2 using the surrounding background as the reference. This observation suggests potential clinical utility, but requires confirmation in larger, prospective studies.

Currently, ⁶⁸Ga-DOTATATE PET is the preferred imaging technique for evaluating NENs, but its role in predicting tumor pathological grade has been less explored and has yielded conflicting results. Most studies report no significant difference in ⁶⁸Ga-DOTATATE uptake between G1 and G2 NENs (11,16,17,20), whereas other studies report differences (18,21). These discrepancies may stem from heterogeneity in tumor sites, tumor sizes, metastatic patterns, and diagnostic standards (biopsy vs. resection). While our results align with the broader literature, the novelty of this study lies in its exclusive focus on small (<20 mm), non-functional, non-metastatic panNENs. This cohort was chosen due to a clear management dichotomy in current guidelines: close surveillance or endoscopic ultrasonography-guided ablative techniques for G1 tumors versus surgical resection for G2 tumors. To our knowledge, this is the first imaging-focused PET study in this narrowly defined population.

Previously, ¹⁸F-FDG PET was regarded as having a low positive detection rate for NENs and was not recommended as a routine examination modality for the evaluation of NENs. However, recent studies suggest that ¹⁸F-FDG PET/CT can serve as a supplemental technique alongside ⁶⁸Ga-DOTATATE PET/CT (22,23). It is generally accepted that ¹⁸F-FDG uptake is greater in G2 NENs than in G1 NENs when it is used to predict tumor pathological grade. Similarly, our study demonstrated that ¹⁸F-FDG PET could differentiate between G1 and G2 panNENs, with quantitative analysis identifying an optimal SUV cutoff of 2.5 for grade differentiation. In addition, although visual analysis was unable to distinguish G1 from G2 panNENs, it demonstrated a high PPV for identifying G2 lesions (89%, 8/9). This finding may have potential clinical value in guiding treatment selection; however, further validation in prospective studies is required.

Additionally, we evaluated the use of multimodal imaging to enhance the ability to predict the pathological grade of panNENs. Compared with ⁶⁸Ga-DOTATATE PET alone, the G-SUV/F-SUV ratio from ⁶⁸Ga-DOTATATE PET and ¹⁸F-FDG PET improved the diagnostic sensitivity but did not increase the efficiency or specificity on distinguishing G1 from G2 panNENs. This result is consistent with a previous panNENs grading study, whereas that study had no eligibility restrictions regarding tumor size, functional status, or metastasis and accepted both biopsy and surgical specimens for diagnosis (18).

Among the imaging parameters analyzed in this study, neither G-SUV nor F-SUV showed significant correlation with lesion size. These findings suggest that F-SUV derived from ¹⁸F-FDG PET imaging is a clinically reliable parameter in our study, as it remains largely unaffected by variations in tumor size.

This study had several limitations. First, its single-center, retrospective design with a small sample necessitates validation through larger, prospective multicenter studies. However, given the low incidence of NENs and our focus on localized, small (<20 mm) panNENs, the findings remain clinically relevant. We plan to expand the cohort in future research. Second, although data were collected over a long period and from different PET scanners, comparative analysis confirmed consistency, supporting the reliability of the integrated dataset. Third, due to heterogeneity in conventional imaging (CT, MRI, ultrasound), we did not compare PET with these modalities—an important direction for future studies. Additionally, limited sample size prevented subgroup analysis within G2 tumors. As the main objective was to evaluate PET’s grading capability, applying varying Ki67 thresholds might have obscured this aim; such analyses will be reserved for future prognostic studies. Furthermore, including only surgically resected patients may limit generalizability to surveillance cohorts, but using histopathology as the reference standard was appropriate for validating noninvasive grading. Future work will compare PET with biopsy-based pathology. Lastly, the lack of survival or progression endpoints precluded assessment of PET’s prognostic value and its impact on clinical decision-making, which will be addressed in subsequent research.

Conclusions

In conclusion, for nonfunctional panNENs under 20 mm in diameter and without metastasis, the SUV or visual assessment on ⁶⁸Ga-DOTATATE PET cannot be used to predict grade. In contrast, both quantitative SUV measurements and visual assessment on ¹⁸F-FDG PET may contribute to tumor grading and help panNENs patients select appropriate treatment options, though their clinical utility requires further validation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2457/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2457/dss

Funding: This study was supported by the National Key R&D Program of China (No. 2023YFC2414201-1), the Postdoctor Research Fund of West China Hospital, Sichuan University (No. 2025HXBH161), and the National Natural Science Foundation of China (No. 81971653).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2457/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of West China Hospital (No. 2023–954), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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