Abstract
The present study aimed to compare the efficacy of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT imaging in the diagnosis, staging, and prognosis evaluation of neuroendocrine tumors (NET). A total of 55 patients (43 were initially evaluated, 12 were evaluated after treatment) who underwent fluorine-18 labeled fluorodeoxyglucose (18F-FDG) and 68Ga DOTATE PET/CT examinations were reviewed retrospectively, and the pathological data were collected. In the initial evaluation, 27/43 were pathologically confirmed as NET patients, as detected by gallium-68 labeld 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaceticacid-D-Phel-Tyr3-Thr8-OC; among them, 23 were correctly detected by 18F-FDG. In lesion-based comparison, 119/168 focal lesions were depicted on 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT, respectively (P = .0363). Strikingly, gallium-68 labeld 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaceticacid-D-Phel-Tyr3-Thr8-OC had higher maximum standard uptake value than 18F-FDG but was negatively related to the NET grade for the former, while the latter was positively related to the NET. The value of 68Ga-DOTATATE PET/CT in the diagnosis and staging of NET is higher than that of 18F-FDG PET/CT in NETs, while the value of 18F-FDG PET/CT cannot be ignored in the NET. The combined application of the 2 tracers has major clinical significance in the management of patients with NET.
Keywords: 18F-FDG, 68Ga-DOTATATE, neuroendocrine neoplasm, neuroendocrine tumors, PET/CT
1. Introduction
Neuroendocrine tumors (NET) are widely distributed and heterogeneous tumors originating from neuroendocrine cells, and the major characteristic of which is that they can express somatostatin receptors (SSTRs).[1,2] NET can occur in any tissue and organ; however, the most common is the pancreas (31.5%), followed by the rectum (29.6%) and stomach (27%).[3] The manifestations of NET in traditional imaging techniques, such as ultrasound, computed tomography (CT), and magnetic resonance imaging, lack specificity, making diagnosis difficult.[4,5] Most patients with NET have lost the opportunity to undergo radical surgery because of distant metastasis of the liver, lung, and bone at the time of diagnosis; hence, an early and accurate diagnosis is essential. As the most common functional imaging technology, 18F-FDG PET/CT has been widely used in the diagnosis, staging, posttreatment response evaluation, and prognosis of various malignant tumors. The molecular probe gallium-68 labeld 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaceticacid-D-Phel-Tyr3-Thr8-OC (68Ga-DOTATATE), obtained using the radionuclide 68Ga-labeled somatostatin analog, was specifically combined with the highly expressed SSTR on the surface of NET cells to complete the targeting imaging.[6,7] However, previous studies have shown that 2 positron emission tomography (PET) radioactive tracers, fluorine-18 labeled fluorodeoxyglucose (18F-FDG) and 68Ga-DOTATATE have different diagnostic efficacy for NENs with different grades and degrees of differentiation.[3,8–10] The present study aimed to compare the efficacy of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT imaging in the diagnostic efficacy of well-differentiated and poorly differentiated NET that would aid in clinical decisions.
2. Materials and methods
2.1. Patients
A retrospective analysis was conducted on patients who underwent 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT from December 2019 to October 2022 at the Affiliated Hospital of Zunyi Medical University, followed by histopathological examination. The interval between 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT imaging was 24 to 48 hours. All patients did not receive radiotherapy, chemotherapy, and radionuclide-labeled SSA treatment within 1 month before imaging, and all patients signed an informed consent form before the examination.
2.2. 18F-FDG PET/CT imaging
18F-FDG PET/CT was performed 24 to 48 hours before the 68Ga-DOTATATE PET/CT. The HM-10HP cyclotron of Sumitomo Corporation of Japan and F300E modular automatic synthesis device of FDG chemical synthesis system was used to produce and synthesize 18F-FDG, and > 95% pure radiochemical was used for imaging after intravenous injection. The patients fasted for at least 6 hours before undergoing the examination, and the fasting blood glucose was controlled to be < 11.1 mmol/L. According to patients weight, 18F-FDG was injected intravenously with 0.1 to 0.15 mCi/kg. Then, the patient was asked to rest quietly for 1 hour, and PET/CT imaging was performed after urination. The imaging equipment adopted the Biograph mCT PET/CT scanner of German GE. The scanning range was from the top of the skull to the middle of the femur. CT scanning was carried out first at the following parameters: tube voltage 120 kV, tube current 119 mA, and layer thickness 5 mm. PET scanning was performed immediately after the completion of CT scanning. The 3-dimensional acquisition mode was 2.0 minutes/bed, with 6 to 7 beds, and PET images were attenuated and corrected with CT data and reconstructed with TrueX + TOF method after image acquisition.
2.3. 68Ga-DOTATATE PET/CT imaging
68Ga-DOTATATE PET/CT was performed 1 to 2 days after 18F-FDG PET/CT. 68Ga was eluted by the “68Ge/68Ga” generator of ITM Medical Isotopes GmbH (Germany) and reacted using the precursor DOTATATE purchased from China Tongfu Co., Ltd to obtain 68Ga-DOTATATE. The radiochemical with > 95% purity was used for imaging after intravenous injection.
According to patients weight, 68Ga- DOTATATE 0.05 mCi/kg was injected intravenously. Then, the patient was asked to drink more water and undergo imaging 45 to 60 minutes after urination post-intravenous injection of the contrast agent. The imaging equipment and technology were the same as for 18F-FDG PET/CT imaging.
2.4. Image analysis and evaluation
Two physicians with > 5 years of experience in nuclear medicine assessed image quality without knowledge of clinical data, including pathological findings, and recorded the location of lesions and their maximum standard uptake value (SUVmax) In case of discrepancy, the third chief doctor with > 10 years of experience was consulted to reach a consensus. The 18F-FDG, 68Ga-DOTATATE imaging agent uptake at the lesion site was higher than the mediastinal blood pool or organ background, which was considered as a positive lesion, and the false positive lesions with high probability were excluded in combination with the shape, location, size of the lesion, and the patient’s traumatic history, surgical history, and other factors. For all primary lesions suspected to be positive on PET/CT, pathological biopsy is the gold standard. PET/CT results consistent with pathological results are true positive (TP) or true negative (TN), and those inconsistent with pathological results are false positive (FP) or false negative (FN). For suspected metastases, it is not possible to biopsy every lesion as it would increase patient suffering and is ethically unfeasible, so CT and magnetic resonance imaging follow-up of at least 3 months with progressive enlargement of the lesion is also considered TP. The sensitivity (TP/TP + FN), specificity (TN + FP), and accuracy (TP + TN/TP + FP + TN + FN) were described to evaluate the diagnostic performance of 18F-FDG and 68Ga- DOTATATE PET/CT for primary NETs.
2.5. Statistical analysis
SPSS 18.0 (IBM Corporation, Armonk, NY) software was used for data analysis. The measurement data conforming to the normal distribution were represented by mean ± standard deviation (x ± SD). The non-normal distribution was represented by the median (upper and lower quartiles), using the t test, χ2 test, Kruskal–Wallis H test, or McNemar test to compare the data between groups, and P < .05 indicated a statistically significant difference.
2.6. Data availability
The data that support these findings are available from the corresponding author upon reasonable request.
3. Results
3.1. Comparison of the diagnostic performance in initial evaluation between 68Ga-DOTATATE and 18F-FDG PET/CT
A total of 55 patients were evaluated by 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT, including 43 patients with the initial evaluation and 12 with posttreatment evaluation. In the initial evaluation, 27/43 (62.8%) patients were confirmed to have neuroendocrine tumors by histological examination, including 10 females and 17 males, aged 25 to 73 (mean: 53.9 ± 11.6) years, while 16/43 (37.2%) patients could not be confirmed. The details of 39 patients with NET, including 27 patients confirmed by pathology in the initial evaluation and 12 evaluated after treatment, are summarized in Table 1. 18F-FDG PET/CT accurately detected tumors in 23/27 patients at a sensitivity of 85.2%. Since other malignant tumors, such as adenocarcinoma, showed high uptake of 18F-FDG PET/CT, leading to false positives in the enrolled patients. Therefore, the specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of 18F-FDG PET/CT in diagnosing NET were low, which were 37.5%, 69.7%, 60% and 67.4%, respectively, and the optimal cutoff value of SUVmax is 2.4. 68Ga-DOTATATE PET/CT correctly detected all patients with NET (27/27), and the sensitivity of diagnosing NENs was 100%. In addition, the specificity, NPV, PPV and accuracy of 68Ga-DOTATATE PET/CT in diagnosing NET were higher than those of 18F-FDG, which were 93.8%, 96.4%, 100%, and 97.7%, respectively, and the optimal cutoff value of SUVmax was 6.9. However, both 68Ga-DOTATATE and 18F-FDG PET/CT were falsely positive in a patient with nesidioblastosis. The diagnostic performance of 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT in NETs is shown in Table 2.
Table 1.
Clinical and epidemiologic characteristics of the patients with neuroendocrine tumors.
| Characteristic | Value | Characteristic | Value | ||
|---|---|---|---|---|---|
| Gender (n) | Male | 23 (59.0%) | Primary site (n) | Pancreas | 19 (48.7%) |
| Female | 16 (41.0%) | Intestine | 10 (27.0%) | ||
| Age (yr) | Median | 50 | Stomach | 5 (13.5%) | |
| Interquartile range | 25-73 | Liver | 3 (7.7%) | ||
| Grade (n) | G1 | 7 (26.0%) | Hindgut | 2 (5.1%) | |
| G2 | 9 (33.3%) | PET/CT indication (n) | Initial evalution | 27 (69.2%) | |
| G3 | 11 (40.7%) | Posttreatment evalution | 12 (30.8%) | ||
PET/CT = positron emission tomography/computed tomography, PET = positron emission tomography.
Table 2.
The diagnostic performance of 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT in NETs.
| Parameter | 18F-FDG | 68Ga-DOTATATE |
|---|---|---|
| Sensitivity | 85.2% (23/27) | 100% (27/27) |
| Specificity | 37.5% (6/16) | 93.8% (15/16) |
| Positive predictive value | 69.7% (23/33) | 96.4% (27/28) |
| Negative predictive value | 60% (6/10) | 100% (15/15) |
| Accuracy | 67.4% (29/43) | 97.7% (42/43) |
F-FDG = fluorine-18 labeled fluorodeoxyglucose, CT = computed tomography, NET = neuroendocrine tumors, PET = positron emission tomography.
3.2. Comparison of tumor detection rates between 68Ga-DOTATATE and 18F-FDG PET/CT
119/168 focal lesions were depicted on 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT, respectively (P = .0363). Lesion-based comparison showed that 68Ga-DOTATATE had a higher detection ability for primary lesions, liver, bone, and lymph node lesions; and a statistically significant difference was detected in bone metastases (P = .0347).
Regarding SUVmax of lesions, 68Ga-DOTATATE demonstrated significantly higher mean uptake for all lesions, including primary lesions and liver, lymph node, and bone lesions, than 18F-FDG (P < .001, Table 3).
Table 3.
Uptake of lesions on 18F-FDG and 68Ga-DOTATATE PET/CT.
| Parameter | Lesions (n) | P value | SUVmax | P value | |||
|---|---|---|---|---|---|---|---|
| 18F- | 68Ga- | 18F- | 68Ga- | ||||
| Primary tumor | 29 | 33 | .7463 | 4.9 ± 0.5 | 23.9 ± 3.8 | <.001 | |
| Liver metastases | 33 | 55 | .2524 | 4.8 ± 1.4 | 42.3 ± 15.3 | <.001 | |
| Lymph node metastases | 34 | 37 | .7849 | 4.6 ± 1.4 | 6.0 ± 1.7 | .0657 | |
| Bone metastases | 16 | 36 | .0347 | 4.1 ± 1.5 | 13.2 ± 4.8 | <.001 | |
| Rare metastases | Peritoneum | 4 | 4 | - | 4.2 ± 1.2 | 14.6 ± 5.8 | - |
| Spleen | 2 | 2 | - | 5.0 ± 1.5 | 20.5 ± 8.0 | - | |
| Portal vein | 1 | 1 | - | 4.1 | 10.4 | - | |
| Total | 119 | 168 | .0363 | 4.7 ± 1.3 | 21.4 ± 6.4 | <.001 | |
F-FDG = fluorine-18 labeled fluorodeoxyglucose, 68Ga-DOTATATE = gallium-68 labeld 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaceticacid-D-Phel-Tyr3-Thr8-OC, CT = computed tomography, PET = positron emission tomography, SUVmax = maximum standard uptake value.
3.3. Correlation of grade with 18F-FDG and 68Ga-DOTATATE PET/CT SUVmax
18F-FDG PET/CT had little effect on the diagnosis of G1 grade NETs. Among 7 cases of G1 grade NET, SUVmax of 4 lesions was similar to the background (Fig. 1), while the other 3 lesions were slightly higher than the background. Conversely, the SUVmax for 68Ga-DOTATATE in G1 NET is high, with an average of 44.6 ± 2.8. The distribution of the maximum standard uptake value (SUVmax) of the lesions in patients with G1 to G3 grade neuroendocrine tumor is shown in Figure 2. The spearman correlation results showed that the 18F-FDG SUVmax of lesions was positively correlated with the grade of NETs, with a coefficient of 0.5528, while the 68Ga-DOTATATE was negatively correlated with NEN grading, with a coefficient of 0.7164.
Figure 1.
(A–D) 18F-FDG PET/CT fusion images of 4 false negative G1 grade NET cases; (A–D) the corresponding 68Ga-DOTATATE PET/CT fusion images showed significant radioactive uptake of the lesions, CT = computed tomography, NET = neuroendocrine tumors, PET = positron emission tomography.
Figure 2.
(A) The distribution of the maximum standard uptake value (SUVmax) of the lesions in patients with G1 to G3 grade neuroendocrine tumor, (B) The correlation between neuroendocrine tumor grade and SUVmax of 18F-FDG and 68Ga-DOTATATE PET/CT. 18F-FDG = fluorine-18 labeled fluorodeoxyglucose, CT = computed tomography, PET = positron emission tomography.
3.4. Posttreatment evaluation of 18F-FDG and 68Ga-DOTATATE PET/CT
The average time from the beginning of treatment to PET/CT evaluation in 12 patients was 22.6 ± 5.0 months, and the results showed that 18F-FDG and 68Ga-DOTATATE PET/CT are crucial in the posttreatment evaluation. The average SUVmax in the operation area was 4.43 ± 0.98 and 2.92 ± 0.62 (18F-FDG vs 68Ga-DOTATATE), respectively, with no statistical significance (P = .2096). Regarding distant metastasis, 2 false positive lesions were detected on 18F-FDG PET/CT: 1 was confirmed as inflammation by biopsy, and the other was sigmoid colon cancer, which was negative on 68Ga-DOTATATE PET/CT (Fig. 3).
Figure 3.
A 53-year-old female patient was found to have increased radioactivity uptake in the liver (white arrows), retroperitoneum (yellow arrows), iliac vessels (green arrows) and sigmoid colon (red arrows) on 18F-FDG PET/CT (A) 1 year after the operation of stomach fundus neuroendocrine tumor, but was negative on 68Ga DOTATE PET/CT (B), which was subsequently proved to be sigmoid adenocarcinoma with multiple metastases by pathology. CT = computed tomography, PET = positron emission tomography.
4. Discussion
PET/CT combines functional imaging with morphological manifestations and is widely used in patients with various malignant tumors, including NET.[11] The current study compared the detection rates of the 2 PET tracers, 18F-FDG and 68Ga-DOTATATE, in the primary and metastatic neuroendocrine tumors. The results showed that the latter’s accuracy was significantly higher than that of the former. As a specific imaging agent targeting SSTR, 68GA-DOTATATE has shown good diagnostic performance for NET, the choice of the treatment scheme, and prognosis evaluation.
Among the 27 cases of NET confirmed by pathology in the present study, 68GA-DOTATATE imaging detected primary lesions missed by 18F-FDG imaging in 4 G1 grade NET patients. This phenomenon may be attributed to 18F-FDG reflecting the glucose metabolism of tumors. Most malignant tumor cells have a strong metabolism and corresponding increased energy consumption, indicating high 18F-FDG uptake, while G1 grade NET is well-differentiated and shows low uptake, thus leading to false negatives. In these detected primary tumors, the uptake of 68Ga-DOTATATE was significantly higher than that of 18F-FDG, which was consistent with the fact that highly differentiated NETs had a high expression of SSTR.[6,12] Similarly, 68Ga-DOTATATE detected several metastatic lesions, including 22 liver, 3 lymph nodes, and 20 metastatic bone lesions that were false negatives on 18F-FDG. The 2 tracers showed significant differences in the detection results of metastatic bone foci.
The grading and differentiation degree of NET plays a key role in clinical treatment decisions. The present study showed that the SUVmax of 18F-FDG and 68Ga-DOTATATE PET/CT is related to the pathological grading of NET. The SUVmax of 18F-FDG is positively related to the grading, that is, the higher the grading, the greater the SUVmax. However, the SUVmax of 68Ga-DOTATATE was negatively correlated with the grading, that is, the better the differentiation, the lower the grading, the higher the SUVmax. The reason for this result is that well-differentiated NETs have higher SSTR expression, so 68Ga-DOTATATE PET/CT imaging effect is better, with larger SUVmax, while 18F-FDG mainly reflects glucose metabolism in tumor tissues, and the higher the grade of NETs, the more vigorous glucose metabolism, so it has high SUVmax in 18F-FDG PET/CT. The detection rates of the 2 tracers in G2 and G3 patients were similar, while only 3/7 G1 patients were detected by 18F-FDG, and the SUVmax of the lesions in these 3 patients was only slightly higher than the background. Therefore, the 18F-FDG PET/CT detection rate in G1 NEN patients was significantly lower than in 68Ga-DOTATATE PET/CT.
In the initial evaluation of 43 cases of primary tumors, 1 patient with nesidioblastosis confirmed by pathology showed a false positive in 18F-FDG and 68Ga-DOTATATE PET/CT. Nesidioblastosis produces bioactive substances similar to NET, including gastrointestinal peptides and serotonin, resulting in high radioactivity uptake on 68GA-DOTATATE. However, the reason for high radioactivity uptake of 18F-FDG in the nodules is puzzling due to its benign nature. In addition to our case, the previous literature revealed that hypophosphatemic osteomalacia and meningioma express SSTR, resulting in 68Ga-DOTATATE uptake and false positives.[13] In addition, PET/CT imaging of 68Ga-labeled somatostatin analogs has been used increasingly in NET. Also, molecular probes, such as DOTANOC, DOTATOC, and DOTA-JR11 labeled with 68Ga have shown superior diagnostic performance in the clinical research of NET.[6,14–18]
In patients evaluated after treatment, 68Ga-DOTATATE PET/CT showed some metastatic lesions not shown by 18F-FDG PET/CT, including bone, liver, and lymph node metastasis, which might be attributed to tumor heterogeneity. Moreover, 18F-FDG PET/CT of 1 patient after gastric NET operation showed a significant radiation uptake in the sigmoid colon, which was suspected to be a NET invasion, while 68Ga-DOTATATE PET/CT was negative. Although adenocarcinoma was confirmed by pathology rather than NET, the specificity of 68Ga-DOTATATE missed the focus, resulting in patients’ inability to obtain timely and effective treatment. Therefore, 68Ga-DOTATATE PET/CT can detect several NET lesions, rendering 18F-FDG PET/CT necessary for improved management of NET patients and accurate evaluation of the patient’s condition.
The small sample size is the primary defect of this study. For example, only 7 cases were G1 grade NET patients. However, errors were detected in the correlation between the statistical pathological grading and imaging characteristics (SUVmax). We would need to expand the sample size for future research. Secondly, this is a single-center retrospective study with limited factors, with bias in the selection of patients. Nonetheless, the current study provides clinical diagnosis reference and treatment decisions through the systematic evaluation of the 2 tracers in diagnosing primary lesions in NET patients, the detection of distant metastatic lesions, evaluating after treatment, and the correlation between pathological grading and imaging features.
In conclusion, the value of 68Ga-DOTATATE PET/CT in the diagnosis and staging of NET is higher than that of 18F-FDG PET/CT in NETs, while the value of 18F-FDG PET/CT in NET cannot be ignored, and the combined application of the 2 tracers has critical clinical significance for the management of patients with NET. The SUVmax of 18F-FDG and 68Ga-DOTATATE PET/CT was closely related to their pathological grading; the former was positively related to the grading of NET, while the latter had a negative correlation.
Acknowledgements
This work is supported by National Natural Science Foundation of China (grant number: 82260353).
Author contributions
Conceptualization: Xianwen Hu, Dandan Li.
Formal analysis: Dandan Li.
Funding acquisition: Jiong Cai.
Investigation: Rui Wang.
Supervision: Pan Wang.
Writing – original draft: Xianwen Hu.
Writing – review & editing: Jiong Cai.
Abbreviations:
- 18F-FDG
- fluorine-18 labeled fluorodeoxyglucose
- 68Ga-DOTATATE
- gallium-68 labeld 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaceticacid-D-Phel-Tyr3-Thr8-OC
- CT
- computed tomography
- FN
- false negative
- FP
- false positive
- NET
- neuroendocrine tumors
- PET
- positron emission tomography
- SSTR
- somatostatin receptors
- SUVmax
- maximum standard uptake value
- TN
- true negative
- TP
- true positive
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
XH and DL contributed equally to this work.
This study was approved by the Ethics Committee of the Affiliated Hospital of Zunyi Medical University [grant number: KLLY(A)-2022-008]. The requirement for informed consent was waived due to the retrospective design of the study, which was approved by the Affiliated Hospital of Zunyi Medical University. The investigations were carried out in accordance with the Declaration of Helsinki of 1975, revised in 2013. All protocols were conducted in accordance with the institutional guidelines and regulations.
The authors have no conflicts of interest to disclose.
How to cite this article: Hu X, Li D, Wang R, Wang P, Cai J. Comparison of the application of 18F-FDG and 68Ga-DOTATATE PET/CT in neuroendocrine tumors: A retrospective study. Medicine 2023;102:19(e33726).
Contributor Information
Xianwen Hu, Email: 541757091@qq.com.
Dandan Li, Email: lidandan@sina.com.
Rui Wang, Email: wangpan@sohu.com.
Pan Wang, Email: wangpan@sohu.com.
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