Comparison the application of 18 F-FDG and 68 Ga-DOTATATE PET/CT in neuroendocrine tumors: A retrospective study

doi:10.21203/rs.3.rs-2337303/v1

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Comparison the application of 18 F-FDG and 68 Ga-DOTATATE PET/CT in neuroendocrine tumors: A retrospective study

https://doi.org/10.21203/rs.3.rs-2337303/v1

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Objective: This study aims 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).

Methodes: We retrospectively reviewed 55 patients (43 patients were initially evaluated; 12 patients were evaluated after treatment) who underwent ¹⁸F-FDG and ⁶⁸Ga DOTATE PET/CT examinations and had pathological results.

Results: In the initial evaluation of 43 patients, 27 patients were pathologically confirmed as NET patients, 23 of which were correctly detected by ¹⁸F-FDG, and all 27 patients were detected by ⁶⁸Ga-DOTATATE. On lession-based comparison, 119 and 168 focal lesions were depicted on ¹⁸F-FDG PET/CT and⁶⁸Ga-DOTATATE PET/CT, respectively (p =0.0363). In all patients, ⁶⁸Ga-DOTATATE has higher SUVmax than ¹⁸F-FDG, and the SUVmax is negatively related to the NET grade for the former, while the latter is positively related to it.

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 two tracers has important clinical significance for the management of patients with NET.

Biological sciences/Cancer

Health sciences/Oncology

Neuroendocrine neoplasm (NEN) is a rare heterogeneous tumor originating from neuroendocrine cells, including relatively well differentiated neuroendocrine tumors (NET) and relatively poorly differentiated neuroendocrine cancers, characterized by the expression of somatostatin receptors (SSTR)^1,2. NET can occur in any tissues and organs, the most common being 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 (MRI) are lack of specificity, so the diagnosis is difficult^4,5. Most patients with NET have lost the opportunity to receive radical surgery because of the existence of distant metastasis of liver, lung, bone, etc. at the time of diagnosis, so early and accurate diagnosis of NET is essential. As the most commonly used functional imaging technology, ¹⁸F-FDG PET/CT has been widely used in the diagnosis, staging, post treatment response evaluation, prognosis, etc. of various malignant tumors. The molecular probe ⁶⁸Ga-DOTATATE, which is obtained by using the radionuclide ⁶⁸Ga labeled somatostatin analog, can specifically combine with the highly expressed SSTR on the surface of NET cells to complete the imaging of NET, and it is a promising method for targeting NET imaging ^6,7. Previous studies have shown that two PET radioactive tracers, ¹⁸F-FDG and ⁶⁸Ga-DOTATATE, have different diagnostic efficacy for NET of different grades and differentiation degrees^8–10.This study aims to compare the efficacy of ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT imaging in the diagnosis, staging and prognosis evaluation of NET, so as to better provide clinical decisions.

Ethics approval and consent to participate

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 its retrospective nature and it was approved by the Affiliated Hospital of Zunyi Medical University. Investigations were carried out as per the rules of the Declaration of Helsinki of 1975, revised in 2013. All methods were performed in accordance with the institutional guidelines and regulations.

Patients

The clinical pathological data and PET/CT results of patients who were diagnosed as NET by pathological examination in the Affiliated Hospital of Zunyi Medical University from December 2019 to October 2022 and who underwent ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT examinations were reviewed and analyzed. The time interval between ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT imaging is 24-48 h. All patients did not receive radiotherapy, chemotherapy and radionuclide labeled SSA treatment within one month before imaging, and all patients signed an informed consent form before examination.

¹⁸F-FDG PET/CT imaging

The ¹⁸F-FDG PET/CT was performed 24-48 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 were used to produce and synthesize ¹⁸F-FDG, and the radiochemical purity>95% can be used for imaging after intravenous injection.The patients fasted for at least 6 hours before receiving the examination, and the fasting blood glucose was controlled to be less than 11.1 mmol/L. According to the patients’ weight, ¹⁸F-FDG was injected intravenously 0.1-0.15 mCi/kg. Ask the patient to rest quietly for 1 hour, and perform PET/CT imaging after urination.The imaging equipment adopts the Biograph mCT PET/CT scanner of German GE. The scanning range was from the top of skull to the middle of femur. CT scanning is carried out first, and the parameters are tube voltage 120 kV, tube current 119 mA, and layer thickness 5 mm. PET scanning shall be performed immediately after the completion of CT scanning. The 3D acquisition mode is 2.0 min/bed, with 6~7 beds, and PET images shall be attenuated and corrected with CT data and reconstructed with TrueX+TOF method after the completion of acquisition.

⁶⁸Ga-DOTATATE PET/CT imaging

⁶⁸Ga-DOTATATE PET/CT was performed after 1~2d of ¹⁸F-FDG PET/CT. ⁶⁸Ga was eluted by the “⁶⁸Ge/⁶⁸Ga” generator of ITM Medical Isotopes GmbH, Germany, and reacted with the precursor DOTATATE purchased from China Tongfu Co., Ltd. to obtain ⁶⁸Ga DOTATATE. The radiochemical purity of>95% can be used for imaging after intravenous injection.

According to the patients’ weight, ⁶⁸Ga- DOTATATE 0.05 mCi/kg was injected intravenously. Ask the patient to drink more water and conduct imaging 45~60 min after urination after intravenous injection of imaging agent. The imaging equipment and technology are the same as ¹⁸F-FDG PET/CT imaging.

Image analysis and evaluation

Two doctors with more than 5 years’ experience in nuclear medicine, without providing clinical data, used blind method to evaluate image quality, record the location of the lesion and its maximum standard uptake value. In case of disagreement, the third chief doctor with more than 10 years’ experience was asked to consult with each other until a consensus was reached. 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, as well as the patient's traumatic history, surgical history and other factors.

Statistical analysis

SPSS 18.0 software was used for data statistical analysis. The measurement data conforming to the normal distribution is represented by x ± s, and the non normal distribution is represented by the median (upper and lower quartiles), using t test, χ² test, Kruskal Wallis H test or Mc Nemar test were used to compare the data between groups, and p<0.05 means the difference is statistically significant.

Data availability

Te data that support the fndings of this study are available from the corresponding author, upon reasonable request.

Comparison the diagnostic performance in initial evalution 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 initial evaluation and 12 patients with post treatment evaluation. In the initial evaluation, 27/43 (62.8%) patients were confirmed as neuroendocrine tumors by histological examination, including 10 females and 17 males, with a age ranged from 25 to 73 years (mean age: 53.9±11.6), while 16/43 (37.2%) patients were not. A total of 39 patients with NET, including 27 patients confirmed by pathology in the initial evaluation and 12 patients evaluated after treatment, are detailed in Table 1. ¹⁸F-FDG PET/CT correctly detected tumors in 23 of 27 patients, and the sensitivity was 85.2%. Since other malignant tumors such as adenocarcinoma appeared in the enrolled patients, whic also showed a high uptake on ¹⁸F-FDG PET/CT, leading to false positive. Therefore, the specificity, NPV, PPV and accuracy of ¹⁸F-FDG PET/CT in diagnosing NET are low. ⁶⁸Ga-DOTATATE PET/CT correctly detected all patients with NET (27/27), and the sensitivity of diagnosing NENs was 100%. 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 was shown in Table 2.

Comparison of tumor detection rates between ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT

In total, 119 and 168 focal lesions were depicted on ¹⁸F-FDG PET/CT and⁶⁸Ga-DOTATATE PET/CT, respectively (p =0.0363). On lession-based comparison, ⁶⁸Ga-DOTATATE demonstrated a higher detection ability for primary lesions, liver, bone and lymph node lesions, among which there is a statistical difference in the detection of bone metastases (p=0.0347).

As for SUVmax of lesions, ⁶⁸Ga-DOTATATE demonstrated signifificantly higher mean uptake for all lesions including primary lesions, liver, lymph nodes and bone than that of ¹⁸F-FDG, and all have statistical significance (p<0.001, as shown in Table 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. In 7 cases of G1 grade NET, SUVmax of 4 lesions was equal to the background (,as shown in Figure 1), and the other 3 lesions were slightly higher than the background. On the contrary, the SUVmax for ⁶⁸Ga-DOTATATE in G1 NET is generally high, with an average of 44.6±2.8. The linear regression results showed that the ¹⁸F-FDG SUVmax of lesions was positively correlated with the grade of NETs , with a correlation coefficient of 0.5042, while the ⁶⁸Ga-DOTATATE was negatively correlated with the NEN grading, with a correlation coefficient of 0.6355 (As shown in Figure 2).

Post-treatment 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 of that ¹⁸F-FDG and ⁶⁸Ga-DOTATATE PET/CT have considerable value in the evaluation after treatment. The average SUVmax in the operation area after operation was 4.43±0.98 and 2.92±0.62 (¹⁸F-FDG vs ⁶⁸Ga-DOTATATE), respectively, with no statistical significance (p=0.2096). In terms of detection of distant metastasis, there were two false positive lesions at ¹⁸F-FDG PET/CT, one of which was confirmed as inflammation by biopsy, and the other was sigmoid colon cancer, which were negative on ⁶⁸Ga-DOTATATE PET/CT (as shown in Figure 3).

PET/CT combines functional imaging with morphological manifestations, and it is more and more widely used in patients with various malignant tumors, including NET¹¹. The current study directly compared the detection rates of two PET tracers, ¹⁸F-FDG and ⁶⁸Ga-DOTATATE, in the primary and metastatic neuroendocrine tumors, and the results showed that the accuracy of the latter was significantly higher than the former. As a specific imaging agent targeting SSTR, ⁶⁸GA-DOTATATE has shown good diagnostic performance in the diagnosis of NET, the choice of treatment scheme and the evaluation of prognosis.

In 27 cases of NET confirmed by pathology in present study, ⁶⁸GA-DOTATATE imaging detected primary lesions missed by ¹⁸F-FDG imaging in 4 patients, who were all G1 grade NET patients. The reason may be that ¹⁸F-FDG mainly reflects the glucose metabolism of tumors. Most malignant tumor cells have strong metabolism and corresponding increased energy consumption, showing high ¹⁸F-FDG uptake, while G1 grade NET is well differentiated and showing low uptake, thus leading to false negative. 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 higher expression of SSTR^6,12. Similarly, ⁶⁸Ga-DOTATATE detected more metastatic lesions, including 22 liver, 3 lymph nodes and 20 bone metastatic lesions that were false negative on ¹⁸F-FDG, and the two tracers showed statistical differences in the detection of bone metastatic foci.

The grading and differentiation degree of NET play a key role in clinical treatment decisions. This present study found 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, namely 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 detection rates of the two tracers in G2 and G3 patients were similar, while only 3 of the 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 detection rate of ¹⁸F-FDG PET/CT in G1 NEN patients was significantly lower than ⁶⁸Ga-DOTATATE PET/CT.

In the initial evaluation of 43 cases of primary tumors, one patient with nesidioblastosis confirmed by pathology showed false positive in ¹⁸F-FDG and ⁶⁸Ga-DOTATATE PET/CT. Nesidioblastosis can produce bioactive substances similar to NET, including gastrointestinal peptides and serotonin, resulting in high radioactivity uptake on ⁶⁸GA-DOTATATE, but the reason why it also shows nodular high radioactivity uptake on ¹⁸F-FDG is puzzling due to its benign nature. In addition to our case, it is worth noting that in the previously published literature, hypophosphatemic osteomalacia and meningioma can also express SSTR, resulting in ⁶⁸GA-DOTATATE uptake and leading to false positive ¹³. PET/CT imaging of ⁶⁸Ga labeled somatostatin analogues has been increasingly widely used in NET. Besides DOTATATE, the molecular probes such as DOTANOC, DOTATOC, DOTA-JR11 labeled with ⁶⁸Ga have also shown superior diagnostic performance in clinical research of NET^6,14-18.

As for the patients evaluated after treatment, ⁶⁸Ga-DOTATATE PET/CT showed some metastatic lesions that were not shown by ¹⁸F-FDG PET/CT, including bone, liver and lymph node metastasis, which may be attributed to tumor heterogeneity. Moreover, ¹⁸F-FDG PET/CT of one patient after gastric NET operation showed significant radiation uptake in the sigmoid colon, which was suspected to be NET invasion, while ⁶⁸Ga-DOTATATE PET/CT showed negative. Although it was finally confirmed by pathology to be adenocarcinoma rather than NET, the specificity of ⁶⁸Ga-DOTATATE, on the contrary, missed the focus, resulting in the patient’s inability to obtain timely and effective treatment. Therefore, ⁶⁸Ga- DOTATATE PET/CT can detect more NET lesions, while it is necessary it is necessary to perform ¹⁸F-FDG PET/CT on the basis of ⁶⁸Ga-DOTATATE PET/CT for better management of NET patients, which will more accurately evaluate the patient’s condition.

Small sample size is the main defect of this study. For example, there are only 7 cases of G1 class NET patients. There may be errors in the correlation between the statistical pathological grading and imaging characteristics (namely SUVmax). In the future, we need to expand the sample size for further research; secondly, the current study is a single center retrospective study with many limited factors, and there may be bias in the selection of patients. But even so, the current study still provides clinical diagnosis reference and treatment decision through the systematic evaluation of the value of the two tracers in the diagnosis of primary lesions in NET patients, the detection of distant metastatic lesions, the evaluation after treatment, and the correlation between pathological grading and image features, etc.

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 two tracers has important clinical significance for the management of patients with NET. The SUVmax of ¹⁸F-FDG and ⁶⁸Ga DOTATATE PET/CT were closely related to their pathological grading, and the former was positively related to the grading of NET, while the latter was negatively related.

Acknowledgements

This work is supported by National Natural Science Foundation of China (grant number: 81571712).

Author contributions

X.H and P.W were responsible for the study design. D.L, R.W., and C.J read and approved the fnal manuscript.

Competing interests

The authors declare no competing interests.

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Table 1

Clinical and epidemiologic characteristics of the patients with NET.
Characteristic		Value	Characteristic		Value
Gender (n)	Male	23 (59.0%)	Primary site (n)	Pancreas	19 (48.7%)
Gender (n)	Female	16 (41.0%)		Intestine	10 (27.0%)
Age (years)	Median	50		Stomach	5 (13.5%)
	Interquartile range	25–73		Liver	3 (7.7%)
Grade (n)^a	G1	7 (26.0%)		Retroperitoneum	2 (5.1%)
	G2	9 (33.3%)	PET/CT indication (n)	Initial evalution	27 (69.2%)
	G3	11 (40.7%)	PET/CT indication (n)	Post-treatment evalution	12 (30.8%)

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%	100%
Specificity	37.5%	93.8%
Positive predictive value	69.7%	100%
Negative predictive value	60%	96.4%
Accuracy	67.4%	97.7%

Table 3

Uptake of lesions on ¹⁸F-FDG and ⁶⁸Ga-DOTATATE PET/CT
Parameter		Lesions (n)		p	SUVmax		p
Parameter		¹⁸F-	⁶⁸Ga-	p	¹⁸F-	⁶⁸Ga-	p
Primary tumor		29	33	0.7463	4.9 ± 0.5	23.9 ± 3.8	< 0.001
Liver metastases		33	55	0.2524	4.8 ± 1.4	42.3 ± 15.3	< 0.001
Lymph node metastases		34	37	0.7849	4.6 ± 1.4	6.0 ± 1.7	0.0657
Bone metastases		16	36	0.0347	4.1 ± 1.5	13.2 ± 4.8	< 0.001
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	0.0363	4.7 ± 1.3	21.4 ± 6.4	< 0.001

No competing interests reported.

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Comparison the application of 18 F-FDG and 68 Ga-DOTATATE PET/CT in neuroendocrine tumors: A retrospective study

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