Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of neoplasms that arise from cells of the endocrine system [
DOTA-peptides specifically bind to somatostatin receptors 2, 3, and 5 and are usually overexpressed on the surfaces neuroendocrine cells [
A large number of previous studies have evaluated the diagnostic accuracy of both tracers in the presence of a relative shortage of information, regarding the correlation to pathological findings and prognostic value. Only a few studies have compared the clinical impact of both 68Ga-DOTATATE and 18F-FDG PET tracers on NENs [
We analyzed the data from 83 (50 males and 33 females) consecutive patients with pathologically proven NENs who underwent contemporaneous PET/CT imaging with 68Ga-DOTATATE and 18F-FDG between June 2013 and December 2016. 68Ga-DOTATATE and 18F-FDG PET/CT scans were performed within an interval of no more than 2 weeks. No patients were treated during this interval. All NENs were classified according to the histopathological reports, which are based on recent consensus statements of the European Neuroendocrine Tumor Society. According to the grade of differentiation, proliferation index (Ki-67), and mitotic count, the well-differentiated (WD) neoplasms are herein defined as NET and graded G1 (Ki-67 ≤ 2%) or G2 (Ki-67 3–20%) and G3a (Ki-67 > 20%); the poorly differentiated (PD) neoplasms are defined as NEC and G3b. G2 patients were further divided into 2 groups as G2a (3–9%) and G2b (10–20%).
Patients fasted for at least 6 h before PET/CT scan. Images were acquired 1 h after injection of 3.7 MBq/kg 18F-FDG or 1 h after the injection of 100–200 MBq 68Ga-DOTATATE. Whole-body scan (brain to mid-thigh) was performed with the patient in the supine position. CT exposure factors for all scans were 120 kV and 100 mA. PET/CT images were reported in consensus by two experienced nuclear medicine physicians who were blinded to the findings of the structural imaging. Any nonphysiological focus of 68Ga-DOTATATE or 18F-FDG uptake greater than the normal liver background was considered positive. At the same time, CT imaging was used to differentiate between lesions and physiological uptake. The maximum standardized uptake value (
Descriptive analyses are presented using mean and SD for normally distributed variables, but median, minimum, and maximum values were used for those that were nonnormally distributed. Analyses were performed using SPSS (version 21.0; IBM). The paired Student’s
A total of 83 (50 males and 33 females) patients were included in the study, with a median age of 56 years (range: 27–77 years). The primary tumors were located in the pancreas in 27 patients (32.5%), gastrointestinal tract in 43 patients (51.8%), and unknown locations in 13 patients (15.7%). Among the subjects, 48 patients (57.8%) had lymph node involvement and 60 patients (72.3%) had distant metastases. Pathological evaluation showed that 51 patients (61.4%) had WD-NET and 32 patients (38.6%) had PD-NEC. Among WD-NETs, there were 14 patients (16.9%) in G1 (≤2%), 19 patients (22.9%) in G2a (3–9%), 9 patients (10.8%) in G2b (10–20%), and 28 patients (33.7%) in G3a (>20%) (Table
Patient characteristics.
Characteristics | NET (%) | NEC (%) | All (%) |
---|---|---|---|
Gender | |||
Female ( | 26 (51.0) | 7 (21.9) | 33 (39.7) |
Male ( | 25 (49.0) | 25 (78.1) | 50 (60.3) |
Primary sites ( | |||
Pancreas | 19 (37.3) | 8 (25.0) | 27 (32.5) |
Gastrointestinal | 24 (47.0) | 19 (59.4) | 43 (51.8) |
Primary unknown | 8 (15.7) | 5 (15.6) | 13 (15.7) |
Metastatic sites ( | |||
Liver | 36 (70.6) | 13 (40.6) | 49 (59.0) |
Lymph nodes | 21 (41.2) | 27 (84.4) | 48 (57.8) |
Bone | 9 (17.6) | 10 (31.3) | 19 (22.9) |
Lung | 4 (7.8) | 1 (3.1) | 5 (6.0) |
Other | 6 (11.7) | 7 (21.9) | 13 (15.7) |
NET, neuroendocrine tumor; NEC, neuroendocrine carcinoma.
For all patients, 68Ga-DOTATATE was positive in 53 cases and negative in 30 cases, while 18F-FDG PET/CT was positive in 62 cases and negative in 21 cases. Overall, 18F-FDG assessment was found to have a better sensitivity (74.7%) compared with 68Ga-DOTATATE (63.8%), although it is not statistically significant (
Table
Sensitivity and uptake of 68Ga-DOTATATE and 18F-FDG PET/CT for different primary sites and grades.
Sensitivity (%) | | |||
---|---|---|---|---|
68Ga-DOTATATE | 18F-FDG PET/CT | 68Ga-DOTATATE | 18F-FDG PET/CT | |
Primary lesion | ||||
Gastrointestinal tract | 55.8% | 74.4% | 16.75 ± 2.62 | 7.56 ± 0.87 |
Pancreas | 85.2% | 66.7% | 29.87 ± 4.77 | 6.51 ± 0.78 |
WD NET | 80.4% | 58.8% | 28.87 ± 3.52 | 4.51 ± 0.45 |
Gastrointestinal NET | 75.0% | 54.2% | 22.68 ± 2.77 | 3.71 ± 0.45 |
Pancreatic NET | 89.5% | 52.6% | 31.19 ± 4.25 | 5.13 ± 0.93 |
PD NEC | 37.5% | 100.0% | 10.86 ± 1.78 | 11.46 ± 0.75 |
Gastrointestinal NEC | 31.6% | 100.0% | 9.26 ± 1.25 | 12.44 ± 1.11 |
Pancreatic NEC | 75.0% | 100.0% | 18.23 ± 5.93 | 10.23 ± 0.67 |
WD, well-differentiated; PD, poorly differentiated; NET, neuroendocrine tumor; NEC, neuroendocrine carcinoma.
Comparison of SUVmax of PET/CT according to primary sites ((a) and (b)) and tumor grade ((c) and (d)). The sensitivity of group A (G1 + G2a = Ki-67 < 10%), group B (G2b + G3a = well-differentiated neoplasms with Ki-67 ≥ 10%), and group C (G3b = poorly differentiated neoplasms with Ki-67 > 20%) in PET/CT imaging.
The sensitivity of 68Ga-DOTATATE and 18F-FDG in G1/G2a/G2b/G3a/G3b was 78.6%/73.3%/88.9%/77.8%/37.5% and 50.0%/52.6%/66.7%/77.8%/100.0%. 68Ga-DOTATATE imaging provided a sensitivity of >73% in WD-NET (G1–G3a) and only 37.5% in PD-NEC (G3b). For G1 and G2a (Ki-67 < 10%), a statistically significant positive correlation between Ki-67 and the sensitivity with 18F-FDG could be found, and the sensitivity in G1 and G2a (Ki-67 < 10%) was about 50%, increasing dramatically when the Ki-67 index was over 10%. The sensitivity in G3a reached 77.8% and that in G3b was 100%. The patients were divided into 3 groups: group A (G1 + G2a), group B (G2b + G3a), and group C (G3b). With this grouping, the sensitivity of 68Ga-DOTATATE and 18F-FDG in group A/B/C was 78.8%/83.3%/37.5% and 52.0%/72.2%/100.0%. Importantly, we found that the sensitivities of imaging with dual tracers in groups A/B/C were 84.8%/100%/100%, which were significantly higher than that with the single tracer. There was a significant negative correlation between Ki-67 and 68Ga DOTATATE
When combining the results of the dual-tracer PET/CT, 37 patients were positive in both tracers, and 16 patients were 68Ga-DOTATATE-positive and 18F-FDG-negative, while 25 patients were 18F-FDG-positive and 68Ga-DOTATATE-negative. 5 patients were negative in both tracers (Table
Concordant and discordant findings.
68Ga-DOTATATE | Positive | Positive | Negative | Negative |
---|---|---|---|---|
18F-FDG PET/CT | Positive | Negative | Positive | Negative |
Primary lesion ( | ||||
Pancreas | 14 | 9 | 4 | 0 |
Gastrointestinal tract | 18 | 6 | 14 | 5 |
CUP | 5 | 1 | 7 | 0 |
Metastatic sites | ||||
Liver | 27 | 11 | 9 | 1 |
Lymph node | 22 | 7 | 18 | 0 |
Bone | 8 | 2 | 8 | 0 |
Ki-67 range | ||||
Group A ( | 15 (45.5%) | 11 (33.3%) | 2 (6.1%) | 5 (15.1%) |
Group B ( | 10 (55.5%) | 5 (27.8%) | 3 (16.7%) | 0 |
Group C ( | 12 (37.5%) | 0 | 20 (62.5%) | 0 |
CUP, Cancer of unknown primary.
68Ga-DOTATATE and 18F-FDG PET/CT findings were concordant in 37 patients with 25 WD-NETs and in 12 PD-NECs. Only 1 patient was diagnosed as localized duodenal NEN. The remaining 36 patients had regional lymph node metastasis, distant metastasis, or both mainly occurring in liver or bone. Of 27 patients with liver metastases, 8 patients (29.6%) examined via 68Ga-DOTATATE showed heterogeneity in SSTR expression. Of 8 patients with bone metastases, imaging findings of 5 patients (62.5%) demonstrated that 68Ga-DOTATATE highlighted more bone lesions than 18F-FDG PET/CT. Of 22 patients with lymph node involvement, the dual tracers with 5 patients (22.7%) showed that 18F-FDG findings could be more prominent than those with 68Ga-DOTATATE (Figure
A 37-year-old women with pancreatic NEC G3 (Ki-67 = 80%) and lymph node, liver, and bone metastases, from whom the primary lesion has been resected. 18F-FDG PET/CT showed more liver lesions, while 68Ga-DOTATATE detected more bone lesions. ((A) and (a)) Liver lesions showed heterogeneity in SSTR expression. ((B) and (b) and (C) and (c)) 18F-FDG PET/CT failed to show bone metastases in rib and lumbar vertebra.
5 patients showed negative results in both two tracers, with a histological diagnosis of group A. 1 patient was diagnosed as duodenal NET G2 (Ki-67: 3%) with multiple liver metastases (largest lesion: 7.2 cm × 4.7 cm). The remaining 4 patients had rectal or gastric NET (G1/2) with lesions smaller than 5 mm.
Of the 83 patients, 26 performed radical surgery; 57 (31 NET and 26 NEC) unresectable patients were treated with palliative surgery, SSA, chemotherapy, and TACE. The median follow-up was 21 months (in the range of 2–62 months). During the follow-up period, 9 (6 NEC and 3 NET) patients died of the progressive disease. Unresectable patients with positive results solely with 18F-FDG showed the worst prognosis, while those positive solely with 68Ga-DOTATATE showed the best prognosis. For unresectable patients with NET (
The overall survival of unresectable patients detected with dual tracers: (a) Kaplan-Meier survival curve for unresectable patients, (A) positive for both tracers, (B) 68Ga-DOTA-TATE only, and (C) 18F-FDG only; (b) unresectable NET patients with 68Ga-DOTA-TATE results (positive or negative); (c) unresectable NET patients with 18F-FDG results (positive or negative); (d) unresectable NEC patients with 68Ga-DOTA-TATE results (positive or negative).
68Ga-DOTATATE and 18F-FDG PET/CT play a crucial role in the diagnosis and clinical management of NENs with morphologic and functional information. 68Ga-DOTATATE was found to be superior to 18F-FDG in WD-NET, whereas 18F-FDG was more sensitive in PD-NEC [
68Ga-DOTATATE imaging and 18F-FDG PET/CT imaging have been compared in several studies which have been shown to have variable sensitivities in detecting NENs with a relatively small number of patients. Naswa et al. [
Our study demonstrated that PET/CT uptake was statistically significantly different between subgroups of GEP-NENs according to grading. The cohort was separated into 3 groups: A (G1 + G2a), B (G2b + G3a), and C (G3b). Group B showed higher sensitivity for 18F-FDG than group A, and the median
Based on our results, dual tracers’ assessment is recommended for WD-NET with Ki-67 ≥ 10% (G2b and G3a). 68Ga-DOTATATE and 18F-FDG were complementary in detecting lesions and dual-trace PET/CT showed an advantage in the assessment of SSA, PRRT, and chemotherapy. We proposed that WD-NET patients with Ki-67 ≥ 10% should be examined using dual tracers upon diagnosis. We also suggest that 68Ga-DOTATATE should be performed solely in WD-NET patients with Ki-67 < 10% and 18F-FDG is sufficient for PD NEC. Moreover, repeated PET/CT is warranted when disease progresses rapidly, considering the heterogeneous expression and complementary findings to histopathology (Figure
PET/CT imaging and treatment regime.
We investigated the correlations between dual tracers and Ki-67 index.
GEP-NENs are a heterogeneous group of neoplasms that display great variability in biological behaviors and clinical outcomes [
The morphological findings and Ki-67 index are considered important prognostic markers in NENs. One major limitation of these histopathological parameters as prognostic markers is the requirement for tissue sampling, which is not always feasible. A few studies have demonstrated the prognostic value of 18F-FDG and 68Ga-DOTATATE PET/CT in patients with NENs. 18F-FDG was an independent predictor of PFS [
Noninvasive dual-tracer imaging with 68Ga-DOTATATE and 18F-FDG PET/CT seems promising as an alternative to tissue sampling, due to its capacity to reflect two different aspects of tumor biology, SSTR expression and glucose metabolism, respectively. Accordingly, imaging with dual tracer is recommended for WD-NET patients with Ki-67 ≥ 10%, providing information for selection of SSA, PRRT, and chemotherapy. Taking the advantages of dual-tracer imaging in detecting lesions is useful for accurate clinical management. Dual-tracer imaging also shows a clearly linear correlation between
Gastroenteropancreatic neoplasms
Poorly differentiated
Well-differentiated
Overall survival
Neuroendocrine tumor
Neuroendocrine carcinoma
Peptide receptor radionuclide therapy.
The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.
Panpan Zhang and Jiangyuan Yu contributed equally to this work. Panpan Zhang and Jiangyuan Yu wrote the manuscript and analyzed the data. Jie Li, Lin Shen, Nan Li, Hua Zhu, Shizhen Zhai, and Yan Zhang collected patient data and technical information. Zhi Yang and Ming Lu reviewed and helped revise the manuscript.