Volume 112, Issue 11 p. 2447-2455
Original Article
Free Access

Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) and 18F-FDG

Irfan Kayani FRCR

Irfan Kayani FRCR

Institute of Nuclear Medicine, University College Hospital, London, UK

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Jamshed B. Bomanji MD, PhD, FRCR

Corresponding Author

Jamshed B. Bomanji MD, PhD, FRCR

Institute of Nuclear Medicine, University College Hospital, London, UK

Fax: (011) 442073809407.

Institute of Nuclear Medicine, University College Hospital, UCLH, 235 Euston Rd., London, NW1 2BU, UK===Search for more papers by this author
Ashley Groves MD

Ashley Groves MD

Institute of Nuclear Medicine, University College Hospital, London, UK

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Gerard Conway MD

Gerard Conway MD

Department of Endocrinology, University College London Hospitals, London, UK

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Sveto Gacinovic MD

Sveto Gacinovic MD

Institute of Nuclear Medicine, University College Hospital, London, UK

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Thida Win MD

Thida Win MD

Department of Respiratory Medicine, Lister Hospital, Stevenage, UK

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John Dickson PhD

John Dickson PhD

Institute of Nuclear Medicine, University College Hospital, London, UK

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Martyn Caplin FRCP

Martyn Caplin FRCP

Department of Gastroenterology, Royal Free Hospital, London, UK

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Peter Joseph Ell FRCR, FRCP

Peter Joseph Ell FRCR, FRCP

Institute of Nuclear Medicine, University College Hospital, London, UK

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First published: 28 March 2008
Citations: 364

Abstract

BACKGROUND.

The aim was to assess the relevant distribution of the novel PET tracer 68Ga-DOTATATE in neuroendocrine tumors (NETs) with combined positron emission tomography / computed tomography (PET/CT) and compare its performance with that of 18F-FDG PET/CT.

METHODS.

The imaging findings with 68Ga-DOTATATE and 18F-FDG on 38 consecutive patients with a diagnosis of primary or recurrent NET were compared and correlated with tumor grade on histology based on ki67 and mitotic index.

RESULTS.

The sensitivity of 68Ga-DOTATATE PET/CT was 82% (31 of 38) and that of 18F-FDG PET/CT was 66% (25 of 38). The sensitivity of combined 68Ga-DOTATATE and 18F-FDG PET/CT was 92% (35 of 38). There was greater uptake of 68Ga-DOTATATE than 18F-FDG in low-grade NET (median SUV 29 vs 2.9, P < .001). In high-grade NET there was higher uptake of 18F-FDG over 68Ga-DOTATATE (median SUV 11.7 vs 4.4, P = .03). There was a significant correlation with predominant tumor uptake of 68Ga-DOTATATE or 18F-FDG and tumor grade on histology (P < .0001).

CONCLUSIONS.

68Ga-DOTATATE PET/CT is a useful novel imaging modality for NETs and is superior to 18F-FDG for imaging well-differentiated NET. Functional imaging with both 68Ga-DOTATATE and 18F-FDG has potential for a more comprehensive tumor assessment in intermediate- and high-grade tumors. Cancer 2008. ©2008 American Cancer Society.

Neuroendocrine tumors (NETs) have distinct biological and clinical characteristics, in particular a high density of somatostatin receptors at the cell membrane. It is this property that allows the use of radiolabeled somatostatin analogs for imaging of these tumors.1 DOTA-DPhe1,Tyr3-octreotate (DOTATATE) is a somatostatin-2 receptor (SSR-2) analog, which is radiolabeled with 68Ga, a positron emitter.2, 3 68Ga (t½ 68 minutes, β+ 88%) is produced by a 68Ge/68Ga generator; production is not dependent on a cyclotron. 68Ga-DOTATATE has high affinity for SSR-2, is rapidly excreted from nontarget sites, offers good target to nontarget imaging properties, and hence is an ideal potential candidate tracer for imaging NETs.2-5 Recent studies have indicated that 68Ga-labeled DOTA peptide DOTATOC has potential to improve imaging for NET over conventional 111indium pentetreotide.5-7

NETs, however, typically have a wide range of cellular differentiation. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is of limited value in well-differentiated NETs as these tumors often have near-normal glucose turnover.8 As both 18F-FDG and 68Ga-DOTATATE exploit distinct tumor characteristics it is possible that they may be complementary for tumor staging. Higher-grade NETs may show higher metabolic turnover and lose expression of SSRs. To date, however, only a few small series have correlated FDG and/or somatostatin receptor scintigraphy (SSRS) with tumor grade.8-11

Aim

The purpose of this study was to compare the performance of 68Ga-DOTATATE and 18F-FDG in confirmed NET and correlate uptake with tumor grade on histology.

MATERIALS AND METHODS

Patients

We retrospectively reviewed the findings in the first 38 patients (25 male, 13 female, aged 14–71 years, median, 53 years) with confirmed primary or recurrent NETs (6 had pulmonary NET, 28 gastroenteropancreatic NET, and 4 metastatic NET with unknown primary) who underwent both 68Ga-DOTATATE PET / computed tomography (CT) and 18F-FDG PET/CT imaging at our institution. All patients gave informed consent and institutional board ethics approval was received for this retrospective study.

All patients with NET were classified into high-, intermediate-, or low-grade tumors according to the tumor histology reports. The histologic grading was based on recent consensus statements of the European Neuroendocrine Tumor Society, using mitotic index and Ki67 index in staging of NET along with immunohistochemistry (IHC).12, 13 On the basis of this system well-differentiated tumors with a Ki67 index of ≤2% and a mitotic index of <2 per HPF (high power field) were classified as low grade. Tumors with a Ki67 index of between 3%–20% and mitotic count of 2–20 per HPF were classified as intermediate grade. Tumors with poor differentiation and Ki67 index of >20% and mitotic count of >20 HPF were classified as high-grade NET. All tumors had IHC for chromogranin and synatophysin and in a majority also for CD56, PGP9.5, and neuron-specific enolase. Mitotic counts were assessed in at least 40 fields (at ×40) magnification and evaluated in areas showing highest mitotic density. The Ki67 index was determined using MIB-1 antibody and expressed as percent of 2000 tumor cells in areas of highest nuclear binding.

Patients were scanned for 1) staging of primary NETs and 2) detection of suspected recurrent NETs. The clinical indications for 68Ga-DOTATATE and 18F-FDG studies were to assess suitability for surgical resection in patients with primary or localized NETs and in patients with metastatic disease to evaluate for targeted radionuclide therapy. In all cases the histology of the primary tumor was available. The diagnosis of recurrent tumor was based on histology of metastatic sites, imaging features of progressive malignancy, and/or elevated and rising tumor marker levels. For the purposes of correlating uptake of tracers with tumor grade, analysis was confined to those patients where both imaging and histopathology was available.

The 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT studies were performed within 3 weeks of each other.

Combined PET/CT

Images were acquired 1 hour postinjection of 370 MBq of 18F-FDG or 45–60 minutes after the injection of 120–200 MBq of 68Ga-DOTATATE. No adverse effects were observed after the injection of 68Ga-DOTATATE. Imaging was performed using dedicated combined GE Discovery ST PET/16 detector CT unit (GE Healthcare, Detroit, Mich); whole-body examinations (brain to mid-thigh) were performed with the patient supine.

The CT exposure factors for all examinations were 120 kVp and 80 mA in 0.8 seconds. Maintaining patient position a whole-body PET emission scan was performed and covered an area identical to that covered by CT. PET acquisition was carried out in 3D with 4 minutes per bed position and 5 slice overlap. PET images were reconstructed using CT for attenuation correction. Transaxial PET data were reconstructed using ordered subsets expectation maximization with 3 iterations and 25 subsets (3D). Transaxial PET slice thickness was 3.27 mm with in-slice pixel size of 4.68 mm. The CT data was reconstructed to axial slices of 3.75 mm and 2.5 mm thickness with a soft tissue reconstruction algorithm and 2.5 mm thickness with a lung reconstruction algorithm.

Image Reporting

The images from 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT were reported in consensus by an experienced dedicated nuclear medicine physician and a dual accredited radiologist/nuclear medicine physician. Areas of abnormal increased focal uptake were documented. The image findings of the 2 modalities were compared with each other and with histology. Tumors were classified as showing either predominant 68Ga-DOTATATE or 18F-FDG uptake according to maximum intensity of tracer uptake (standardized uptake value, SUVmax) and number of detected tumor lesions.

The diagnosis of tumor was established on the basis of histology, elevated and rising hormonal and tumor marker levels, or progressive imaging features of malignancy. Where metastatic disease was confirmed by histopathology at 1 tumor site detected by both 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT, it was assumed that other lesions detected by either imaging modality were metastatic lesions from the primary.

Statistical Analysis

A comparison of numbers of tumors showing positive 68Ga-DOTATATE or 18F-FDG uptake was performed using a McNemar paired test. A P value <.05 was taken as significant for all statistical tests. A Fisher exact test was used to correlate the number of patients with predominant uptake of 68Ga-DOTATATE and 18F-FDG with tumor grade. The Mann-Whitney test was used to test for difference in uptake using SUVmax for individual tracers between different tumor grades. A Wilcoxon matched pairs signed rank test was used to compare uptake of 68Ga-DOTATATE and 18F-FDG within the same tumor grades.

RESULTS

68Ga-DOTATATE PET/CT revealed tumor lesions in 31 of 38 patients (SUVmax range, 4.6–50; median SUVmax, 18) with confirmed disease, but failed to detect tumor in 7 of 38 patients. Of these 7 patients 18F-FDG PET/CT detected disease in 5.

18F-FDG PET/CT revealed disease in 25 of 38 patients (SUVmax, 2.9–22; median SUV, 9.5) with confirmed tumors, but failed to detect tumor in 13 of 37. Of these 13 patients 68Ga-DOTATATE PET/CT detected disease in 10 patients.

The sensitivity of 68Ga-DOTATATE PET/CT alone was 82% (31 of 38); for 18F-FDG PET/CT was 66% (25 of 38); and combined 68Ga-DOTATATE and 18F-FDG PET/CT was 92% (35 of 38).

In 3 patients no uptake of either tracer (false-negative) was seen in CT-documented lesions. In these patients histology demonstrated low-grade NET (1 patient), intermediate-grade NET (1 patient), and high-grade NET in a third patient with high-grade goblet cell carcinoid.

Correlation of Tracer Uptake With Tumor Grade and Ki67 Index

In 25 of 38 patients histology was available for sites imaged by PET-CT (Table 1). Thirteen had low-grade NET with Ki67 index ranging from <1% to 2%, 6 intermediate-grade NET with Ki67 index ranging from 5 to 15%, and 6 high-grade NET with Ki67 index 20% to 60%. For these sites there was a significant correlation between low and high tumor grades and tracer uptake (for both 68Ga-DOTATATE and 18F-FDG, Table 2). There was higher uptake of 68Ga-DOTATATE in low-grade NET compared with 68Ga-DOTATATE uptake in high-grade NET (median SUV 29 vs 4.3, P = .0019). Conversely, there was higher uptake of 18F-FDG in high-grade NET compared with 18F-FDG uptake in low-grade NET (median SUV 11.7 vs 2.9, P = .0033). There was also higher uptake of FDG in intermediate versus low-grade NET (median SUV 10.5 vs 2.9, P = .029). There was no significant difference in tracer uptake between low and intermediate for 68Ga-DOTATATE and intermediate and high-grade NET for both 68Ga-DOTATATE and 18F-FDG.

Table 1. Correlation of Tracer Uptake of 18F-FDG and 68Ga-DOTATATE With Tumor Grades on Histology
Tumor Sites of tumor involvement Prior medical therapy Grade Indication Method of tissue collection 18F-FDG SUVmax 68Ga-DOTATATE SUVmax
1 Foregut Mesenteric nodes mediastinal nodes Low Suspected recurrence Percutaneous biopsy 3.4 16.9
2 PNET Retroperitoneal lymph nodes Low Suspected recurrence Resection 1.5 34.9
3 PNET Primary tumor local nodal involvement Low Primary Resection 5.4 32.5
4 Typical bronchial carcinoid Primary tumor Low Primary Resection 1.5 26
5 Typical bronchial carcinoid Primary tumor Low Primary Percutaneous biopsy 3.2 12
6 Mid-gut Liver, retroperitoneal nodes and mesenteric nodes IF Low Suspected recurrence Percutaneous biopsy 1.6 11.3
7 PNET Mesenteric and retroperitoneal nodes Low Suspected recurrence Surgical excision biopsy 1.8 40
8 PNET Primary tumor mesenteric nodes Low Primary Percutaneous biopsy 5.1 45
9 Unknown primary Liver Low Metastatic disease Percutaneous biopsy 2.3 3.3
10 Mid-gut Mesenteric nodes Low Metastatic disease Surgical excision biopsy 2.3 29
11 PNET Low Suspected recurrence Surgical excision biopsy 12 31
12 Typical bronchial carcinoid Primary tumor Low Primary Resection 2.9 18
13 Typical bronchial carcinoid Primary tumor Low primary Resection 4 45
14 Mid-gut Liver mesenteric nodes Intermediate Suspected recurrence Percutaneous biopsy 9 50
15 Unknown primary Mesenteric retroperitoneal mediastinal nodes Intermediate Metastatic disease Percutaneous biopsy 12 4.6
16 PNET Liver mesenteric nodes bone deposits FCIST chemo Intermediate Suspected recurrence Percutaneous biopsy 12.6 45
17 Mid-gut carcinoid Liver mesenteric retroperitoneal nodes Intermediate Suspected recurrence Percutaneous biopsy 4.2 25.9
18 Unknown primary Retroperitoneal nodes Intermediate Metastatic disease Percutaneous biopsy 13.9 5
19 PNET Liver retroperitoneal node Intermediate Suspected recurrence Surgical excision biopsy 2 1.8
20 Mid-gut Mesenteric retroperitoneal mediastinal cervical nodes Y90 lanreotide High Suspected recurrence Surgical excision biopsy 7.4 2.7
21 PNET Primary tumor liver High Primary Percutaneous biopsy 4.1 1.6
22 PNET Primary tumor mesenteric nodes liver High Primary Percutaneous biopsy 14.6 6
23 Unknown primary Mesenteric retroperitoneal inguinal nodes High Metastatic disease Surgical excision biopsy 12.5 7.5
24 Mid-gut Retroperitoneal nodes lung deposits High Suspected recurrence Surgical excision biopsy 10.8 8.9
25 Mid-gut Mesenteric retroperitoneal nodes liver Bleomycin, cisplatin, etopiside High Suspected recurrence Surgical excision biopsy 16.4 1.9
  • PNET indicates pancreatic neuroendocrine tumor; 68Ga-DOTATATE, 68Ga-DOTA-DPhe1,Tyr3-octreotate; 18F-FDG, 18F-Fluorodeoxyglucose; FCIST, 5 Fluorouracil cisplatin and streptozocin; IF, interferon.
Table 2. Numbers of Patients Showing Predominant Uptake of 68Ga-DOTATATE or 18F-FDG According to Tumor Grade
Predominant uptake of 68Ga-DOTATATE Predominant uptake of 18F-FDG Total
High/intermediate-grade NET 3 11 14
Low-grade NET 21 0 21
Total 24 11 35
  • Two-tailed P < .0001. Fisher exact T-test.
  • NET indicates neuroendocrine tumors; 68Ga-DOTATATE, 68Ga-DOTA-[SCAP]D[R]Phe1,Tyr3-octreotate; 18F-FDG, 18F-Fluorodeoxyglucose.

There was a significant correlation between numbers of patients showing predominant uptake of 68Ga-DOTATATE or 18F-FDG and tumor grade (Table 3). There was greater uptake of 68Ga-DOTATATE over 18F-FDG in low-grade tumors (Table 3, median SUVmax 29 vs 2.9, P <.001). In high-grade tumors there was higher uptake of 18F-FDG over 68Ga-DOTATATE (Table 3, median SUVmax 11.7 vs 4.3, P = .03). There was no significant difference in uptake of tracers for intermediate-grade NET.

Table 3. SUVmax of 68Ga-DOTATATE and 18F-FDG According to Tumor Grade
68Ga-DOTATATE 18F-FDG P
All NET 16.9 (1.6–50) 4.2 (1.4–16.4) .005
Low-grade NET Ki67 index ≤2% 29 (3.3–45) 2.9 (1.5–12) <.001
Intermediate NET Ki67 index 3%–20% 15.5 (1.8–50) 10.5 (2.0–13.9) NS
High-grade NET Ki67 index >20% 4.4 (1.6–8.9) 11.7 (4.1–16.4) .03
  • SUVmax is the median SUVmax with range in parentheses.
  • SUVmax indicates maximum standardized uptake value; NET, neuroendocrine tumor; 68Ga-DOTATATE, 68Ga-DOTA-[SCAP]D[R]Phe1,Tyr3-octreotate; 18F-FDG, 18F-Fluorodeoxyglucose.

Lesion Analysis

68Ga-DOTATATE and 18F-FDG detected a total of 293 lesions, 186 were positive with 68Ga-DOTATATE and 176 with 18F-FDG (Table 4). Lesion size ranged from 6 to 13 cm in diameter. In addition, there were a further 10 lesions (6 liver metastases, 2 mesenteric nodes, 2 peritoneal nodules) that were negative for both 68Ga-DOTATATE and 18F-FDG but with confirmed tumor on histology and/or serial imaging with CT. Five of these lesions were small (7–13 mm). Tumor size otherwise did not significantly affect tracer uptake.

Table 4. Number of Lesions Demonstrating 68Ga-DOTATATE and/or 18F-FDG Uptake in High-, Intermediate-, and Low-Grade NET Tumors
High-grade NET Intermediate-grade NET Low-grade NET Total
Uptake of 68Ga-DOTATATE and 18F-FDG 5 45 21 71
Uptake of 68Ga-DOTATATE but not 18F-FDG 0 18 97 115
Uptake of 18F-FDG but not 68Ga-DOTATATE 72 33 0 105
No uptake of either 68Ga-DOTATATE or 18F-FDG 2 5 3 10
Total 79 101 121 303
  • NET indicates neuroendocrine tumors; 68Ga-DOTATATE, 68Ga-DOTA-[SCAP]D[R]Phe1,Tyr3-octreotate; 18F-FDG, 18F-Fluorodeoxyglucose.

There were 6 sites (2 in lung, 1 in hilar lymph node, 1 in mediastinal lymph node, 2 in cervical nodes) of increased tracer uptake at sites of inflammation with 18F-FDG (Fig. 1). No cases of 68Ga-DOTATATE uptake at sites of inflammation were documented.

Details are in the caption following the image

(A) 68Ga-DOTATATE and (B) 18F-FDG PET/CT images from a patient with well-differentiated (‘typical’) bronchial carcinoid tumor. The primary tumor (left hilum, arrow) is positive for (A) 68Ga-DOTATATE but negative for (B) 18F-FDG. Histology showed that the left lung had postcollapse pneumonitis that was negative for (A) 68Ga-DOTATATE uptake but positive for (B, broken arrow) 18F-FDG.

In high-grade NET only 5 of 79 detected lesions were positive with 68Ga-DOTATATE and only 2 of 79 negative for 18F-FDG uptake. Conversely, in patients with low-grade NET 21 of 123 detected lesions were positive with 18F-FDG while only 3 lesions were negative for 68Ga-DOTATATE uptake. No lesion exhibited exclusive uptake of either 68Ga-DOTATATE in high-grade or 18F-FDG in low-grade NET.

In 3 patients (1 low grade and 2 intermediate grade) the tumor exhibited variable affinity for tracers at different sites, so that some lesions were positive only with 68Ga-DOTATATE and others only with 18F-FDG in the same tumor. In 4 patients there was variable uptake of tracers at the same lesion site (Fig. 2).

Details are in the caption following the image

Axial 68Ga-DOTATATE (top panel) and 18F-FDG (bottom panel) PET/CT images in a 54-year-old female patient with metastatic carcinoid tumor (primary cecal carcinoma). There are 2 liver metastases showing intense 68Ga-DOTATATE uptake. The lesions show 68Ga-DOTATATE uptake along the whole circumference of the lesion, whereas there is only focal 18F-FDG uptake at the margin (arrow).

Impact on Management of 18F-FDG PET/CT

In 4 patients (3 high-grade NET and 1 intermediate-grade NET) 68Ga-DOTATATE showed low and 18F-FDG more intense and more widespread uptake (Fig. 3). In view of this pattern it was felt that radionuclide therapy would not be appropriate and therefore the patients were assigned to receive systemic chemotherapy.

Details are in the caption following the image

MIP (maximum intensity projection) images for 68Ga-DOTATATE (right panel) and 18F-FDG (left panel) in a 55-year-old female patient with metastatic neuroendocrine carcinoma with unknown primary (Ki67 index 15%). There is positive uptake of 68Ga-DOTATATE tracer (arrows) in lesions in the mediastinum and abdomen. The tumor, however, shows more intense uptake of 18F-FDG, with many additional lesions not seen with 68Ga-DOTATATE.

DISCUSSION

PET-CT has been of limited use in the imaging of NET, as the most widely available tracer has reduced sensitivity for well-differentiated NET. The development of selective Ga-68 DOTA-labeled somatostatin analogs allows the use of PET-CT to selectively image somatostatin receptor subtype 2 and offers the potential of a wider application of PET-CT in NET.2, 3 Recently 68Ga-DOTATOC has been shown to be more accurate than conventional imaging with 111Indium-pentetreotide.5-7 Our results are the first to report on the use of PET-CT with the related 68Ga-DOTA peptide DOTATATE. By using a receptor-targeted approach with 68Ga-DOTATATE we have shown an improvement in diagnostic performance of PET-CT imaging of NET tumors relative to 18F-FDG. Overall, the total number of detected lesions was greater with the combined use of 18F-FDG and 68Ga-DOTATATE than with either tracer alone (Table 4), in keeping with findings of other studies that used a combination of functional imaging modalities.14, 15

In our study tumor grade influenced tracer uptake (Tables 2–4). It is difficult to establish a link between tracer avidity and histopathologic indices of tumor proliferation. In many patients there were a large number of tumor lesions, often with multiple lesions in the same organ (eg, liver metastases). In some patients there was variable uptake of tracer at different lesion sites. Moreover, heterogeneous uptake within tumor lesions indicates percutaneous biopsy may not fully reflect in vivo tumor heterogeneity. Despite these limitations, which to a large extent are inevitable in an imaging study, tumor grade and proliferation appeared to be related to tumor 68Ga-DOTATATE and 18F-FDG uptake. There was higher uptake of 68Ga-DOTATATE in low-grade versus high-grade NET. Conversely, there was significantly higher uptake of 18F-FDG in high-grade versus low-grade NET. In addition, for low- and high-grade NET there was significant difference in relative intensity of tumor uptake of 68Ga-DOTATATE versus 18F-FDG (Table 2).

68Ga-DOTATATE PET CT was superior to 18F-FDG in the detection of NET because of its higher sensitivity in low-grade tumor. Although some studies have shown a correlation between 18F-FDG uptake and histology of NET as determined by Ki67 index,10, 11 others have failed to demonstrate such a relationship.9 Data from PET somatostatin receptor ligand studies are limited. Dynamic PET studies have shown that while 68Ga-DOTATOC uptake is most closely correlated with the pharmacokinetic K1 parameter, 18F-FDG uptake is most influenced by the VB (fractional blood volume) parameter.16, 17 Our observation that 18F-FDG uptake was high in high-grade tumors may serve as a prognostic indicator.

Although tumor grade was predictive of 68Ga-DOTATATE and 18F-FDG uptake there were 3 patients with low-, intermediate-, and high-grade NETs that showed no uptake of either tracer. The absence of 68Ga-DOTATATE in low-grade tumor and 18FDG in high-grade tumor is difficult to explain. In 1 patient the diagnosis of recurrent NET was based on progressive imaging features of malignancy (peritoneal thickening and ascites) without positive histology. In another patient it is possible that small volume and necrotic nature of tumor resulted in lack of detectable avidity for tracer. Furthermore, in some patients variable tracer uptake was seen at different sites in the same tumor; some tumor lesions showed uptake of 68Ga-DOTATATE over 18F-FDG, while the converse was true of others. Variable tracer uptake was even seen within the same lesion site. These findings suggest the wide spectrum of differentiation of NET, heterogeneity of cellular differentiation within the same tumor mass, and also reflect the potential ability of PET to map these cellular characteristics.

There are data to suggest that patients with well-differentiated NET are suitable candidates for targeted radionuclide therapy with 90Y- or 177Lu-labeled DOTATATE.18-20 In patients with high-grade metastatic NET there is often limited somatostatin receptor expression and systemic chemotherapy may be favored over radionuclide therapy.21 It is speculated that as a prelude to therapy dual imaging with 18F-FDG and 68Ga-DOTATATE in NET may be helpful to map the extent of disease and guide therapy. In our cohort the use of 18F-FDG led to a change in clinical management from radionuclide to systemic chemotherapy in 25% (4 of 16) of intermediate- and high-grade NET. These NETs had positive 68Ga-DOTATATE uptake but with much greater and widespread 18F-FDG uptake. The ability of PET to reflect tumor heterogeneity within and between tumor sites indicates that with the use of DOTATATE and other functional tracers, such as 11C-5-hydroxytryptophan and 18F-DOPA, PET-CT may provide a noninvasive metabolic map of in vivo molecular pathology. If the use of PET tracers can be shown with prospective controlled trials to positively impact management then this would help planning and monitoring of therapy to individual tumor biology.22, 23

There are advantages of PET/CT imaging of NETs, as some of the primary lesions are small and difficult to detect with conventional imaging. 68Ga-DOTATATE has superior affinity and uptake at the SSR-2, and combined PET and CT imaging of this tracer has superior spatial resolution compared with conventional 111In-pentetreotide imaging. This allows more accurate anatomical localization even of small (6 mm) receptor-positive tumor lesions. As 68Ga-DOTATATE is generator-produced it can also provide a convenient and cost-effective on-site source of tracer.3 In addition, 68Ga-DOTATATE PET allows a more rapid examination relative to 111In-pentetreotide.

Study limitations include a rather heterogeneous population of NET types including primary and metastatic lesions. This has to be balanced against a reasonable-sized population especially given that these tumors are relatively rare. Only patients with confirmed clinical diagnosis of primary or metastatic NET were included. Patients free from tumor, which were much harder to identify with retrospective analysis, were not included. Our study cannot therefore comment on the specificity or negative predictive value of 68Ga-DOTATATE and 18F-FDG. Another difficulty is that, although histology was available for all patients this was obviously not possible for all lesions. This is a frequent problem in imaging studies especially given the number of individual metastatic lesions in some of the patients.

Conclusions

This study shows that 1) Well-differentiated NETs show greater avidity for 68Ga-DOTATATE and poorly differentiated NETs show greater avidity for 18F-FDG. 2) 68Ga-DOTATATE-PET/CT and 18F-FDG PET/CT exploit different tumor characteristics of NETs for imaging. The roles of the 2 tracers may be complementary in mapping spread completely in patients with metastatic tumors.