Ct in the detection of unknown primary metastatic neuroendocrine tumors (cup-net)

, , , , , , Gian Carlo Montini, , and

Journal of Nuclear Medicine

General Clinical Specialties: Special Session


Neuroendocrine tumors (NETs) are a heterogenous group of rare neoplasms. From indolent slow growing masses causing local symptoms to severe debilitating systemic syndromes, they can present with a wide spectrum of clinical presentation. One aspect of their initial presentation can be the presence of a metastatic lesion (most commonly in the liver), with no clear evidence of the primary lesion (unknown primary; CUPNET). The aim of this study was to evaluate the role of receptor based PET/CT using 68Ga-DOTA-NOC in the evaluation of such patients.

Twenty-one patients (11 M/10F; mean age of 50.5year) with such presentation were evaluated. 20 patients presented with evidence of liver metastasis on conventional imaging (CI) while 7 patients had additional skeletal metastasis at presentation. All patients had evidence of biopsy proven metastatic NET lesions (mostly from the liver) with no definite evidence of the primary tumor on conventional imaging (CI).

The ability of NETs to express somatostatin receptors can be exploited for functional imaging using tracers targeted at these receptors. A special subset of NETs are CUP-NET where detection of the primary tumor is important for adequate management. Here is our experience with 68Ga-DOTA-NOC PET/CT which stands apart as the most important non-invasive imaging modality in such category of patients

The recent introduction of 68Ga-DOTA-peptide PET/CT for the evaluation of neuroendocrine tumors (NETs) has significantly improved the diagnostic work-up, previously based only on conventional imaging (CI) modalities (ultrasound, CT, endoscopy, MRI) and somatostatin receptor scintigraphy (SRS) (1,2). Because of the low cost and wide availability, ultrasound and CT are generally performed as first-line investigations in NET patients. In the past decade, nuclear medicine procedures, such as SRS, have played a central role in the functional assessment of NET. More recently, the development of novel PET tracers (68Ga-DOTA-peptides) specifically binding to somatostatin receptors (SSRs) overexpressed on the surface of NET cells allowed the visualization of NET on 68Ga-DOTA-peptide PET/CT scans. Several different DOTA-peptides (DOTATOC, DOTANOC, and DOTATATE) have been used in the clinical setting for either NET diagnosis or peptide receptor radionuclide therapy (PRRT). The major difference among these compounds relies on a slightly different affinity to SSR subtypes (sst). Although all tracers can bind to sst2—the predominant receptor type in NET—and DOTATOC and DOTANOC also bind to sst5, only DOTANOC presents a good affinity for sst3

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. 68Ga-DOTANOC, compared with similar diagnostic compounds, was also reported to present a favorable dosimetry


PET/CT with 68Ga-DOTA-peptides was reported to present a higher sensitivity for the detection of well-differentiated NET than other imaging procedures (particularly CT and SRS) (5–8). P ET was especially useful in detecting small lesions, particularly at bone and node level

, and in patients with unusual anatomic localization


The aim of the present study was to evaluate the effect of 68Ga-DOTANOC PET/CT on the clinical management of patients with NET.


PET/CT scans were obtained 60 min after the intravenous injection of about 180 MBq (120–185 MBq) of 68Ga-DOTANOC using a dedicated PET/CT tomograph (Discovery STE or Discovery LS; GE Healthcare) from the skull base to the middle part of the thigh. P ET scan emission images were recorded for 4 min per bed position in 2-dimensional mode using the Discovery LS or 3 min per bed position in 3-dimensional mode using the Discovery STE. All images in each scan were corrected for scatter, randoms, dead time, and decay. C T acquisition parameters were 120 kV, 60 mA, 0.8-s tube rotation, and 5-mm thickness; scaled CT images were used to obtain CT attenuation-corrected PET images. Low-dose CT was performed without intravenous contrast enhancement.

Discovery LS images were reconstructed with a 2-dimensional ordered-subset expectation maximization iterative reconstruction algorithm (2 iterations, 28 subsets), and Discovery STE images were reconstructed using a fully 3-dimensional iterative reconstruction algorithm.

PET/CT images were read by 2 experienced nuclear medicine specialists, and the final report was based on the readers’ consensus.

To evaluate the clinical impact of PET findings, all referring physicians were contacted after PET and were asked information on how patients were managed and how PET results influenced clinical decisions. Each referring physician was contacted by telephone and asked to retrieve all clinical data on the patients included in the study; clinical data referring to the time before and after the 68Ga-DOTANOC PET/CT scan were recorded. In particular, referring physicians were asked whether the PET result led to any changes in clinical management, such as initiation or exclusion of targeted therapy after the demonstration of presence or lack of SSRs, scheduling of surgery, exclusion of surgical procedures because of the presence of diffuse disease, initiation of radiotherapy or chemotherapy, or use of further diagnostic procedures. Stage or therapy modifications after PET were independently recorded, and the overall impact was evaluated patient by patient if the PET report either changed the stage or affected therapy. Disease was staged according to the classification reported by Rindi et al. (11,12) and Travis et al. (13,14).


The recent development of 68Ga-DOTA-peptides for PET led to an increasing interest in the use of PET/CT for the assessment of NET (6,15). In this clinical setting, PET has been used both for the diagnosis of disease extent and as a preliminary procedure to evaluate SSR expression before the start of PRRT or cold SSA treatment.

It is well known that treatment with SSAs in patients with SSR-expressing lesions is associated with the reduction of signs and symptoms of hormone hypersecretion, improvement of quality of life, and slowing of tumor growth, with a consistent survival benefit

. In particular, in an Italian multicenter trial cold SSAs (octreotide or lanreotide) were used mainly to obtain symptomatic control of hypersecretory syndromes—with biochemical responses in 73% and 77% of patients, respectively—with only 3% objective responses in carcinoids

. In a recent paper describing the outcomes of 92 patients with metastatic carcinoid, the median overall survival was almost 2 times longer in patients receiving long-acting SSAs than in untreated patients (112 vs. 53 mo)


Several clinical phase I–II trials indicated that PRRT with radiolabeled SSAs is among the promising newly developed targeted tools in NET

. Although a large variation in the inclusion criteria, dosage, and treatment scheme and overall antitumor effects was reported between studies

, treatment with either 90Y-DOTATOC or 177Lu-DOTATATE allows the delivery of high-absorbed doses to tumors expressing sst2 receptors, with partial and complete objective responses in up to 30% of patients


In our study population, 68Ga-DOTANOC PET/CT was performed in 1 patient to exclude the presence of disease—which would have prohibited the patient from the liver transplant waiting list—at sites other than the liver. Although performed in a minority of patients, liver transplantation in NET patients with hepatic secondary lesions has been reported to ensure good palliation in highly selected patients: symptomatic patients refractory to systemic medical treatment or unsuitable for interventional procedures and those with a progressive hepatic tumor load (28,29). In patients not meeting these criteria, the risks of surgery-related morbidity and mortality, tumor progression, and immunosuppressive treatment might favor a conservative approach. Although both SRS and 68Ga-DOTA-peptide PET/CT proved to be valuable preliminary studies before liver transplantation, Frilling et al. encouraged the replacement of SRS with PET in all screening protocols (28).


Ninety patients (54 men, 36 women; mean age, 58 y; age range, 22–86 y) were enrolled in the study. The clinical and epidemiologic characteristics of the studied population are reported in Table 1.

Patient Clinical and Epidemiologic Characteristics

PET/CT findings (Table 2) were concordant with CI in 47 of 90 patients (52.2%), discordant in 42 of 90 patients (46.7%), and equivocal in 1 patient (1.1%).

Comparison of 68Ga-DOTANOC PET/CT and CI Findings and Their Impact on Stage or Therapy Modifications

Considering PET and CI concordant cases (47/90), PET provided relevant information for therapeutic management in 17 of 47 patients (36.2%). In particular, 68Ga-DOTANOC PET/CT results suggested 12 patients for PRRT (with either 90Y-DOTATOC or 177Lu-DOTATATE) and 2 patients for cold somatostatin analog (SSA) medical treatment. P ET showed the response to treatment in 2 patients. In 1 patient, PET was performed to exclude the presence of SSR-expressing lesions—other than the ones known at liver level—that would have made the patient ineligible to receive a liver transplant. P ET did not affect disease staging in any of the CI-concordant cases, although in most patients PET detected a higher number of lesions.

Discordant 68Ga-DOTANOC PET/CT and CI findings were observed in 42 of 90 patients. P ET resulted in a modification of either stage or therapy in 32 patients (76.2%). In particular, stage was modified on the basis of PET results in 12 patients (28.6%). P ET upstaged the disease in 5 of 32 patients (identifying new sites of metastatic disease), and in 7 patients PET downstaged the disease: PET results were negative in 5 patients and in 2 patients excluded metastatic disease at liver and nodal levels. In the remaining 20 patients, PET did not change disease stage but determined modification of the therapeutic approach.

In 6 patients, PET findings recommended the patients for surgical treatment (in 3 of these 6 patients, the recommendation was based on identification of the site of the unknown primary). In 1 of the 3 UPC patients, PRRT was performed in addition to surgery. Of the remaining 3 of 6 patients who were surgically treated after PET, local relapse was identified in 2 patients and a single liver metastatic site in 1 patient.

Although both PET and CI results were inconclusive in 1 patient, PET images showed suggestive findings at the duodenum level, and further diagnostic procedures were recommended. The patient was later investigated with upper gastrointestinal endoscopy, which revealed the presence of a NET duodenal lesion that was subsequently surgically excised.

Overall Impact of PET on Clinical Management


Our data showed that 68Ga-DOTANOC PET/CT provided relevant information for NET patients’ clinical management: in our series PET affected the therapeutic approach in more than half the patients. Our results indicate PET as a mandatory procedure to guide treatment planning.


  • Received for publication October 20, 2009.
  • Accepted for publication February 3, 2010.
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