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area show a higher proportion of low-grade versus high- some studies fail to demonstrate such a relationship, [11,14]
grade malignant neoplasia. Among GEP-NENs, midgut these observations suggest overall that F-FDG PET/
[29]
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NENs are low-grade in more than half of cases (G1), CT may provide information on tumor grade in NENs,
whereas pancreatic NENs are more evenly distributed with showing a high accuracy in the distinction of NECs from
regard to Ki-67 labeling index and consequently tumor NETs, and promising outcomes in the stratification of
grade. It should be noted that higher grade NENs tend well-/moderately-differentiated NETs. [40]
[30]
to show a significant uptake of Ga-DOTA peptides and,
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conversely, significantly lower F-FDG avidity. ROLE OF DOUBLE TRACER PET/CT AT
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DIAGNOSIS
18 F-FDG PET/CT is positive in 97% of patients with
high-grade thoracic NENs (SCLC), in 75% of patients Diagnostic workup and staging
[31]
with low-grade thoracic NENs (carcinoids), in 53- 68 Ga-DOTA-peptide PET/CT is considered fundamental in
[32]
57% of patients with pancreatic NENs and in 29% of the diagnostic workup in patients with suspected thoracic
gastrointestinal low-grade NENs (carcinoids). [33] and/or GEP NETs. [41]
18 F-FDG and Ga-DOTA-peptide PET/CT and SSTR-based PET studies with Ga-labeled SSAs ( Ga-
68
68
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tumor grade DOTA-peptides) represent the evolution of SRS with In-
111
The WHO grading system defines 3 categories of NENs pentreotide which emerged in the late eighties as the gold
based on mitotic count and Ki-67 proliferative index (G1, standard in diagnosing, staging and follow-up of patients
mitotic count < 2 cells/10 high-power fields (HPF) and Ki- with NET, [4,42] with reported sensitivity and specificity
67 index ≤ 2%; G2, mitotic count 2-20 cells/10 HPF or Ki- ranging between 60-99% (except only for insulinomas
67 index 3-20%; and G3, mitotic count > 20 cells/10 HPF which show a low SSTR2 expression) and 85-98%,
[8]
or Ki-67 index > 20%). [34,35] Tumors with higher Ki-67 respectively. [4,43,44] Despite these encouraging results, which
expression display an increased proliferative activity and were superior to those achieved by CT or MRI, [4,45,46] SRS
are associated with a less favorable prognosis. F-FDG was limited by a low spatial resolution and an inability
[36] 18
PET/CT gives an index of cellular glycolytic activity, but to precisely localize neoplastic lesions, especially prior to
it has also been hypothesized that it may reflect also tumor the introduction of SPECT/CT hybrid systems. These
[8]
proliferation, based on correlations of F-FDG uptake shortcomings have been overcome by the development of
18
with the number of S-phase cells. As expected, the 68 Ga-labeled SSAs suitable for PET imaging. PET studies
[37]
proportion of patients with a positive F-FDG PET scan with Ga-labeled SSAs have several advantages over SRS
68
18
was found to be markedly higher in patients harboring including better diagnostic accuracy for the detection of
high-grade, highly-proliferating NECs compared with lung and bone lesions, higher affinity for SSTR2, higher
patients with well-differentiated, slowly-proliferating spatial resolution, lower radiation exposure, better patient
NETs (83% vs. 12,5%). In a surgical series of pancreatic comfort, and faster reporting. Results are typically available
[12]
NENs, F-FDG PET SUV max (maximum standardized within a few hours rather than 24 or even 48 h for SRS
18
uptake value) significantly correlated with tumor grade with 111In-pentreotide. Results also have the possibility
(Spearman rank correlation 0.584; P = 0.0018), and the of quantifying radionuclide biodistribution which includes
sensitivity, specificity, and accuracy of differentiating the potential to use data for monitoring the response to
G3 tumors from G1/G2 tumors were 100.0%, 62.5%, anticancer agents. [4,47,48] Combining PET and CT scans
and 66.7%, respectively. When well/moderately and additionally increased the diagnostic accuracy, as CT
[34]
[25]
poorly differentiated NENs are considered together, both provides complementary anatomic information. Among
68 Ga-DOTATATE and F-FDG PET/CT positivity seem the various Ga-labeled SSAs, Ga-DOTATOC shows a
68
18
68
to correlate with tumor grade: a higher uptake of Ga- particularly high affinity for SSTR2 which permits even the
68
DOTATATE has been described in low-grade compared detection of small lesions with lower SSTR expression. [4,49]
with high-grade tumors (P = 0.019) and, conversely, a 68 Ga-DOTATATE and Ga-DOTANOC are also clinically
68
higher uptake in high-grade compared with low-grade useful because of their high affinity to SSTR2 and, of
NENs (P = 0.029). When considering only intermediate particular importance, to SSTR3 and SSTR5 for Ga-
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[38]
and low-grade tumors, only F-FDG PET/CT maintained DOTANOC. [4,50,51] In a meta-analysis on the diagnostic
18
a significant correlation with tumor grade, showing higher performance of SSTR-based PET or PET/CT in patients
tracer uptake in intermediate versus low-grade NENs. On with suspicious thoracic and/or GEP NETs, sensitivity and
the contrary, Ga-DOTATATE PET/CT showed similar specificity of PET or PET/CT with Ga-DOTA-peptides
68
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uptake values in G1 and G2 NENs. That notwithstanding, in detecting NETs on a per patient-based analysis ranged
[38]
even in G1 NETs the rate of F-FDG PET/CT positivity from 72% to 100% and from 67% to 100%, with pooled
18
may be high. For example, in a prospective series of 98 estimates of 93% (95% CI: 91-95%) and 91% (95% CI:
patients with NENs, F-FDG PET/CT was positive in 40% 82-97%), respectively. The area under the ROC curve was
18
of patients with G1 NETs (Ki-67 labeling index < 2%), found to be 0.96, demonstrating that SSTR-based PET or
70% of patients with Ki-67 labeling index 2-15% and 93% PET/CT with Ga-DOTA-peptides are accurate diagnostic
68
of patients with Ki-67 labeling index > 15%. Although methods in NET diagnosis. Being able to detect NET
[39]
[41]
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦ 323