The diagnosis and subsequent therapy of neuroendocrine neoplasms (NENs) have long-relied on somatostatin receptor (SSTR) expression. The field of theranostics now uses newer SSTR based Positron Emission Tomography (SSTR-PET) imaging with 68Ga-DOTA0-Tyr3-Octreotate (68Ga-DOTATATE) or 68Ga-DOTA0-Tyr3-Octreotide (68Ga-DOTATOC), as a prerequisite for the administration of peptide receptor radionuclide therapy (PRRT). In the US, 177Lu-Dotatate, a form of PRRT, gained FDA approval in 2018 for use in gastroenteropancreatic NENs and was based on prolonged progression-free survival (PFS) vs. high dose Octreotide LAR in a phase III clinical trial of well-differentiated midgut NENs. Well-differentiated, grade 1 and grade 2 NENs have a low proliferation index (Ki-67 < 20%) and longer overall survival > 10 years while higher grade (grade 3) NENs have a high Ki-67 > 20% and shorter overall survival < 1 year. Here, we present a review on the newest histologic classification of NENs and the role of both SSTR-based imaging and PRRT in grade 3 (G3) NENs. Some studies suggest that G3 disease is less likely to be positive on SSTR-based imaging (but more likely in FDG PET) as compared to low grade disease, but these data are limited. Additionally, we found only eleven studies mentioning the use of PRRT in G3 NENs and a total of only forty-nine patients across these studies in which radiologic response was measured. Out of these forty-nine patients, twenty-seven (55%) demonstrated at least stable disease or a partial response, indicating that some G3 NENs can be responsive to PRRT. We suggest that patients with G3 NENs should receive both 18F-FDG PET and SSTR-based imaging to aide in both diagnosis and treatment selection. However, prospective studies are needed to understand the role of PRRT in G3 NENs, especially in well- versus poorly-differentiated G3 disease.
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