Somatostatin receptor expression in lymphomas: a source of false diagnosis of neuroendocrine tumor at ⁶⁸Ga-DOTANOC PET/CT imaging

<p><b>Background:</b>⁶⁸Ga-DOTANOC PET/CT is routinely used to image neuroendocrine tumors (NETs). A case of lymphoma initially thought to be NET based on a positive ⁶⁸Ga-DOTANOC PET/CT was recently seen at our institution. This prompted us to determine prospectively somatostatin receptor (SSTR) status in patients with lymphoma by immunohistochemical analysis of SSTR subtypes 2, 3 and 5 (SSTR_2,3,5) and ⁶⁸Ga-DOTANOC PET/CT imaging.</p> <p><b>Material and methods:</b> Twenty-one patients with newly diagnosed lymphoma were referred to ⁶⁸Ga-DOTANOC and FDG PET/CT prior to any treatment. Tracer uptake was evaluated visually by two nuclear medicine specialists. Maximum standardized uptake values (SUVmax) were determined from 14 nodal and two extranodal regions with highest uptake in each patient. Lesions were then graded with Deauville score (1–5) on FDG PET/CT and modified Krenning score (0–4) on ⁶⁸Ga-DOTANOC PET/CT, respectively. SSTR_2,3,5 status was analyzed from routine biopsies of lymphomatous tissue and matched to corresponding PET/CT findings.</p> <p><b>Results:</b> About 20/21 patients had FDG-positive lymphoma (Deauville score ≥3). Uptake of ⁶⁸Ga-DOTANOC was regarded as positive if Krenning score was ≥2 and resulted in 13/21 (62%) patients having ⁶⁸Ga-DOTANOC-positive lymphomas. The highest uptake of ⁶⁸Ga-DOTANOC was seen in Hodgkin’s lymphoma of nodular sclerosis subtype and in diffuse large B-cell lymphoma (SUVmax median 9.8 and 9.7, respectively). Both cases showed strong SSTR₂ immunopositivity in tumor cells. Some patients had SSTR₂ immunopositivity predominantly in endothelial and dendritic cells and follicular centers of lymph nodes contributing to a positive PET/CT with probably low tumor-specific uptake. SSTR₃ and SSTR₅ were negative in most lymphoma subtypes.</p> <p><b>Conclusions:</b> According to this pilot study, ⁶⁸Ga-DOTANOC PET/CT is positive in some lymphoma subtypes which express SSTRs. These tumors present a potential risk of being misinterpreted as NETs if a representative tumor sample is not available. Lymphomas with high expression of SSTRs may be amenable to treatments targeting these receptors.</p

Feasibility of experimental BT4C glioma models for somatostatin receptor 2-targeted therapies

<div><p></p><p>Somatostatin receptor subtype 2 (sstr₂) is regarded as a potential target in malignant gliomas for new therapeutic approaches. Therefore, visualizing and quantifying tumor sstr₂ expression in vivo would be highly relevant for the future development of sstr₂-targeted therapies. The purpose of this study was to evaluate sstr₂ status in experimental BT4C malignant gliomas.</p><p><b>Methods.</b> Rat BT4C malignant glioma cells were injected into BDIX rat brain or subcutaneously into nude mice. Tumor uptake of [⁶⁸Ga]DOTA-(Tyr³)-Octreotide ([⁶⁸Ga]DOTATOC), a somatostatin analog binding to sstr₂, was studied by positron emission tomography/computed tomography (PET/CT). Additionally, subcutaneous tumor-bearing mice underwent PET imaging with 5-deoxy-5-[¹⁸F]fluororibose-NOC ([¹⁸F]FDR-NOC), a novel glycosylated peptide tracer also targeting sstr₂. Ex vivo tissue radioactivity measurements, autoradiography and immunohistochemistry were performed to study sstr₂ expression.</p><p><b>Results.</b> Increased tumor uptake of [⁶⁸Ga]DOTATOC was detected at autoradiography with mean tumor-to-brain ratio of 68 ± 30 and tumor-to-muscle ratio of 9.2 ± 3.8 for rat glioma. High tumor-to-muscle ratios were also observed in subcutaneous tumor-bearing mice after injection with [⁶⁸Ga]DOTATOC and [¹⁸F]FDR-NOC with both autoradiography (6.7 ± 1.5 and 4.3 ± 0.8, respectively) and tissue radioactivity measurements (6.5 ± 0.8 and 4.8 ± 0.6, respectively). Furthermore, sstr₂ immunohistochemistry showed positive staining in both tumor models. However, surprisingly low tumor signal compromised PET imaging. Mean SUV_max for rat gliomas was 0.64 ± 0.28 from 30 to 60 min after [⁶⁸Ga]DOTATOC injection. The majority of subcutaneous tumors were not visualized by [⁶⁸Ga]DOTATOC or [¹⁸F]FDR-NOC PET.</p><p><b>Conclusions.</b> Experimental BT4C gliomas show high expression of sstr₂. Weak signal in PET imaging, however, suggests only limited benefit of [⁶⁸Ga]DOTATOC or [¹⁸F]FDR-NOC PET/CT in this tumor model for in vivo imaging of sstr₂ status.</p></div