Neuroendocrine Tumors: Diagnostics.

Neuroendocrine neoplasms (NEN) are rare tumors arising from neuroendocrine cells. NEN are ideally suited for a theragnostic approach due to their specific expression of somatostatin receptors (SSTR). SSTR imaging of NEN dates back to the 1980s, but has evolved recently due to the introduction of more sensitive SSTR PET radiotracers. SSTR PET is a primary imaging modality for identifying NEN and characterizing SSTR expression. SSTR PET is complementary to anatomic imaging for assessing tumor response to treatment. SSTR PET is mandated to determine eligibility for peptide receptor radionuclide therapy. Here, the role of imaging to aid management of NEN is reviewed.

[Multiple ileal neuroendocrine tumors 10mm in diameter with lymph node metastasis detected on endoscopy:a case report].

A 53-year-old man with an abnormal routine physical examination was referred to our hospital. Colonoscopy showed a 5-mm submucosal tumor that was 7cm proximal to the ileocecal valve. It was identified as a neuroendocrine tumor (NET) on biopsy. Preoperatively, we conducted a double balloon endoscopy to examine the entire small intestine. Another 7-mm submucosal tumor was found on the ileocecal valve, which was missed during the first colonoscopy. A final diagnosis of multiple ileal NETs (<10mm in diameter) was made, and the patient underwent ileocecal resection with lymphadenectomy. Histopathological evaluation of the surgical specimen verified the diagnosis of NET Grade 1 with submucosal invasion. Metastasis to lymph node #202 was also detected. He remained relapse-free for 5 years and 5 months after the operation. In conclusion, this was a case of multiple ileal NETs (<10mm in diameter) with lymph node metastasis that could not be detected preoperatively on contrast-enhanced computed tomography. This case highlights the significance of detailed endoscopic observation of the terminal ileum.

Outcome prediction of SSTR-RADS-3A and SSTR-RADS-3B lesions in patients with neuroendocrine tumors based on 68Ga-DOTATATE PET/MR.

PURPOSE: Somatostatin receptor (SSTR)-targeted PET imaging has emerged as a common approach to evaluating those patients with well-differentiated neuroendocrine tumors (NETs). The SSTR reporting and data system (SSTR-RADS) version 1.0 provides a means of categorizing lesions from 1 to 5 according to the likelihood of NET involvement, with SSTR-RADS-3A (soft-tissue) and SSTR-RADS-3B (bone) lesions being those suggestive of but without definitive NET involvement. The goal of the present study was to assess the ability of 68Ga-DOTATATE PET/MR imaging data to predict outcomes for indeterminate SSTR-RADS-3A and 3B lesions. METHODS: NET patients with indeterminate SSTR-RADS-3A or SSTR-RADS-3B lesions who underwent 68Ga-DOTATATE PET/MR imaging from April 2020 through August 2023 were retrospectively evaluated. All patients underwent follow-up through December 2023 (median, 17 months; (3-31 months)), with imaging follow-up or biopsy findings ultimately being used to classify lesions as malignant or benign. Lesion maximum standardized uptake value (SUVmax) along with minimum and mean apparent diffusion coefficient (ADCmin and ADCmean) values were measured and assessed for correlations with outcomes on follow-up. RESULTS: In total, 33 indeterminate SSTR-RADS-3 lesions from 22 patients (19 SSTR-RADS-3A and 14 SSTR-RADS-3B) were identified based upon baseline 68Ga-DOTATATE PET/MR findings. Over the course of follow-up, 16 of these lesions (48.5%) were found to exhibit true NET positivity, including 9 SSTR-RADS-3A and 7 SSTR-RADS-3B lesions. For SSTR-RADS-3A lymph nodes, a diameter larger than 0.7 cm and an ADCmin of 779 × 10-6mm2/s or lower were identified as being more likely to be associated with metastatic lesions. Significant differences in ADCmin and ADCmean were identified when comparing metastatic and non-metastatic SSTR-RADS-3B bone lesions (P < 0.05), with these parameters offering a high predictive ability (AUC = 0.94, AUC = 0.86). CONCLUSION: Both diameter and ADCmin can aid in the accurate identification of the nature of lesions associated with SSTR-RADS-3A lymph nodes, whereas ADCmin and ADCmean values can inform the accurate interpretation of SSTR-RADS-3B bone lesions.

111 In-Pentetreotide-Guided Radiosurgery for Intraoperative Localization of Retroperitoneal Nodal Metastasis in a Patient With Ileal Neuroendocrine Tumor.

ABSTRACT: 64 Cu-DOTATATE PET/CT of a 44-year-old man with an ileal neuroendocrine tumor demonstrated the primary tumor, local nodal metastases, and a pericaval nodal metastasis. Localization of the pericaval node during surgery may be difficult, thus 4.4 mCi of 111 In-pentetreotide was administered before surgery to assist with localization and resection. At surgery, the pericaval nodal metastasis was readily detected by gamma probe, which could then be resected and pathologically proven to be a metastasis. This demonstrates the use of somatostatin receptor-targeted imaging for intraoperative localization of an otherwise difficult to surgically localize metastasis. Without intraoperative somatostatin receptor-targeted radiosurgery, disease may have been incompletely resected.

Safety and Efficacy of 177 Lu-DOTATATE in Children and Young Adult Population : A Single-Center Experience.

PURPOSE: This single-center retrospective study explores the safety and efficacy of 177 Lu-DOTATATE in children and young adult population with metastatic/inoperable neuroendocrine tumors (NETs). PATIENTS AND METHODS: This study is a retrospective analysis of all children and young adult patients (≤29 years) with advanced inoperable/metastatic epithelial or nonepithelial NETs who were administered a median of 4 cycles of 177 Lu-DOTATATE therapy and low-dose oral capecitabine as a radiosensitizer every 8-12 weeks, except 2 patients who received CAPTEM chemotherapy. The radiological response was assessed using RECIST 1.1 on interim and end-of-treatment 68 Ga-DOTANOC PET/CT. The primary endpoint was objective response rate, whereas disease control rate, toxicity profile, progression-free survival, and overall survival were secondary endpoints. RESULTS: Nineteen biopsy-proven NET patients (median age, 22 ± 10 years) with 8 of them adolescents (10-18 years) and the remaining young adults (19-29 years) were included. Fourteen patients had gastroenteropancreatic neuroendocrine tumor (pancreas being most common primary site), whereas the rest had non-gastroenteropancreatic neuroendocrine tumor. A total of 65 cycles of 177 Lu-DOTATATE (range, 1-6 cycles) were administered with a median cumulative activity of 600 mCi (range, 100-1000 mCi). The objective response rate and disease control rate were 41% and 94%, respectively. Grade 1 and 2 adverse events were observed in 14 (74%) and 5 (26%) of 19 patients, respectively. In a total of 8 events (42%), 4 events each of disease progression and death occurred during a median follow-up of 80.1 months with an estimated 5-year progression-free survival and overall survival of 54% (95% confidence interval, 30-78) and 63% (95% confidence interval, 39-87), respectively. CONCLUSIONS: 177 Lu-DOTATATE appears safe and effective in children and young adults with metastatic/inoperable NETs. Large prospective trials are required to validate these results.

Triple Tumors (Neuroendocrine Tumor, Schwannoma, and Papillary Thyroid Carcinoma) With Brain Lesions in a Single Patient Demonstrating Avidity on 68 Ga-DOTATATE PET/CT and Their Characterization With FDG-PET/CT and Brain MRI.

ABSTRACT: Neuroendocrine tumor (NET) typically spreads to the liver, lymph nodes, lungs, and skeleton. Brain metastasis in NET is uncommon. Therefore, each case of detected brain metastases in NET is crucial for the development of treatment guidelines for these types of tumors. We present a unique case of triple tumors (NET, papillary thyroid carcinoma, and schwannoma) in a single patient who presented with neurological symptoms and somatostatin receptor-avid T2 hyperintense multiple metastatic brain lesions from NET on 68 Ga-DOTATATE-PET/CT scan and brain MRI. Despite the rarity of brain metastases in NET, we conclude that the presence of neurological sign or symptoms and/or the detection of somatostatin receptor-avid brain lesions in patients with NET should raise suspicion of brain metastases.

Nodular image in the appendix observed on ultrasound: endometriosis or neuroendocrine neoplasia?

Objective: To evaluate the association between clinical and imaging with surgical and pathological findings in patients with suspected neuroendocrine tumor of appendix and/or appendix endometriosis. Methods: Retrospective descriptive study conducted at the Teaching and Research Institute of Hospital Israelita Albert Einstein, in which medical records and databases of patients with suspected neuroendocrine tumor of appendix and/or endometriosis of appendix were analyzed by imaging. Results: Twenty-eight patients were included, all of which had some type of appendix alteration on the ultrasound examination. The pathological outcome of the appendix found 25 (89.3%) lesions compatible with endometriosis and three (10.7%) neuroendocrine tumors. The clinical findings of imaging and surgery were compared with the result of pathological anatomy by means of relative frequency. Conclusion: It was possible to observe a higher prevalence of appendix endometriosis when the patient presented more intense pain symptoms. The image observed on ultrasound obtained a high positive predictive value for appendicular endometriosis.

Al18F-NOTA-Octreotide outperforms 18F-FDG in identifying rare renal metastases from pancreatic neuroendocrine tumor.

We presented a case involving a 56-year-old man who had been experiencing shoulder and back pain for over a year, with extensive bone metastases revealed by a bone scan. To identify the primary source of these issues, the patients underwent a fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scan, which indicated moderate uptake in the right renal soft mass and low uptake in multiple osteolytic lesions. Pathological examination and immunohistochemical staining of the renal mass supported the diagnosis of neuroendocrine tumors. Subsequently, a novel somatostatin receptor imaging agent, Al18F-NOTA-octreotide (18F-OC), was performed to further investigate the source of metastatic lesions and to stage the tumor. The 18F-OC scan revealed a high-uptake lesion in the pancreatic head, as well as additional lymph node and bone metastases lesions. Compared to 18F-FDG, the 18F-OC demonstrated superior imaging capabilities and a significantly higher tumor-to-background ratio in neuroendocrine neoplasms, which contributed to improving the staging and treatment management.

Imaging Intratumoral Heterogeneity of Diffuse Pancreatic Neuroendocrine Tumor With Multitracer PET/CT.

ABSTRACT: Diffuse involvement of pancreatic neuroendocrine tumor (PNET) is a rare presentation. Here, we report a case of suspected autoimmune pancreatitis with 18 F-FDG and 18 F-FAPI-42 PET/CT showing increased tracer uptake in the entire pancreas, which was eventually confirmed by biopsy pathologic analysis as diffuse PNET. 18 F-AlF-NOTA-octreotide PET/CT imaging showed heterogeneous tracer uptake in the entire pancreas.

68 Ga-DOTATATE and 68 Ga-FAPI Imaging in Neuroendocrine Neoplasms of Different Grades.

ABSTRACT: We report findings from 68 Ga-DOTATATE and 68 Ga-FAPI PET/CT in a 43-year-old woman with neuroendocrine neoplasms. DOTATATE and FAPI uptake differed in different lesions. These results suggest a potential value for dual-tracer imaging in the evaluation of neuroendocrine neoplasms that have different grades.

Solitary Pulmonary Perivascular Epithelial Cell Tumor Mimicking Pulmonary Metastasis on 68 Ga-DOTATATE PET/CT in a Patient With Pancreatic Neuroendocrine Tumor.

ABSTRACT: We report the findings of 68 Ga-DOTATATE PET/CT in a 56-year-old woman with solitary pulmonary perivascular epithelioid cell tumor. 68 Ga-DOTATATE PET/CT showed a lesion with intense uptake in the region of pancreatic head and a solitary nodule with moderate uptake in the left lung. Pancreatic neuroendocrine tumor with pulmonary metastasis was considered. The postoperative pathological results showed a benign perivascular epithelioid cell tumor of the lung. This case emphasizes the need to increase awareness of benign perivascular epithelioid cell tumors in the differential diagnosis of solitary pulmonary nodule with moderate DOTATATE activity.

Heterogeneous Uptake of 68 Ga-DOTATATE and 18 F-FDG in Initial Diagnosed Neuroendocrine Tumors Patients : Which Patients Are Suitable for Dual-Tracer PET Imaging?

PURPOSE: This study was designed to assess the uptake heterogeneity in neuroendocrine tumor (NET) patients at initial diagnosis with dual-tracer PET imaging and the staging changes and prognostic value it brings to explore the indication of the use of dual-tracer PET. METHODS: Fifty-one newly diagnosed patients with pathologically confirmed NET who underwent 18 F-FDG and 68 Ga-DOTATATE PET imaging between January 2020 and September 2022 were enrolled. Dual-tracer uptake patterns were classified into 3 groups: A. 68 Ga-DOTATATE positive and 18 F-FDG negative, B. 68 Ga-DOTATATE positive and 18 F-FDG positive, and C. 68 Ga-DOTATATE negative and 18 F-FDG positive. Descriptive statistics were used to evaluate the heterogeneity of dual-tracer uptake patterns among different grading (G) groups, between primary and metastatic lesions, and staging changes. Moreover, dual-tracer uptake patterns, grade, age, sex, and stage were compared with progression-free survival (PFS) by Cox regression. RESULTS: In the different G groups, none of the patients with dual-tracer uptake pattern A had grade 3 histology, but 57% of patients with grade 1 disease had FDG avidity (25% of them resulting in dual-tracer uptake pattern C). Patients with no metastasis were well differentiated, but one of them presented with dual-tracer uptake pattern C. Different uptake patterns were also observed between primary and metastatic lesions, particularly 44% of patients with dual-tracer uptake pattern A of primary with FDG avidity of metastases. Moreover, 9 (17.6%) had new lesions detected by additional 18 F-FDG PET imaging, and 3 of them (5.9%) had clinical stage changed accordingly. The Cox regression test showed that the dual-tracer uptake patterns were significantly correlated with PFS by univariate and multivariate analyses ( P = 0.026 and 0.039, respectively), whereas the grade and stage did not correlate with survival (all P >0.05). CONCLUSION: The current study has proven the uptake heterogeneity of the NET at initial diagnosis and demonstrated the staging and prognostic value of dual-tracer PET imaging. Our preliminary results have confirmed the importance of dual-tracer imaging modalities and concluded that dual-tracer PET imaging could be considered as prognostic tool for all patients with an initial diagnosis of NET.

Recent developments in the diagnosis of pancreatic neuroendocrine neoplasms.

INTRODUCTION: Pancreatic Neuroendocrine Neoplasms (PanNENs) are characterized by a highly heterogeneous clinical and biological behavior, making their diagnosis challenging. PanNENs diagnostic work-up mainly relies on biochemical markers, pathological examination, and imaging evaluation. The latter includes radiological imaging (i.e. computed tomography [CT] and magnetic resonance imaging [MRI]), functional imaging (i.e. 68Gallium [68 Ga]Ga-DOTA-peptide PET/CT and Fluorine-18 fluorodeoxyglucose [18F]FDG PET/CT), and endoscopic ultrasound (EUS) with its associated procedures. AREAS COVERED: This review provides a comprehensive assessment of the recent advancements in the PanNENs diagnostic field. PubMed and Embase databases were used for the research, performed from inception to October 2023. EXPERT OPINION: A deeper understanding of PanNENs biology, recent technological improvements in imaging modalities, as well as progresses achieved in molecular and cytological assays, are fundamental players for the achievement of early diagnosis and enhanced preoperative characterization of PanNENs. A multimodal diagnostic approach is required for a thorough disease assessment.

Alpha-emitter Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) has become mainstream therapy of metastatic neuroendocrine tumors not controlled by somatostatin analog therapy. Currently, beta particle-emitting radiopharmaceuticals are the mainstay of PRRT. Alpha particle-emitting radiopharmaceuticals have a theoretic advantage over beta emitters in terms of improved therapeutic efficacy due to higher cancer cell death and lower nontarget tissue radiation-induced adverse events due to shorter path length of alpha particles. We discuss the available evidence for and the role of alpha particle PRRT.

Functional imaging in neuroendocrine tumors: assessment of molecular heterogeneity using [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT.

OBJECTIVE: The aim of the study was evaluate the diagnostic performance of [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT in patients with histologically proven neuroendocrine tumors (NETs), as well as the correlation of the visualized findings with the tumor grade. MATERIAL AND METHODS: We included 50 patients with NETs who underwent both [68Ga]Ga-DOTA-TOC and [18F]FDG PET/TC. The pooled sensitivity of both scans was compared, as well as [68Ga]Ga-DOTA-TOC and [18F]FDG for each tumor grade (grade 1/G1, grade 2/G2 and grade 3/G3). Also, the sensitivity of [68Ga]Ga-DOTA-TOC and [18F]FDG as a function of the continuous variable Ki-67 was investigated. Finally, the number of lesions detected by both PET radiopharmaceuticals for each tumor grade was compared. RESULTS: The pooled sensitivity of both PET/CT (96%) was higher than [68Ga]Ga-DOTA-TOC (84%) and [18F]FDG (44%) separately, with statistically significant differences. The sensitivity of [68Ga]Ga-DOTA-TOC was higher than [18F]FDG in both G1 (p = 0.004) and G2 (p < 0.001). In G3 the performance of both scans detected disease in 100% of this subgroup. The sensitivity of [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT correlated significantly with the Ki-67 proliferative index. In G2 patients the number of lesions detected with [68Ga]Ga-DOTA-TOC was higher than [18F]FDG. CONCLUSIONS: The performance of both PET/CT, particularly in G2 and G3, demonstrates the molecular heterogeneity of metastatic NETs and contributes to the selection of a more appropriate treatment, particularly in those high-grade patients who may benefit from radionuclide therapy (PRRT).

Prevalence of metastases outside the liver and abdominal lymph nodes on 68Ga-DOTATOC-PET/CT in patients with small intestinal and pancreatic neuroendocrine tumours.

Metastases outside the liver and abdominal/retroperitoneal lymph nodes are nowadays detected frequently in patients with neuroendocrine tumours (NETs), owing to the high sensitivity of positron emission tomography (PET) with Gallium-68-DOTA-somatostatin analogues (68Ga-SSA) and concomitant diagnostic computed tomography (CT). Our aim was to determine the prevalence of extra-abdominal metastases on 68Ga-DOTATOC-PET/CT in a cohort of patients with small intestinal (Si-NET) and pancreatic NET (Pan-NET), as well as that of pancreatic metastasis in patients with Si-NET. Among 2090 patients examined by 68Ga-DOTATOC-PET/CT at two tertiary referral centres, a total of 1177 patients with a history of Si- or Pan-NET, were identified. The most recent 68Ga-DOTATOC-PET/CT report for each patient was reviewed, and the location and number of metastases of interest were recorded. Lesions outside the liver and abdominal nodes were found in 26% of patients (n = 310/1177), of whom 21.5% (255/1177) were diagnosed with Si-NET and 4.5% (55/1177) Pan-NET. Bone metastases were found in 18.4% (215/1177), metastases to Virchow's lymph node in 7.1% (83/1177), and lung/pleura in 4.8% (56/1177). In the subset of 255 Si-NET patients, 5.4% (41/255) manifested lesions in the pancreas, 1.5% in the breast (18/255), 1.3% in the heart (15/255) and 1% in the orbita (12/255). In Si-NET patients, the Ki-67 proliferation index was higher in those with ≥2 metastatic sites of interest, than with 1 metastatic site, (p <0.001). Overall, extra-abdominal or pancreatic metastases were more often found in patients with Si-NET (34%) than in those with Pan-NET (13%) (p <0.001). Bone metastases were 2.6 times more frequent in patients with Si-NET compared to Pan-NET patients (p <0.001). Lesions to the breast and orbita were encountered in almost only Si-NET patients. In conclusion, lesions outside the liver and abdominal nodes were detected in as many as 26% of the patients, with different prevalence and metastatic patterns in patients with Si-NET compared to Pan-NET. The impact of such metastases on overall survival and clinical decision-making needs further evaluation.

Absorbed Dose-Response Relationship in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE: One Step Closer to Personalized Medicine.

[177Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from 177Lu. The objective of this work was to explore how postinfusion [177Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Methods: Patients with GEP-NETs treated with [177Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. Results: In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation (P < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. Conclusion: In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.

Radionuclide Theranostics in Neuroendocrine Neoplasms: An Update.

PURPOSE OF REVIEW: This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT). RECENT FINDINGS: Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.

Multimodal management of foregut neuroendocrine neoplasms.

The foregut, which includes the esophagus, stomach and duodenum, represents one of the most common sites for neuroendocrine neoplasms. These are highly heterogenous with different risk of progression depending on location, cell-type of origin, size, grade and other factors. Various endoscopic and imaging modalities exist to inform therapeutic decision-making, which may be in the form of surgical or endoscopic resection and medical therapy depending on the extent of the disease after diagnostic evaluation. This narrative review aims to explore the literature on the multimodal management of such foregut neuroendocrine neoplasms.