[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.

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.

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.

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.

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.

The Impact of Posttreatment Imaging in Peptide Receptor Radionuclide Therapy.

Posttreatment imaging of γ-emissions after peptide receptor radionuclide therapy (PRRT) can be used to perform quantitative dosimetry as well as assessment response using qualitative measures. We aimed to assess the impact of qualitative posttreatment imaging on the management of patients undergoing PRRT. Methods: In this retrospective study, we evaluated 100 patients with advanced well-differentiated neuroendocrine tumors undergoing PRRT, who had posttreatment SPECT/CT imaging at 24 h. First, we evaluated the qualitative assessment of response at each cycle. Then using a chart review, we determined the impact on management from the posttreatment imaging. The changes in management were categorized as major or minor, and the cycles at which these changes occurred were noted. Additionally, tumor grade was also evaluated. Results: Of the 100 sequential patients reviewed, most (80% after cycle 2, 79% after cycle 3, and 73% after cycle 4) showed qualitatively stable disease during PRRT. Management changes were observed in 27% (n = 27) of patients; 78% of those (n = 21) were major, and 30% (n = 9) were minor. Most treatment changes occurred after cycle 2 (33% major, 67% minor) and cycle 3 (62% major, 33% minor). Higher tumor grade correlated with increased rate of changes in management (P = 0.006). Conclusion: In this retrospective study, qualitative analysis of posttreatment SPECT/CT imaging informed changes in management in 27% of patients. Patients with higher-grade tumors had a higher rate of change in management, and most of the management changes occurred after cycles 2 and 3. Incorporating posttreatment imaging into standard PRRT workflows could potentially enhance patient management.

177 Lu-DOTATATE Salvage Therapy in Rapidly Progressing Neuroendocrine Tumor With Poor Performance Status.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) has shown to be effective and safe in metastatic gastroenteropancreatic and nongastroenteropancreatic neuroendocrine tumors. However, the selection criteria for PRRT are restricted to patients with good performance status (Eastern Cooperative Oncology Group score ≤2 or Karnofsky performance score ≥60). This denies many patients with adequate somatostatin receptor expression and biochemical profiles from the beneficial effects of PRRT on the quality of life, daily function, and overall survival. The 2 cases highlight the favorable response of PRRT in patients with metastatic neuroendocrine tumor having a very poor performance status initially.

Efficacy and Safety of 225 Ac-DOTATATE in the Treatment of Neuroendocrine Neoplasms With High SSTR Expression.

PURPOSE: We aimed to evaluate the efficacy and safety of 225 Ac-DOTATATE targeted α therapy (TAT) in various neuroendocrine neoplasms (NENs) with high somatostatin receptor (SSTR) expression. PATIENTS AND METHODS: This single-center prospective study included 10 patients with histologically diagnosed NENs that exhibited increased SSTR expression on 68 Ga-DOTATATE PET/CT imaging. All patients received 225 Ac-DOTATATE TAT. The primary end points were molecular imaging-based response and disease control rate (DCR), measured using the slightly modified Positron Emission Tomography Response Criteria in Solid Tumors 1.0. The secondary end points were adverse event profiles and clinical responses. The adverse event profile was determined according to the Common Terminology Criteria for Adverse Events version 5.0. Clinical response was assessed using the EORTC QLQ-C30 v3.0 (European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire version 3.0). RESULTS: A molecular imaging-based partial response was observed in 40% of all patients, SD in 40%, PD in 20%, and DCR in 80%. The DCR was 83.3% (5/6) in patients who were previously treated with 177 Lu-DOTATATE. According to the EORTC QLQ-C30 v3.0 score, most symptoms improved after 225 Ac-DOTATATE treatment, with only diarrhea showing no improvement. Grade III/IV hematological, kidney, and liver toxicities were not observed. The median follow-up time was 14 months (7-22 months), and no deaths were reported. CONCLUSIONS: This initial study suggests that 225 Ac-DOTATATE is a potentially promising option for treating NENs with elevated SSTR expression, with an acceptable toxicity profile and well-tolerated adverse effects.

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.

Pancreatic neuroendocrine tumour resection in circumportal pancreas: a rare anatomical anomaly with important surgical implications.

Various congenital anomalies of the pancreas have been reported due to its complex embryological development involving the fusion of two separate buds. Circumportal pancreas is a rare anatomical anomaly where the pancreatic head and uncinate process fuse abnormally with the pancreatic body, encasing the portal vein and/or superior mesenteric vein completely. This anomaly poses several challenges to hepatobiliary surgeons, as the encasement of the portal vein by the abnormal pancreatic tissue makes an additional parenchymal transection necessary. Vascular variants have also been reported with circumportal pancreas, which, if not recognised preoperatively, can be catastrophic. Therefore, careful preoperative evaluation and planning are essential, to ensure safe pancreatic resection and recovery in a patient with circumportal pancreas. We present a case of a successful subtotal pancreatectomy and splenectomy in a patient with circumportal pancreas, for a suspected pancreatic duct adenocarcinoma. The aim of this case report is to contribute valuable insights that can aid hepatobiliary surgeons in enhancing their preoperative planning when encountered with patients with similar anatomical variances.

Investigation of Clinical, Laboratory, Imaging Findings and Histopathological Features of Patients with Gastric Neuroendocrine Cell Hyperplasia.

BACKGROUND/AIMS: Neuroendocrine cell hyperplasia is a non-neoplastic proliferation of enterochromaffin-like cells and is considered a premalignant lesion because of their potential to progress to neuroendocrine tumor. In this study, we aimed to evaluate the demographic and clinical features, laboratory, radiological and endoscopic findings, gastric biopsy histopathological features, follow-up frequency, and histopathological findings of patients diagnosed with gastric neuroendocrine cell hyperplasia as well as to investigate the factors that play a role in the development of neuroendocrine tumors on the basis of neuroendocrine cell hyperplasia. MATERIALS AND METHODS: The study has been conducted in 2 centers with 282 patients that were grouped as those with and without neuroendocrine tumor. Individuals with control endoscopy were separated as those with regression of neuroendocrine cell hyperplasia and those without regression, and the determined parameters were evaluated between the groups. RESULTS: The most common histological subtype of neuroendocrine cell hyperplasia was linear+micronodular (50.4%). Neuroendocrine tumor developed in 4.3% (12/282) of the patients with neuroendocrine cell hyperplasia after a mean of 36 months. The presence of polyps as confirmed via endoscopy and dysplasia as confirmed via histopathological examination was significantly higher in favor of the group with neuroendocrine tumor (P = .01). In patients with neuroendocrine cell hyperplasia regressed and patients in whom it did not regress were examined, the rate of asymptomatic patients and increased sedimentation rate were found in favor of the group that did not regress (P = .02 and P = .02), but no difference was found in other parameters. CONCLUSION: Neuroendocrine tumor development rate was found to be 4.3% in the background of neuroendocrine cell hyperplasia. Two factors predicting progression from neuroendocrine cell hyperplasia to neuroendocrine tumor can be elaborated as the presence of polypoid appearance due to neuroendocrine cell hyperplasia as confirmed via endoscopy and dysplasia as confirmed via histopathological examination.

Pituitary apoplexy as the first manifestation of non­functioning pituitary neuroendocrine tumour.

Not required for a Clinical Vignette.

Efficacy of [67Cu]Cu-EB-TATE Theranostic Against Somatostatin Receptor Subtype-2-Positive Neuroendocrine Tumors.

ß--emitting 177Lu-octreotate is an approved somatostatin receptor subtype 2 (SSTR2)-directed peptide receptor radionuclide therapy for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). However,177Lu-octreotate has fast pharmacokinetics, requiring up to 4 treatment doses. Moreover, 177Lu is less than ideal for theranostics because of the low branching ratio of its γ-emissions, which limits its SPECT imaging capability. Compared with 177Lu, 67Cu has better decay properties for use as a theranostic. Here, we report the preclinical evaluation of a long-lived somatostatin analog, [67Cu]Cu-DOTA-Evans blue-TATE (EB-TATE), against SSTR2-positive NETs. Methods: The in vitro cytotoxicity of [67Cu]Cu-EB-TATE was investigated on 2-dimensional cells and 3-dimensional spheroids. In vivo pharmacokinetics and dosimetry were studied in healthy BALB/c mice, whereas ex vivo biodistribution, micro-SPECT/CT imaging, and therapy studies were done on athymic nude mice bearing QGP1.SSTR2 and BON1.SSTR2 xenografts. Therapeutic efficacy was compared with [177Lu]Lu-EB-TATE. Results: Projected human effective doses of [67Cu]Cu-EB-TATE for male (0.066 mSv/MBq) and female (0.085 mSv/MBq) patients are tolerable. In vivo micro-SPECT/CT imaging of SSTR2-positive xenografts with [67Cu]Cu-EB-TATE showed tumor-specific uptake and prolonged accumulation. Biodistribution showed tumor accumulation, with concurrent clearance from major organs over a period of 72 h. [67Cu]Cu-EB-TATE was more effective (60%) at eliminating tumors that were smaller than 50 mm3 within the first 15 d of therapy than was [177Lu]Lu-EB-TATE (20%) after treatment with 2 doses of 15 MBq administered 10 d apart. Mean survival of [67Cu]Cu-EB-TATE-treated groups was 90 d and more than 90 d, whereas that of [177Lu]Lu-EB-TATE was more than 90 d and 89 d against vehicle control groups (26 d and 53 d), for QGP1.SSTR2 and BON1.SSTR2 xenografts, respectively. Conclusion: [67Cu]Cu-EB-TATE exhibited high SSTR2-positive NET uptake and retention, with favorable dosimetry and SPECT/CT imaging capabilities. The antitumor efficacy of [67Cu]Cu-EB-TATE is comparable to that of [177Lu]Lu-EB-TATE, with [67Cu]Cu-EB-TATE being slightly more effective than [177Lu]Lu-EB-TATE for complete remission of small tumors. [67Cu]Cu-EB-TATE therefore warrants clinical development.

Metastatic neuroendocrine carcinoma: Liver metastases presenting with diffuse nodular calcifications on CT.

We report a case of the 46-year-old female patient, who presented with diffuse nodular liver calcifications on computed tomography. Histopathology of the calcified nodules revealed neuroendocrine tumors (NETs). Calcified NET liver metastases are extremely rare and need to be considered in the differential diagnosis with other benign and malignant liver calcification.

An automated methodology for whole-body, multimodality tracking of individual cancer lesions.

Objective. Manual analysis of individual cancer lesions to assess disease response is clinically impractical and requires automated lesion tracking methodologies. However, no methodology has been developed for whole-body individual lesion tracking, across an arbitrary number of scans, and acquired with various imaging modalities.Approach. This study introduces a lesion tracking methodology and benchmarked it using 2368Ga-DOTATATE PET/CT and PET/MR images of eight neuroendocrine tumor patients. The methodology consists of six steps: (1) alignment of multiple scans via image registration, (2) body-part labeling, (3) automatic lesion-wise dilation, (4) clustering of lesions based on local lesion shape metrics, (5) assignment of lesion tracks, and (6) output of a lesion graph. Registration performance was evaluated via landmark distance, lesion matching accuracy was evaluated between each image pair, and lesion tracking accuracy was evaluated via identical track ratio. Sensitivity studies were performed to evaluate the impact of lesion dilation (fixed versus automatic dilation), anatomic location, image modalities (inter- versus intra-modality), registration mode (direct versus indirect registration), and track size (number of time-points and lesions) on lesion matching and tracking performance.Main results. Manual contouring yielded 956 lesions, 1570 lesion-matching decisions, and 493 lesion tracks. The median residual registration error was 2.5 mm. The automatic lesion dilation led to 0.90 overall lesion matching accuracy, and an 88% identical track ratio. The methodology is robust regarding anatomic locations, image modalities, and registration modes. The number of scans had a moderate negative impact on the identical track ratio (94% for 2 scans, 91% for 3 scans, and 81% for 4 scans). The number of lesions substantially impacted the identical track ratio (93% for 2 nodes versus 54% for ≥5 nodes).Significance. The developed methodology resulted in high lesion-matching accuracy and enables automated lesion tracking in PET/CT and PET/MR.

Extravasation After [ 177 Lu]Lu-HA-DOTATATE Therapy.

ABSTRACT: Extravasation of the radiopharmaceutical during peptide receptor radionuclide therapy infusion is an unwanted infrequently reported event. We present the case of a 74-year old woman with a neuroendocrine tumor who was referred for peptide receptor radionuclide therapy. During intravenous infusion of 7.4 GBq [ 177 Lu]Lu-HA-DOTATATE in the upper right arm, extravasation of the radiopharmaceutical occurred through a displaced intravenous catheter. Planar scintigraphy showed pooling of radioactivity in the right upper arm. After 24 hours, the swelling in the arm was decreased; however, erythema was increased. One week later, symptoms had disappeared, and the patient did not experience any complications during follow-up of 11 months.