Critical updates in neuroendocrine tumors: Version 9 American Joint Committee on Cancer staging system for gastroenteropancreatic neuroendocrine tumors.

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP-NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP-NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP-NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP-NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix.

Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

Entinostat in patients with relapsed or refractory abdominal neuroendocrine tumors.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms with an increasing annual incidence and prevalence. Many are metastatic at presentation or recur following surgical resection and require systemic therapy, for which somatostatin analogs such as octreotide or lanreotide comprise typical first-line therapies. Nonetheless, treatment options remain limited. Epigenetic processes such as histone modifications have been implicated in malignant transformation and progression. In this study, we evaluated the anti-proliferative effects of a histone deacetylase (HDAC) inhibitor, entinostat, which was computationally predicted to show anti-cancer activity, as confirmed in in vitro and in vivo models of GEP-NETs. METHODS: This was a phase II study to evaluate the efficacy and safety of entinostat in patients with relapsed or refractory abdominal NETs. The primary objective was to estimate the objective response rate to entinostat. Additionally, with each patient as his/her own control we estimated the rates of tumor growth prior to enrollment on study and while receiving entinostat. Patients received 5 mg entinostat weekly until disease progression or intolerable toxicity. The dose could be changed to 10 mg biweekly for patients who did not experience grade ≥ 2 treatment-related adverse events (AEs) in cycle 1, but was primarily administered at the starting 5 mg weekly dose. RESULTS: The study enrolled only 5 patients due to early termination by the drug sponsor. The first patient that enrolled had advanced disease and died within days of enrollment before follow-up imaging due to a grade 5 AE unrelated to study treatment and was considered non-evaluable. Best RECIST response for the remaining 4 patients was stable disease (SD) with time on study of 154+, 243, 574, and 741 days. With each patient as his/her own control, rates of tumor growth on entinostat were markedly reduced with rates 20%, 33%, 54%, and 68% of the rates prior to enrollment on study. Toxicities possibly or definitely related to entinostat included grade 2/3 neutrophil count decrease [2/4 (50%)/ 2/4 (50%)], grade 3 hypophosphatemia [1/4, (25%)], grade 1/2 fatigue [1/4 (25%)/ 2/4 (50%)], and other self-limiting grade 1/2 AEs. CONCLUSION: In the treatment of relapsed or refractory abdominal NETs, entinostat 5 mg weekly led to prolonged SD and reduced the rate of tumor growth by 32% to 80% with an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03211988).

Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

DNA Methylation Profiling Enables Accurate Classification of Nonductal Primary Pancreatic Neoplasms.

BACKGROUND & AIMS: Cytologic and histopathologic diagnosis of non-ductal pancreatic neoplasms can be challenging in daily clinical practice, whereas it is crucial for therapy and prognosis. The cancer methylome is successfully used as a diagnostic tool in other cancer entities. Here, we investigate if methylation profiling can improve the diagnostic work-up of pancreatic neoplasms. METHODS: DNA methylation data were obtained for 301 primary tumors spanning 6 primary pancreatic neoplasms and 20 normal pancreas controls. Neural Network, Random Forest, and extreme gradient boosting machine learning models were trained to distinguish between tumor types. Methylation data of 29 nonpancreatic neoplasms (n = 3708) were used to develop an algorithm capable of detecting neoplasms of non-pancreatic origin. RESULTS: After benchmarking 3 state-of-the-art machine learning models, the random forest model emerged as the best classifier with 96.9% accuracy. All classifications received a probability score reflecting the confidence of the prediction. Increasing the score threshold improved the random forest classifier performance up to 100% with 87% of samples with scores surpassing the cutoff. Using a logistic regression model, detection of nonpancreatic neoplasms achieved an area under the curve of >0.99. Analysis of biopsy specimens showed concordant classification with their paired resection sample. CONCLUSIONS: Pancreatic neoplasms can be classified with high accuracy based on DNA methylation signatures. Additionally, non-pancreatic neoplasms are identified with near perfect precision. In summary, methylation profiling can serve as a valuable adjunct in the diagnosis of pancreatic neoplasms with minimal risk for misdiagnosis, even in the pre-operative setting.

PITX2 as a Sensitive and Specific Marker of Midgut Neuroendocrine Tumors: Results from a Cohort of 1157 Primary Neuroendocrine Neoplasms.

As neuroendocrine tumors (NETs) often present as metastatic lesions, immunohistochemical assignment to a site of origin is one of the most important tasks in their pathologic assessment. Because a fraction of NETs eludes the typical expression profiles of their primary localization, additional sensitive and specific markers are required to improve diagnostic certainty. We investigated the expression of the transcription factor Pituitary Homeobox 2 (PITX2) in a large-scale cohort of 909 NET and 248 neuroendocrine carcinomas (NEC) according to the immunoreactive score (IRS) and correlated PITX2 expression groups with general tumor groups and primary localization. PITX2 expression (all expression groups) was highly sensitive (98.1%) for midgut-derived NET, but not perfectly specific, as non-midgut NET (especially pulmonary/duodenal) were quite frequently weak or moderately positive. The specificity rose to 99.5% for a midgut origin of NET if only a strong PITX2 expression was considered, which was found in only 0.5% (one pancreatic/one pulmonary) of non-midgut NET. In metastases of midgut-derived NET, PITX2 was expressed in all cases (87.5% strong, 12.5% moderate), whereas CDX2 was negative or only weakly expressed in 31.3% of the metastases. In NEC, a fraction of cases (14%) showed a weak or moderate PITX2 expression, which was not associated with a specific tumor localization. Our study independently validates PITX2 as a very sensitive and specific immunohistochemical marker of midgut-derived NET in a very large collective of neuroendocrine neoplasms. Therefore, our data argue toward implementation into diagnostic panels applied for NET as a firstline midgut marker.

Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

PURPOSE: DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE. METHODS: This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE. RESULTS: Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P < 0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE. CONCLUSIONS: Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging.

Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols.

BACKGROUND: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach. METHODS: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed. RESULTS: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001). CONCLUSIONS: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Accuracy and Prognostic Impact of Nodal Status on Preoperative Imaging for Management of Pancreatic Neuroendocrine Tumors: A Multi-Institutional Study.

BACKGROUND: We sought to define the accuracy of preoperative imaging to detect lymph node metastasis (LNM) among patients with pancreatic neuroendocrine tumors (pNETs), as well as characterize the impact of preoperative imaging nodal status on survival. METHODS: Patients who underwent curative-intent resection for pNETs between 2000 and 2020 were identified from eight centers. Sensitivity and specificity of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and OctreoScan for LNM were evaluated. The impact of preoperative lymph node status on lymphadenectomy (LND), as well as overall and recurrence-free survival was defined. RESULTS: Among 852 patients, 235 (27.6%) individuals had LNM on final histologic examination (hN1). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 12.4%, 98.1%, 71.8%, and 74.4% for CT, 6.3%, 100%, 100%, and 80.1% for MRI, 9.5%, 100%, 100%, and 58.7% for PET, 11.3%, 97.5%, 66.7%, and 70.8% for OctreoScan, respectively. Among patients with any combination of these imaging modalities, overall sensitivity, specificity, PPV, and NPV was 14.9%, 97.9%, 72.9%, and 75.1%, respectively. Preoperative N1 on imaging (iN1) was associated with a higher number of LND (iN1 13 vs. iN0 9, p = 0.003) and a higher frequency of final hN1 versus preoperative iN0 (iN1 72.9% vs. iN0 24.9%, p < 0.001). Preoperative iN1 was associated with a higher risk of recurrence versus preoperative iN0 (median recurrence-free survival, iN1→hN1 47.5 vs. iN0→hN1 92.7 months, p = 0.05). CONCLUSIONS: Only 4% of patients with LNM on final pathologic examine had preoperative imaging that was suspicious for LNM. Traditional imaging modalities had low sensitivity to determine nodal status among patients with pNETs.

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10-10 and p = 8.5 × 10-9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10-4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10-8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70-0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.

Models using comprehensive, lesion-level, longitudinal [68Ga]Ga-DOTA-TATE PET-derived features lead to superior outcome prediction in neuroendocrine tumor patients treated with [177Lu]Lu-DOTA-TATE.

PURPOSE: Somatostatin receptor (SSTR) imaging features are predictive of treatment outcome for neuroendocrine tumor (NET) patients receiving peptide receptor radionuclide therapy (PRRT). However, comprehensive (all metastatic lesions), longitudinal (temporal variation), and lesion-level measured features have never been explored. Such features allow for capturing the heterogeneity in disease response to treatment. Furthermore, models combining these features are lacking. In this work we evaluated the predictive power of comprehensive, longitudinal, lesion-level 68GA-SSTR-PET features combined with a multivariate linear regression (MLR) model. METHODS: This retrospective study enrolled NET patients treated with [177Lu]Lu-DOTA-TATE and imaged with [68Ga]Ga-DOTA-TATE at baseline and post-therapy. All lesions were segmented, anatomically labeled, and longitudinally matched. Lesion-level uptake and variation in uptake were measured. Patient-level features were engineered and selected for modeling of progression-free survival (PFS). The model was validated via concordance index, patient classification (ROC analysis), and survival analysis (Kaplan-Meier and Cox proportional hazards). The MLR was benchmarked against single feature predictions. RESULTS: Thirty-six NET patients were enrolled and stratified into poor and good responders (PFS ≥ 25 months). Four patient-level features were selected, the MLR concordance index was 0.826, and the AUC was 0.88 (0.85 specificity, 0.81 sensitivity). Survival analysis led to significant patient stratification (p<.001) and hazard ratio (3⨯10-5). Lastly, in a benchmark study, the MLR modeling approach outperformed all the single feature predictors. CONCLUSION: Comprehensive, lesion-level, longitudinal 68GA-SSTR-PET analysis, combined with MLR modeling, leads to excellent predictions of PRRT outcome in NET patients, outperforming non-comprehensive, patient-level, and single time-point feature predictions. MESSAGE: Neuroendocrine tumor, peptide receptor radionuclide therapy, Somatostatin Receptor Imaging, Outcome Prediction, Treatment Response Assessment.

The inferior performance of [68Ga]Ga-FAPI-04 PET/CT as a diagnostic and theranostic biomarker in [177Lu]Lu-DOTATATE refractory well-differentiated neuroendocrine tumors.

PURPOSE: We aimed to investigate the potential of [68Ga]Ga-FAPI-04 PET/CT as an alternative diagnostic and theranostic tool in well-differentiated NETs refractory to [177Lu]Lu-DOTATATE therapy. METHODS: Patients who received at least two cycles of [177Lu]Lu-DOTATATE therapy for metastatic NETs and progressed under treatment were included. All patients had performed [68Ga]Ga-DOTATATE and [68Ga]Ga-FAPI-04 PET/CT within 3 weeks. The number of PET-positive lesions related to NETs and tumor sites was documented. Mann-Whitney U and chi-square tests were used to compare SUVmax levels of tracers and the number of detected metastases. RESULTS: Twelve patients (7 male, 5 female) who met the eligibility criteria were included in the study. Ten patients had grade 1-2 NET of various origins, and two had paraganglioma and pheochromocytoma. One hundred ninety-eight of 230 lesions (86%) were SSTR positive with a median SUVmax of 16.6 (2.2-76.5), and 88 of 230 lesions (38.2%) were [68Ga]Ga-FAPI-04 positive with a median SUVmax of 5.1 (2.3-21). Median SUVmax level and detected number of tumors were significantly higher in [68Ga]Ga-DOTATATE PET/CT (p=<0.001). [68Ga]Ga-FAPI-04 PET/CT was completely (n:2) or almost completely (n:3) negative in 5 (42%) patients. Two (17%) patients had flip-flop SSTR/FAPI uptake in tumors. In four patients (33%), tumor uptake or the number of PET-positive lesions was inferior in [68Ga]Ga-FAPI-04 PET/CT. In only one patient (8%), tumor uptakes were higher in [68Ga]Ga-FAPI-04 PET/CT. Low-dose [177Lu]Lu-FAPI-46 dosimetry was performed on the FAPI-dominant patient; absorbed radiation doses per GBq were 1.26 Gy, 0.36 Gy, 0.32 Gy, and 0.2 Gy for kidneys, liver, spleen, and total body, respectively. The mean absorbed dose per GBq was 0.33 Gy for liver mass and 0.41 Gy for metastatic lymph nodes. CONCLUSION: Our preliminary results demonstrated that [68Ga]Ga-FAPI-04 PET/CT mainly failed in well-differentiated NETs refractory to [177Lu]Lu-DOTATATE therapy and had a limited role as an alternative diagnostic or theranostic agent. Further investigations with a larger patient population are required to determine the impact of [68Ga]Ga-FAPI-04 PET/CT on NETs.

Evaluation of the safety, biodistribution, dosimetry of [18F]AlF-NOTA-LM3 and head-to-head comparison with [68Ga]Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors: an interim analysis of a prospective trial.

PURPOSE: 18F-labelled somatostatin receptor (SSTR) analogs offer several advantages over 68Ga in terms of yield, cost, spatial resolution and detection rate. This study presents an interim analysis of a prospective trial designed to assess the safety, biodistribution and dosimetry of [18F]AlF-NOTA-LM3, and compare its diagnostic efficacy and clinical management outcomes with [68Ga]Ga-DOTATATE or [68Ga]Ga-NODAGA-LM3 in patients with well-differentiated NETs. METHODS: Twenty-one patients with histologically confirmed well-differentiated neuroendocrine tumors (G1 and G2) were prospectively recruited. The first eight patients underwent serial PET scans at 5, 15, 30, 45, 60, and 120 min after [18F]AlF-NOTA-LM3 injection to assess biodistribution and dosimetry. The remaining patients underwent whole-body PET/CT scans. [18F]AlF-NOTA-LM3 and [68Ga]Ga-DOTATATE PET/CT were done within a week, with a minimum 24-hour interval between the two scans. Focal uptake above the surrounding background activity and could not be explained by physiologic uptake was considered lesions of NETs. Lesion number, tumor uptake, and tumor-to-background ratio (TBR) were compared. In patients with discrepant findings, the size of the smallest lesions (measured on coregistered CT) detected on [68Ga]Ga-DOTATATE and [18F]AlF-NOTA-LM3 was compared. RESULTS: [18F]AlF-NOTA-LM3 was safe and well-tolerated. Physiological uptake of [18F]AlF-NOTA-LM3 was significantly lower than that of [68Ga]Ga-DOTATATE in abdominal organs and bone marrow, but higher in blood pool and lung. The mean effective dose was 0.024 ± 0.014 mSv/MBq. [18F]AlF-NOTA-LM3 detected significantly more liver lesions (457 vs. 291, P = 0.006) and lymph node lesions (30 vs. 22, P = 0.011) compared to [68Ga]Ga-DOTATATE. The tumor uptake was comparable, but TBR was significantly higher with [18F]AlF-NOTA-LM3 for lesions from all sites except for the duodenum. The size of the minimum liver lesions (0.54 ± 0.15 vs. 1.01 ± 0.49, P<0.001) and lymph node lesions (0.50 ± 0.19 vs. 1.26 ± 0.86, P = 0.024) detected on [18F]ALF-NOTA-LM3 were significantly smaller than those detected on [68Ga]Ga-DOTATATE. CONCLUSION: [18F]AlF-NOTA-LM3 shows favorable biodistribution, higher spatial resolution and superior performance than [68Ga]Ga-DOTATATE in detecting liver and lymph node metastases, with higher TBR. Notably, it is the first SSTR analog to show superiority in detecting lymph node lesions when compared to [68Ga]Ga-DOTATATE. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT06056362.

Paget Disease of Bone Harboring Bone Metastatic Neuroendocrine Cancer: A Case Report.

In this case report, we describe an uncommon case of neuroendocrine cancer of unknown origin began with cauda equina syndrome in a patient affected by Paget disease of bone (PDB). A 76-year-old man with diagnosis of PDB, without history of pain or bone deformity, developed sudden severe low back pain. Bone alkaline phosphatase was increased and MRI and whole-body scintigraphy confirmed the localization of the disease at the third vertebra of the lumbar spine. Treatment with Neridronic Acid was started, but after only 2 weeks of therapy anuria and bowel occlusion occurred together with lower limb weakness and walking impairment. Cauda equina syndrome consequent to spinal stenosis at the level of L2-L3 was diagnosed after admission to Emergency Department and the patient underwent neurosurgery for spinal medulla decompression. The histologic results showed a complete subversion of bone structure in neoplastic tissue, consistent with metastatic neuroendocrine carcinoma of unknown origin. In conclusion, low back pain in the elderly may require deep investigation to individuate rare diseases. In asymptomatic patients with apparently stable PDB, the sudden appearance of pain or neurologic symptoms may alert the clinician for the possibility of other superimposing diseases, like bone metastases.

Radiologic tumor border can further stratify prognosis in patients with pancreatic neuroendocrine tumor.

BACKGROUND AND OBJECTIVES: Pancreatic neuroendocrine tumor (PanNET), although rare in incidence, is increasing in recent years. Several clinicopathologic and molecular factors have been suggested for patient stratification due to the extensive heterogeneity of PanNETs. We aimed to discover the prognostic role of assessing the tumor border of PanNETs with pre-operative computed tomography (CT) images and correlate them with other clinicopathologic factors. METHODS: The radiologic, macroscopic, and microscopic tumor border of 183 surgically resected PanNET cases was evaluated using preoperative CT images (well defined vs. poorly defined), gross images (expansile vs. infiltrative), and hematoxylin and eosin-stained slides (pushing vs. infiltrative). The clinicopathologic and prognostic significance of the tumor border status was compared with other clinicopathologic factors. RESULTS: A poorly defined radiologic tumor border was observed in 65 PanNET cases (35.5 %), and were more frequent in male patients (P = 0.031), and tumor with larger size, infiltrative macroscopic growth pattern, infiltrative microscopic tumor border, higher tumor grade, higher pT category, lymph node metastasis, lymphovascular and perineural invasions (all, P < 0.001). Patients with PanNET with a poorly defined radiologic tumor border had significantly worse overall survival (OS) and recurrence-free survival (RFS; both, P < 0.001). Multivariable analysis revealed that PanNET with a poorly defined radiologic border is an independent poor prognostic factor for both OS (P = 0.049) and RFS (P = 0.027). CONCLUSION: Pre-operative CT-based tumor border evaluation can provide additional information regarding survival and recurrence in patients with PanNET.

Long-term outcomes of endoscopic resection for well-differentiated nonampullary duodenal neuroendocrine tumors.

BACKGROUND & AIMS: Nonampullary duodenal neuroendocrine tumors (NAD-NETs) are rare with limited evidence regarding endoscopic treatment. The study aimed to investigate the efficacy and safety of endoscopic resection of well-differentiated NAD-NETs and evaluate long-term outcomes, including local recurrence and metastasis. METHODS: A total of 78 patients with NAD-NETs who underwent endoscopic resection between January 2011 and August 2022 were included. The clinicopathologic characteristics and treatment outcomes were collected and analyzed. RESULTS: En bloc resection was achieved for 74 of the tumors (94.9%) and R0 resection was obtained in 68 of the tumors (87.2%). Univariate analysis identified tumors in the second part of the duodenum, tumor size ≥ 10 mm and muscularis propria invasion as risk factors for non-curative resection. Two patients with R1 resection (vertical margin involvement) and two patients with lymphovascular invasion underwent additional surgery. Four patients experienced adverse events (5.1%), including two cases of delayed bleeding and two cases of perforation, all successfully managed conservatively. During a median follow-up period of 62.6 months, recurrence and lymph node metastasis were only detected in one patient with R1 resection 3 months after the original procedure. CONCLUSION: Endoscopic resection is safe and effective and provides a favorable long-term outcome for patients with well-differentiated NAD-NETs without regional lymph node or distant metastasis.

Low Prognostic Nutritional Index Is Common and Associated with Poor Outcomes following Curative-Intent Resection for Gastro-Entero-Pancreatic Neuroendocrine Tumors.

INTRODUCTION: To investigate the impact of prognostic nutritional index (PNI) on short- and long-term outcomes of patients who underwent curative-intent resection for gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). METHODS: Patients with GET-NETs who underwent curative-intent resection were identified from a multi-center database. The prognostic impact of clinicopathological factors including PNI on post-operative outcomes were evaluated. A novel nomogram was developed and externally validated. RESULTS: A total of 2,099 patients with GEP-NETs were included in the training cohort; 255 patients were in the external validation cohort. Median PNI (n = 973) was 47.4 (IQR 43.1-52.4). At the time of presentation, 1,299 (61.9%) patients presented with some type of clinical symptom. Low-PNI (≤42.2) was associated with gastrointestinal symptoms, as well as nodal metastasis and distant metastasis (all p < 0.05). Patients with a low PNI had a higher incidence of severe (≥Clavien-Dindo grade IIIa: low PNI 24.9% vs. high PNI 15.4%, p = 0.001) and multiple (≥3 types of complications: low PNI 14.5% vs. high PNI 9.2%, p = 0.024) complications, as well as a worse overall survival (OS)(5-year OS, low PNI 73.7% vs. high PNI 88.5%, p < 0.001), and RFS (5-year RFS, low PNI 68.5% vs. high PNI 79.8%, p = 0.008) versus patients with high PNI (>42.2). A nomogram based on PNI, tumor grade and metastatic disease demonstrated excellent discrimination and calibration to predict OS in both the training (C-index 0.748) and two external validation (C-index 0.827, 0.745) cohorts. CONCLUSIONS: Low PNI was common and associated with worse short- and long-term outcomes among patients with GEP-NETs.

Gender Differences in Lung Neuroendocrine Tumors: A Single-Center Experience.

INTRODUCTION: Gender difference may affect lung neuroendocrine tumor (L-NET) onset, progression, and outcomes as emerged in other cancers. This study aimed to analyze gender difference in L-NET to identify potential prognostic factors, to improve patient follow-up and therapeutic strategies. METHODS: Patients with histologically confirmed L-NEN diagnosis referred to the ENETS CoE of the Endocrinology Unit, Federico II University of Naples, from 2013 to 2023, were retrospectively evaluated. RESULTS: Among 48 patients with L-NEN, 38 (79.2%) with sporadic L-NET were enrolled: 22 typical (57.9%) and 16 atypical (42.1%) carcinoids, 22 (57.9%) female and 16 (42.1%) male, mean age at diagnosis 57.3 years (range 16-84). Median follow-up was 70.5 months (range 12-305). No statistical difference resulted regarding smoking habit, BMI, primary site (left/right and central/peripheral), and histological characteristics, between cohorts. Metastasis at diagnosis was found in 20 patients (52.3%), 10 female (10%) and 10 male (10%) (p: 0.20). Progressive disease (PD) was observed in 14 (36.8%) patients, and male sex developed PD more frequently 9/14 (64.3%) than female 5 (35.7%), p: 0.05. Male sex seemed to show more frequently bone metastasis without reaching statistical difference, 7 male/10 (70%), p: 0.06. Among 9 deaths (23.7%), 7 (77.8%) were men and 7 died for PD, p < 0.03. Male had a poorer prognosis than female regarding progression-free survival (PFS) (p: 0.04) and overall survival (p: 0.001), also when sub-groups of patient metastatic at diagnosis were compared (p: 0.02 and p: 0.02). CONCLUSIONS: This study showed a worse prognosis in male than female with L-NET, despite similar clinical features, tumor type, stage, and treatment, with regard to PFS, OS, and metastatic spread. These findings may suggest a closer follow-up in men, with potential positive impact on outcomes.

Neuroendocrine neoplasms of the gallbladder: A single institute analysis of outcomes and prognostic factors.

INTRODUCTION: Neuroendocrine neoplasms (NENs) are classified as neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine and nonneuroendocrine neoplasms (MiNENs) according to World Health Organization classification. We present our experience of NENs of the gallbladder (GB) from a high-volume cancer hospital. MATERIALS AND METHODS: The present study is a retrospective analysis of all patients with GB NENs who presented between January 2015 and June 2023. The patient details and treatment received with follow-up were noted. The primary endpoint was overall survival (OS). RESULTS: A total of 147 patients were included in the study. The median age was 52 (27-81) years. There was a female predominance (70.7%). NEC was the most common subtype (84.4%) followed by MiNEN (12.9%) and NET (2.7%). The most common stage at presentation was metastatic (70.7%) followed by locally advanced (21.8%), and early disease (7.5%). The median follow-up was 9.92 (1.77-76.06) months. Median OS was 6.14 (3.93-8.35) months. Median OS in patients who received multimodality treatment was 20.20 (17.99-22.41) months versus 4.00 (2.91-5.10) months in those who did not receive it. CONCLUSION: GB NENs are rare, but aggressive tumors with NEC being the most common type. Multimodality treatment yields favorable outcomes. However, the development of better systemic therapy is needed to help improve survival further.

Assessing risk stratification in long-term outcomes of rectal neuroendocrine tumors following endoscopic resection: a multicenter retrospective study.

OBJECTIVES: While endoscopic resection of rectal neuroendocrine tumors (NETs) has significantly increased, long-term data on risk factors for recurrence are still lacking. Our aim is to analyze the long-term outcomes of patients with rectal NETs after endoscopic resection through risk stratification. METHODS: In this multicenter retrospective study, we included patients who underwent endoscopic resection of rectal NETs from 2009 to 2018 and were followed for ≥12 months at five university hospitals. We classified the patients into three risk groups according to the clinicopathological status of the rectal neuroendocrine tumors: low, indeterminate, and high. The high-risk group was defined if the tumors have any of the followings: size ≥ 10 mm, lymphovascular invasion, muscularis propria or deeper invasion, positive resection margins, or mitotic count ≥2/10. RESULTS: A total of 346 patients were included, with 144 (41.6%), 121 (35.0%), and 81 (23.4%) classified into the low-, indeterminate-, and high-risk groups, respectively. Among the high-risk group, seven patients (8.6%) received salvage treatment 28 (27-67) days after the initial endoscopic resection, with no reported extracolonic recurrence. Throughout the follow-up period, 1.1% (4/346) of patients experienced extracolonic recurrences at 56.5 (54-73) months after the initial endoscopic resection. Three of these patients (75%) were in the high-risk group and did not undergo salvage treatment. The risk of extracolonic recurrence was significantly higher in the high-risk group compared to the other groups (p = 0.039). CONCLUSION: Physicians should be concerned about the possibility of metastasis during long-term follow-up of high-risk patients and consider salvage treatment.