Utility of histopathological revision in the management of gastro-entero-pancreatic neuroendocrine neoplasia.

BACKGROUND: Histological evaluation and grading assessment are key points in the diagnostic work-up of gastroentero-pancreatic neuroendocrine neoplasms (GEP-NENs). AIM: To analyze the impact of histopathological revision on the clinical management of patients with GEP-NEN. MATERIALS AND METHODS: Patients referred to our Center of Excellence between 2015 and 2021 were included in this study. Immunohistochemical slides at the time of initial diagnosis were reviewed to assess tumor morphology, diagnostic immunohistochemistry, and Ki67. RESULTS: 101 patients were evaluated, with 65 (64.4%) gastrointestinal, 25 (24.7%) pancreatic, and 11 (10.9%) occult neoplastic lesions suspected to be of GEP origin. The main changes resulting from the revision were: first Ki-67 assessment in 15.8% of patients, Ki-67 change in 59.2% of patients and grading modification in 23.5% of patients. An additional immunohistochemical evaluation was performed in 78 (77.2%) patients, leading to a confirmation of GEP origin in 10 of 11 (90.9%) of unknown primary site neoplastic lesions and an exclusion of NEN diagnosis in 2 (2%) patients. After histopathological revision, a significant modification in clinical management was proposed in 42 (41.6%) patients. CONCLUSIONS: Histopathological revision in a referral NEN center is strongly advised in newly diagnosed GEP-NENs to properly plan prognostic stratification and therapeutic choice.

Management of Functional Pancreatic Neuroendocrine Neoplasms.

OPINION STATEMENT: Functional pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous diseases in terms of both clinical and pathological aspects. These tumors secrete hormones or peptides, which may cause a wide variety of symptoms related to a clinical syndrome. The management of functional pNENs is still challenging for clinicians due to the need to control both tumor growth and specific symptoms. Surgery remains the cornerstone in the management of local disease because it can definitively cure the patient. However, when the disease is not resectable, a broad spectrum of therapeutic options, including locoregional therapy, somatostatin analogs (SSAs), targeted therapies, peptide-receptor radionuclide therapy (PRRT), and chemotherapy, are available. The present review summarizes the main key issues regarding the clinical management of these tumors, providing a specific highlight on their therapeutic approach.

The Antiproliferative Activity of High-Dose Somatostatin Analogs in Gastro-Entero-Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis.

Background: The antiproliferative activity of a high dose of somatostatin analogs (HD-SSA) in treating gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) remains under debate. Methods: A systematic review and proportion meta-analysis were made. The primary endpoint was the efficacy measured as incidence density ratio (IDR) at one year. The secondary endpoints were the disease control rate (DCR) and severe adverse events (SAEs). The heterogeneity (I2), when high (>50%), was interpreted by performing a univariate metaregression analysis, analyzing as covariates: type and design of the study, location (Europe or USA), sample size, grading according to 2017 WHO, the metastatic disease rate, previous therapy including surgery, and quality of the study. Results: A total of 11 studies with 783 patients were included. The IDR was 62 new progressions of 100 patients treated with HD-SSA every one year. The heterogeneity was high. The study's year, type and design, primary tumor, grading, previous treatments, and quality of the studies did not influence the IDR. The IDR was significantly higher in USA centers and studies with more than 50 patients. The IDR was lower when a high rate of metastatic patients was present in the studies. The DCR was 45%. The heterogeneity was high. The DCR was lower in USA studies and in prospective trials. Conclusion: Given the limited efficacy of HD-SSA in preventing the disease progression in unresectable GEP-NENs after failure of standard dose SSA, the use of this therapeutic approach is advisable in selected cases when other antiproliferative treatments are not feasible.

CT-based radiomics for prediction of therapeutic response to Everolimus in metastatic neuroendocrine tumors.

AIM: To test radiomic approach in patients with metastatic neuroendocrine tumors (NETs) treated with Everolimus, with the aim to predict progression-free survival (PFS) and death. MATERIALS AND METHODS: Twenty-five patients with metastatic neuroendocrine tumors, 15/25 pancreatic (60%), 9/25 ileal (36%), 1/25 lung (4%), were retrospectively enrolled between August 2013 and December 2020. All patients underwent contrast-enhanced CT before starting Everolimus, histological diagnosis, tumor grading, PFS, overall survival (OS), death, and clinical data collected. Population was divided into two groups: responders (PFS ≤ 11 months) and non-responders (PFS > 11 months). 3D segmentation was performed on whole liver of naïve CT scans in arterial and venous phases, using a dedicated software (3DSlicer v4.10.2). A total of 107 radiomic features were extracted and compared between two groups (T test or Mann-Whitney), radiomics performance assessed with receiver operating characteristic curve, Kaplan-Meyer curves used for survival analysis, univariate and multivariate logistic regression performed to predict death, and interobserver variability assessed. All significant radiomic comparisons were validated by using a synthetic external cohort. P < 0.05 is considered significant. RESULTS: 15/25 patients were classified as responders (median PFS 25 months and OS 29 months) and 10/25 as non-responders (median PFS 4.5 months and OS 23 months). Among radiomic parameters, Correlation and Imc1 showed significant differences between two groups (P < 0.05) with the best performance (internal cohort AUC 0.86-0.84, P < 0.0001; external cohort AUC 0.84-0.90; P < 0.0001). Correlation < 0.21 resulted correlated with death at Kaplan-Meyer analysis (P = 0.02). Univariate analysis showed three radiomic features independently correlated with death, and in multivariate analysis radiomic model showed good performance with AUC 0.87, sensitivity 100%, and specificity 66.7%. Three features achieved 0.77 ≤ ICC < 0.83 and one ICC = 0.92. CONCLUSIONS: In patients affected by metastatic NETs eligible for Everolimus treatment, radiomics could be used as imaging biomarker able to predict PFS and death.

Role of [18F]FDG PET/CT in the management of G1 gastro-entero-pancreatic neuroendocrine tumors.

PURPOSE: Since the role of [18F]FDG PET/CT in low-grade gastroenteropancreatic (GEP) neuroendocrine neoplasia (NET) is not well established, this study was aimed to evaluate the role of [18F]FDG PET/CT in grade 1 (G1) GEP-NETs. METHODS: This is a retrospective study including patients with G1 GEP-NETs who underwent [18F]FDG PET/CT. RESULTS: 55 patients were evaluated, including 24 (43.6%) with pancreatic NETs and 31 (56.4%) with gastrointestinal NETs. At the time of diagnosis, 28 (51%) patients had metastatic disease, and 50 (91%) patients were positive by 68-Ga sstr PET/CT. Overall, 27 patients (49%) had positive findings on [18F]FDG PET/CT. Following [18F]FDG PET/CT, therapeutic management was modified in 29 (52.7%) patients. Progression-free survival was longer in patients with negative [18F]FDG PET/CT compared with positive [18F]FDG PET/CT (median PFS was not reached and 24 months, respectively, p = 0.04). This significance was particularly evident in the pancreatic group (p = 0.008). CONCLUSIONS: Despite having low proliferative activity, approximately half of GEP-NETs G1 showed positive [18F]FDG PET/CT, with a corresponding negative impact on patients' clinical outcomes. These data are in favor of a more "open" attitude toward the potential use of [18F]FDG PET/CT in the diagnostic work-up of G1 GEP-NETs, which may be used in selected cases to detect those at higher risk for an unfavorable disease course.

Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review.

BACKGROUND: In the last decades, the incidence of neuroendocrine neoplasia (NEN) increased from 1 to 5 new diagnoses/100,000 persons/year. The synthetic somatostatin analogues (SSAs) represent the first-choice treatment for both functionally active and inactive gastro-enteric-pancreatic NEN. This systematic review examines the role of octreotide long-acting release (LAR) in combination with other therapies for NEN management. METHODS: Primary outcomes were the disease control rate and the progression free survival (PFS), defined as the time between treatment initiation and progression of disease. Secondary outcomes were overall survival (OS) and safety. RESULTS: This systematic review identified 13 studies, concerning the use of octreotide LAR in association with other therapies in advanced NENs and included 1,206 patients. Patients were treated with octreotide LAR in combination with other drugs, mainly with everolimus (404 patients, 35%), but even with Peptide Receptor Radionuclide Therapy, bevacizumab, interferon or fluoride-derivatives. Disease control was observed in 85% cases with SSAs in combination with other therapies; PFS ranged from 15 to 16.4 months and OS from 25 to 61.9 months. SSAs are very well tolerated drugs, with few side effects which are usually mild, not requiring drug withdrawn. CONCLUSIONS: The review summarizes the effectiveness and available safety data on octreotide LAR in combination with other therapies in patients with NEN and may provide suggestions to address the therapeutic strategy. Further comparative head-to-head studies are needed to understand which is the best combination treatment for patients with progressive NEN after failure of first-line therapy.

Comparison of Endoscopic Techniques in the Management of Type I Gastric Neuroendocrine Neoplasia: A Systematic Review.

BACKGROUND: Endoscopic resection is considered the treatment of choice for type I gastric neuroendocrine neoplasia (gNEN) given its indolent behaviour; however, the favoured endoscopic technique to remove these tumours is not well established. AIMS: This systematic review is aimed at investigating the best endoscopic management for type I gNEN. METHODS: PubMed Central/Medline and Scopus were systematically searched for records up to August 31, 2020. RESULTS: After screening the 675 retrieved records, 6 studies were selected for the final analysis. The main endoscopic resection techniques described were endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Overall, 112 gNENs were removed by EMR and 77 by ESD. Both techniques showed similar results for complete and en bloc resection (97.4% and 98.7%; 92.3% and 96.3% with ESD and EMR, respectively). ESD was associated with a higher rate of complications than EMR (11.7% vs. 5.4%), but this difference was not statistically significant (p = 0.17). The rates of recurrence during follow-up were 18.2% and 11.5% for EMR and ESD, respectively. CONCLUSIONS: To date, there are no sufficient data showing superiority of a given endoscopic technique over others. Both ESD and EMR seem to be effective in the management of type I gNEN, with a relatively low rate of recurrence.

Efficacy of Lutetium-Peptide Receptor Radionuclide Therapy in Inducing Prolonged Tumour Regression in Small-Bowel Neuroendocrine Tumours: A Case of Favourable Response to Retreatment after Initial Objective Response.

INTRODUCTION: The efficacy of 177Lu-Dotatate was shown in the NETTER-1 trial, an international, open-label, multicentre phase III clinical trial that evaluated the safety and efficacy of 177Lu-Dotatate in patients with well-differentiated, advanced midgut neuroendocrine tumours (NETs) with evidence of disease progression. Recently, retreatment with peptide receptor radionuclide therapy (PRRT) has been proposed as a valid therapeutic option in patients without other effective options who had responded to initial PRRT; however, data on this therapeutic option are still inadequate. CASE REPORT: In this report, we present the case of a patient who achieved a delayed complete radiological response after initial 177Lu-Dotatate treatment and who had a complete tumour response with PRRT retreatment 5 years later. CONCLUSIONS: This case report shows that, although rare, a complete, prolonged tumour response may occur in patients with advanced small-bowel NETs receiving PRRT. Retreatment with PRRT may be a valid option in cases of subsequent disease recurrence.

Occurrence of exocrine pancreatic insufficiency in patients with advanced neuroendocrine tumors treated with somatostatin analogs.

BACKGROUND: Although exocrine pancreatic insufficiency (EPI) has been described in patients with neuroendocrine neoplasia (NEN) treated with somatostatin analogs (SSAs), its role in the therapeutic management of these patients is not well established. AIM: To determine the frequency of EPI in patients with NEN long-term treated with SSAs. METHODS: This is a prospective single-center study evaluating 35 patients treated with SSAs for >12 months due to unresectable/advanced nonpancreatic well-differentiated NEN. Clinical evaluation, biochemical parameters, and fecal elastases 1 (FE-1) were assessed to diagnose EPI. RESULTS: A total of 7 patients (20%) had EPI, given the presence of abdominal symptoms and a median FE-1 value of 180 mcg/g stool (150-198). No patient had severe EPI, defined as FE-1 < 100 mcg/g stool. Elevated glycated Hb levels were a significant predictor for developing EPI (OR 4.81, p = 0.01). No significant difference in terms of duration of SSA treatment was observed between patients with or without EPI diagnosed (84 months and 72 months, respectively; p = 0.950). CONCLUSIONS: Mild-moderate EPI is a relatively common condition in patients receiving long-term treatment with SSAs. Specific clinical and biochemical evaluations, including FE-1, should be planned in these patients to diagnose this relevant condition early, which may deteriorate quality of life and cause malnutrition.

CT texture analysis of liver metastases in PNETs versus NPNETs: Correlation with histopathological findings.

PURPOSE: To compare CT and Texture features of liver metastases in Pancreatic Neuroendocrine Tumors (PNETs) and in Non-Pancreatic Neuroendocrine Tumors (NPNETs) according to tumor grading, overall survival (OS), time to progression (TTP) and Ki67 index. METHODS: 23 patients with PNETs and 25 patients with NPNETs affected by liver metastases were compared. The lesions were G1 and G2 according to WHO classification of tumors. Texture parameters (Mean, Standard Deviation, Entropy, Kurtosis, Skewness, Mean of Positive Pixel) at different spatial scale image filtration (SSF) were evaluated in both arterial and portal phase using a dedicated software for volumetric analysis. All CT images were acquired before the beginning of any medical treatment. RESULTS: The following significant results (P < 0.05) were found: in the arterial phase for value of Skewness between PNETs G2 and NPNETs G2; in the portal phase between PNETs versus NPNETs, PNETs G1 versus NPNETs G1, PNETs G2 versus NPNETs G2; value of Mean in portal phase in PNETs vs NPNETs. Regarding PNETs, a P < 0.05 was found in: inverse correlation between Entropy and TTP; direct correlation between Mean and OS; correlating Kurtosis and high risk of death; correlating Skewness and low risk of death. Regarding NPNETs, P < 0.05 was found in: inverse correlation between Entropy and OS; correlating Entropy and high risk of dying. CONCLUSIONS: This study shows that CT texture features are significantly different in PNETs from NPNETs. Additionally, textural features such as Entropy, Kurtosis and Skewness, were found to have significant correlation with higher mortality risk.

Role of Combined [68Ga]Ga-DOTA-SST Analogues and [18F]FDG PET/CT in the Management of GEP-NENs: A Systematic Review.

Gastro-entero-pancreatic neuroendocrine neoplasia (GEP-NENs) are rare tumors, but their frequency is increasing. Neuroendocrine tumors normally express somatostatin (SST) receptors (SSTR) on cell surface, especially G1 and G2 stage tumors, but they can show a dedifferentiation in their clinical history as they become more aggressive. Somatostatin receptor imaging has previously been performed with a gamma camera using [111In]In or [99mTc]Tc-labelled compounds, while [68Ga]Ga-labelled compounds and PET/CT imaging has recently become the gold standard for the diagnosis and management of these tumors. Moreover, in the last few years 18F-fluorodeoxyglucose ([18F]FDG) PET/CT has emerged as an important tool to define tumor aggressiveness and give relevant prognostic information, particularly when coupled with [68Ga]Ga-labelled SST analogues PET/CT. This review focuses on the importance of combined imaging with [68Ga]Ga-labelled SST analogues and [18F]FDG for the management of GEP-NENs.

Multidisciplinary Management of Neuroendocrine Neoplasia: A Real-World Experience from a Referral Center.

PURPOSE: Multidisciplinary approach is widely advised for an effective care of patients with neuroendocrine neoplasia (NEN). Since data on efficacy of multidisciplinary management of NENs patients in referral centers are scanty, this study aimed at analyzing the modality of presentation and clinical outcome of patients with NENs managed by a dedicated multidisciplinary team. METHODS: In this prospective observational study, we included all consecutive new patients visiting the Sant'Andrea Hospital in Rome (ENETS-Center of Excellence) between January 2014 and June 2018. RESULTS: A total of 195 patients were evaluated. The most frequent sites were pancreas (38.5%), small bowel (22%), and lung (9.7%). Median Ki67 was 3%. After the first visit at the center, additional radiological and/or nuclear medicine procedures were requested in 163 patients (83.6%), whereas histological data revision was advised in 84 patients (43.1%) (revision of histological slides: 27.7%, new bioptic sampling: 15.4%). After that, disease imaging staging and grading was modified in 30.7% and 17.9% of patients, respectively. Overall, a change in therapeutic management was proposed in 98 patients (50.3%). CONCLUSIONS: Multidisciplinary approach in a dedicated team may lead to change of disease imaging staging and grading in a significant proportion of patients. Enhancing referral routes to dedicated-NEN center should be promoted, since it may improve patients' clinical outcome.