Reliability and Agreement of Radiological and Pathological Tumor Size in Patients with Multiple Endocrine Neoplasia Type 1-Related Pancreatic Neuroendocrine Tumors: Results from a Population-Based Cohort.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor size is still regarded as the main prognostic factor and therefore used for surgical decision-making. We assessed reliability and agreement of radiological and pathological tumor size in a population-based cohort of patients with MEN1-related pNETs. METHODS: Patients were selected from the Dutch MEN1 database if they had undergone a resection for a pNET between 2003 and 2018. Radiological (MRI, CT, and endoscopic ultrasonography [EUS]) and pathological tumor size were collected from patient records. Measures of agreement (Bland-Altman plots with limits of agreement [LoA] and absolute agreement) and reliability (intraclass correlation coefficients [ICC] and unweighted kappa) were calculated for continuous and categorized (< or ≥2 cm) pNET size. RESULTS: In 73 included patients, the median radiological and pathological tumor sizes measured were 22 (3-160) and 21 (4-200) mm, respectively. Mean bias between radiological and pathological tumor size was -0.2 mm and LoA ranged from -12.9 to 12.6 mm. For the subgroups of MRI, CT, and EUS, LoA of radiological and pathological tumor size ranged from -9.6 to 10.9, -15.9 to 15.8, and -13.9 to 11.0, respectively. ICCs for the overall cohort, MRI, CT, and EUS were 0.80, 0.86, 0.75, and 0.76, respectively. Based on the 2 cm criterion, agreement was 81.5%; hence, 12 patients (18.5%) were classified differently between imaging and pathology. Absolute agreement and kappa values of MRI, CT, and EUS were 88.6, 85.7, and 75.0%, and 0.77, 0.71, and 0.50, respectively. CONCLUSION: Within a population-based cohort, MEN1-related pNET size was not systematically over- or underestimated on preoperative imaging. Based on agreement and reliability measures, MRI is the preferred imaging modality.

Health-related quality of life and treatment effects in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms: A systematic review and meta-analysis.

INTRODUCTION: Gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) are often diagnosed in an advanced stage. As the optimal sequence of therapy remains largely unclear, all treatment-related outcomes, including health-related quality of life (HRQoL) prospects, should be assessed according to patients' preferences. METHODS: A targeted search was performed in PubMed and EMBASE to identify studies on treatment effect and HRQoL, measured using the EORTC QLQ-C30 tool, in patients with advanced, well-differentiated GEPNENs. Study quality was assessed, and meta-analyses were performed for global health status/QOL and tumour response. RESULTS: The search yielded 1,322 records, and 20 studies were included, examining somatostatin analogues (SSA), peptide receptor radionuclide therapies (PRRT), chemotherapy, SSA-based combination therapies, and targeted therapies. Global HRQoL was stable, and rates for disease stabilisation were moderate to high across all treatments. Meta-analyses for global health status/QOL after SSA treatment were not significant (mean difference: -0.3 [95% CI: -1.3 to 0.7]). The highest pooled overall tumour response rate was 33% (95% CI: 24-45%) for PRRT. The highest pooled clinical benefit rate was 94% (95% CI: 65-99%) for chemotherapy. CONCLUSION: All treatments appeared beneficial for disease stabilisation while maintaining stable global health status/QOL. High-quality HRQoL reporting was lacking. HRQoL should be a central outcome next to well-established outcomes.

Indications and outcomes of enucleation versus formal pancreatectomy for pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatoduodenectomy (PD) or distal pancreatectomy (DP) are common procedures for patients with a pancreatic neuroendocrine tumor (pNET). Nevertheless, certain patients may benefit from a pancreas-preserving resection such as enucleation (EN). The aim of this study was to define the indications and differences in long-term outcomes among patients undergoing EN and PD/DP. METHODS: Patients undergoing resection of a pNET between 1992 and 2016 were identified. Indications and outcomes were evaluated, and propensity score matching (PSM) analysis was performed to compare long-term outcomes between patients who underwent EN versus PD/DP. RESULTS: Among 1034 patients, 143 (13.8%) underwent EN, 304 (29.4%) PD, and 587 (56.8%) DP. Indications for EN were small size (1.5 cm, IQR:1.0-1.9), functional tumors (58.0%) that were mainly insulinomas (51.7%). After PSM (n = 109 per group), incidence of postoperative pancreatic fistula (POPF) grade B/C was higher after EN (24.5%) compared with PD/DP (14.0%) (p = 0.049). Median recurrence-free survival (RFS) was comparable among patients who underwent EN (47 months, 95% CI:23-71) versus PD/DP (37 months, 95% CI: 33-47, p = 0.480). CONCLUSION: Comparable long-term outcomes were noted among patients who underwent EN versus PD/DP for pNET. The incidence of clinically significant POPF was higher after EN.

A New Scoring System to Predict Recurrent Disease in Grade 1 and 2 Nonfunctional Pancreatic Neuroendocrine Tumors.

OBJECTIVE: The aim of this study was to predict recurrence in patients with grade 1 or 2 nonfunctioning pancreatic neuroendocrine tumors (NF-pNET) after curative resection. BACKGROUND: Surgical resection is the preferred treatment for NF-pNET; however, recurrence occurs frequently after curative surgery, worsening prognosis of patients. METHODS: Retrospectively, patients with NF-pNET of 3 institutions were included. Patients with distant metastases, hereditary syndromes, or grade 3 tumors were excluded. Local or distant tumor recurrence was scored. Independent predictors for survival and recurrence were identified using Cox-regression analysis. The recurrence score was developed to predict recurrence within 5 years after curative resection of grade 1 to 2 NF-pNET. RESULTS: With a median follow-up of 51 months, 211 patients with grade 1 to 2 NF-pNET were included. Thirty-five patients (17%) developed recurrence. The 5- and 10-year disease-specific/overall survival was 98%/91% and 84%/68%, respectively. Predictors for recurrence were tumor grade 2, lymph node metastasis, and perineural invasion. On the basis of these predictors, the recurrence score was made. Discrimination [c-statistic 0.81, 95% confidence interval (95% CI) 0.75-0.87] and calibration (Hosmer Lemeshow Chi-square 11.25, P = 0.258) indicated that the ability of the recurrence score to identify patients at risk for recurrence is good. CONCLUSIONS: This new scoring system could predict recurrence after curative resection of grade 1 and 2 NF-pNET. With the use of the recurrence score, less extensive follow-up could be proposed for patients with low recurrence risk. For high-risk patients, clinical trials should be initiated to investigate whether adjuvant therapy might be beneficial. External validation is ongoing due to limited availability of adequate cohorts.

International survey on opinions and use of minimally invasive surgery in small bowel neuroendocrine neoplasms.

INTRODUCTION: Although minimally invasive surgery is becoming the standard technique in gastrointestinal surgery, implementation for small bowel neuroendocrine neoplasms (SB-NEN) is lagging behind. The aim of this international survey was to gain insights into attitudes towards minimally invasive surgery for resection of SB-NEN and current practices. METHODS: An anonymous survey was sent to surgeons between February and May 2021 via (neuro)endocrine and colorectal societies worldwide. The survey consisted of questions regarding experience of the surgeon with minimally invasive SB-NEN resection and training. RESULTS: A total of 58 responses from five societies across 20 countries were included. Forty-one (71%) respondents worked at academic centers. Thirty-seven (64%) practiced colorectal surgery, 24 (41%) endocrine surgery and 45 (78%) had experience in advanced minimally invasive surgery. An open, laparoscopic or robotic approach was preferred by 23 (42%), 24 (44%), and 8 (15%) respondents, respectively. Reasons to opt for a minimally invasive approach were mainly related to peri-operative benefits, while an open approach was preferred for optimal mesenteric lymphadenectomy and tactile feedback. Additional training in minimally invasive SB-NEN resection was welcomed by 29 (52%) respondents. Forty-three (74%) respondents were interested in collaborating in future studies, with a cumulative median (IQR) annual case load of 172 (86-258). CONCLUSIONS: Among respondents, 69% applies minimally invasive surgery for resection of SB-NEN. Arguments for specific operative approaches differ, and insufficient training in advanced laparoscopic techniques seems to be a barrier. Future collaborative studies can provide better insight in selection criteria and optimal technique.

Sporadic nonfunctional pancreatic neuroendocrine tumors: Risk of lymph node metastases and aggressiveness according to tumor size: A multicenter international study.

BACKGROUND: Although the correlation between tumor size and aggressiveness is clearly established in sporadic nonfunctional pancreatic neuroendocrine tumors, the management of tumors ≤2 cm remains debated. In recent guidelines, the cut-off size to operate ranged from 1 to 2 cm. The aim of this retrospective study was to report the rate of lymph nodes metastases in resected sporadic nonfunctional pancreatic neuroendocrine tumors, according to tumor size and, second, to identify risk factors of lymph node metastases and disease-free survival. METHODS: Resected sporadic nonfunctional pancreatic neuroendocrine tumors from 9 international expert centers were included (1999-2017). Functional pancreatic neuroendocrine tumors, genetic syndromes, and R2 resection were excluded. Aggressiveness was defined as microvascular invasion, perineural invasion, lymph node metastases, G3 grading, distant metastases, and/or recurrence. RESULTS: Overall, 495 resected sporadic nonfunctional pancreatic neuroendocrine tumors were included. For tumors up to 5 cm, the risk of lymph node metastases was increased by 1.73 for every 1 cm increase in size (odds ratio = 1.73; 95% confidence interval = 1.46-2.03). Tumor size >2 cm (P < .001), perineural invasion (P = .002), microvascular invasion (P < .001), and distant metastases (P = .008) were independently associated with lymph node metastases. Tumor size >2 cm (P = .003), R1 status (P = .004), lymph node metastases (P < .001), and World Health Organization grade 3 (P = .002) were independently associated with disease-free survival. Aggressiveness rate was 13.1% in tumors ≤1 cm and 29% in tumors between 1.1 and 2 cm. CONCLUSION: In resected sporadic nonfunctional pancreatic neuroendocrine tumors, the risk of lymph node metastases is correlated to tumor size. Considering that sporadic nonfunctional pancreatic neuroendocrine tumors between 1.1 and 2 cm had a higher risk of lymph node metastases and recurrence compared to tumors ≤1 cm, the decision to perform surgery in this subgroup of patients should be individualized in surgically fit patients.

Identifying Risk Factors and Patterns for Early Recurrence of Pancreatic Neuroendocrine Tumors: A Multi-Institutional Study.

BACKGROUND: Identifying patients at risk for early recurrence (ER) following resection for pancreatic neuroendocrine tumors (pNETs) might help to tailor adjuvant therapies and surveillance intensity in the post-operative setting. METHODS: Patients undergoing surgical resection for pNETs between 1998-2018 were identified using a multi-institutional database. Using a minimum p-value approach, optimal cut-off value of recurrence-free survival (RFS) was determined based on the difference in post-recurrence survival (PRS). Risk factors for early recurrence were identified. RESULTS: Among 807 patients who underwent curative-intent resection for pNETs, the optimal length of RFS to define ER was identified at 18 months (lowest p-value of 0.019). Median RFS was 11.0 months (95% 8.5-12.60) among ER patients (n = 49) versus 41.0 months (95% CI: 35.0-45.9) among non-ER patients (n = 77). Median PRS was worse among ER patients compared with non-ER patients (42.6 months vs. 81.5 months, p = 0.04). On multivariable analysis, tumor size (OR: 1.20, 95% CI: 1.05-1.37, p = 0.007) and positive lymph nodes (OR: 4.69, 95% CI: 1.41-15.58, p = 0.01) were independently associated with ER. CONCLUSION: An evidence-based cut-off value for ER after surgery for pNET was defined at 18 months. These data emphasized the importance of close follow-up in the first two years after surgery.

A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms: An International Multicenter Cohort Study.

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off ≥0.2mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size ≥3.0cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p < 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival.

Treatment of Liver Metastases from Midgut Neuroendocrine Tumours: A Systematic Review and Meta-Analysis.

Strong evidence comparing different treatment options for liver metastases (LM) arising from gastroenteropancreatic neuroendocrine tumours (GEP-NET) is lacking. The aim of this study was to determine which intervention for LMs from GEP-NETs shows the longest overall survival (OS). A systematic search was performed in MEDLINE, Embase and the Cochrane Library in February 2018. Studies reporting on patients with LMs of any grade of sporadic GEP-NET comparing two intervention groups were included for analysis. Meta-analyses were performed where possible. Eleven studies, with a total of 1108, patients were included; 662 patients had LM from pancreatic NETs (pNET), 164 patients from small-bowel NETs (SB-NET) and 282 patients of unknown origin. Improved 5-year OS was observed for surgery vs. chemotherapy (OR .05 95% CI [0.01, 0.21] p < 0.0001), for surgery vs. embolization (OR 0.18 95% CI [0.05, 0.61] p = 0.006) and for LM resection vs. no LM resection (OR 0.15 95% CI [0.05, 0.42] p = 0.0003). This is the largest meta-analysis performed comparing different interventions for LMs from GEP-NETs. Despite the high risk of bias and heterogeneity of data, surgical resection for all tumour grades results in the longest overall survival. Chemotherapy and embolization should be considered as an alternative in case surgery is not feasible.