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Background: Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. Aim: To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. Methods: Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). Results: Median OS was 36 (95% CI: 26–46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9–9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1–7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). Conclusion: (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide.

Background: Small intestinal neuroendocrine tumors (siNET) are one of the most common neuroendocrine neoplasms. Radical surgery is the only curative treatment. Method: We utilized a single-center study including consecutive patients diagnosed from 2000 to 2020 and followed them until death or the end of study. Disease-specific survival and recurrence-free survival (RFS) were investigated by Cox regression analyses with the inclusion of prognostic factors. Aims/primary outcomes: We identified three groups: (1) disease specific-survival in the total cohort (group1), (2) RFS and disease-specific survival after intended radical surgery (group2), (3) disease specific-survival in patients with unresectable disease or residual tumor after primary resection (group3). Results: In total, 615 patients, with a mean age (SD) 65 ± 11 years were included. Median (IQR) Ki-67 index was 4 (2–7)%. Median disease-specific survival in group1 was 130 months. Median RFS in group2 was 138 months with 5- and 10-year RFS rates of 72% and 59% with age, plasma chromogranin A (p-CgA) and Ki-67 index as prognostic factors. The ten year disease-specific survival rate in group2 was 86%. The median disease-specific survival in group3 was 85 months with age, Ki-67 index, p-CgA and primary tumor resection as prognostic factors. When proliferation was expressed by WHO grade, no difference was observed between G1 vs. G2 for any of the primary outcomes. Conclusions: Recurrence rates remained high 5–10 years after surgery (group2) supporting long-term follow-up. Median disease-specific survival in patient with unresectable disease (group3) was 7 years, with a favorable impact of primary tumor resection. Our data does not support the current grading system since no significant prognostic information was detected in G1 vs. G2 tumors.

Introduction: The prognosis and impact of different prognostic factors in pancreatic neuroendocrine neoplasms (pNEN) remain controversial. Aim: To investigate prognostic factors for recurrence-free survival and disease-specific survival in patients with pNEN, divided into three groups: patients undergoing surveillance (tumor size < 2 cm, group 1), patients followed after curative-intended surgery (group 2), and patients with unresectable disease or residual tumors after resection (group 3). Method: A single-center retrospective study including consecutive patients over a 20-year period. Multivariate Cox regression analyses were performed to identify risk factors. Results: 413 patients were included, with a mean (SD) age of 62 ± 14 years. In group 1 (n = 51), median (IQR) follow-up was 29 (21–34) months, and tumor size was 1.0 (0.8–1.4) cm. One progressed and had a tumor resection. In group 2 (n = 165), follow-up 59 (31–102) months, median tumor size 2 (1.2–3.4) cm, median Ki-67 index 5 (3–10)%, the 5-year recurrence rate was 21%. Tumor size (p < 0.001), Ki-67 index (p = 0.02), and location in the pancreatic head (p < 0.001) were independent risk factors. In group 3 (n = 197), follow-up 19 (6–46) months, median tumor size 4.2 (2.6–7.0) cm, Ki-67 index 17 (9–64)%, the median disease-specific survival was 22 (6–75) months—99 in NET G1; 54 in NET G2; 14 in NET G3; and 6 months in neuroendocrine carcinomas (NEC). Age (p = 0.029), plasma chromogranin A (p = 0.014), and proliferation, expressed by grade (p = 0.001) and Ki-67 index (p < 0.001), were risk factors. Conclusion: Growth in pNET < 2 cm requiring surgery was observed in 1/51. Tumor size, Ki-67 index, and location in the head were prognostic factors for disease recurrence, while age, plasma chromogranin A, and proliferation predicted mortality in patients with unresectable disease or residual tumors after resection.

Background: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis (2010–2011 vs. 2019–2020), (2) changes in the initial indication for diagnostic workup and 3) the differences in stage between incidentally discovered vs. symptomatic disease during the entire study period. Methods: We performed a retrospective study, that includes consecutive siNET and pNET patients referred to the Copenhagen ENETS center of excellence in 2010–2011 and 2019–2020. Results: The annual incidence of siNET per 100,000 increased from 1.39 to 1.84, (p = 0.05). There was no change in the stage at diagnosis, and in both periods approximately 30% of patients were incidentally diagnosed (p = 0.62). Dissemination was found in 72/121 (60%) of symptomatic vs. 22/50 (44%) of incidentally discovered SI tumors in the entire cohort, (p = 0.06). The annual incidence of pNET increased from 0.42 to 1.39 per 100,000, (p < 0.001). The proportion of patients with disseminated disease decreased from 8/21 (38%) to 12/75 (16%), (p = 0.02) and the number of incidental findings increased from 4/21 (19%) to 43/75 (57%), (p = 0.002). More symptomatic patients had disseminated disease compared to patients with incidentally discovered tumors (15/49 (31%) vs. 5/47 (11%), (p = 0.01)). Conclusion: The incidence of siNET and pNETs increased over the past decade. For siNETs, the stage of disease and the distribution of symptomatic vs. incidentally discovered tumors were unchanged between the two periods. Patients with pNETs presented with more local and incidentally discovered tumors in the latter period. Patients with incidentally discovered siNETs had disseminated disease in 44% of the overall cases. The vast majority of incidentally found pNETs were localized.

Background: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable. Objective: To assess the positive predictive value (PPV) of CgA plasma concentrations above the upper reference limit (URL) in patients with suspected NET. Method: Patients referred to the NET Centre, Rigshospitalet, Copenhagen from 2015 to 2019 with clinically suspected NET were included if a CgA measurement was performed prior to referral. The utility of CgA was assessed by comparing pre-referral CgA concentrations to the outcome of a thorough workup. In 47 selected cases with continuously unexplained elevated CgA concentrations, a processing-independent analysis (PIA) for CgA was performed. Results: A total of 197 patients were included. NET was ultimately diagnosed in 25 patients. CgA plasma concentrations were above the URL (elevated) in 19/25 patients diagnosed with NET. In total, 167/197 had elevated CgA concentrations at referral. The positive predictive value (PPV) of elevated CgA concentration was 11% (19/167). Proton pump inhibitor (PPI) treatment was identified as the possible cause of CgA elevation in 55/148 patients with falsely elevated CgA. CgA concentration was normal in 28/47 patients when using PIA. Conclusion: Our data do not support using measurement of CgA for screening when NET is suspected since the PPV was rather low. PPI treatment is a common cause of increased CgA concentrations and should always be discontinued before CgA measurement. PIA of CgA could be a way of excluding NET when suspicion is based primarily on elevated CgA.