Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites.

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.

Blood-based Proteomic Signatures Associated With MEN1-related Duodenopancreatic Neuroendocrine Tumor Progression.

PURPOSE: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression. EXPERIMENTAL DESIGN: Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 [14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)]. Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl). RESULTS: A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice. CONCLUSIONS: Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.

Precision radiotherapy using MR-linac for pancreatic neuroendocrine tumors in MEN1 patients (PRIME): a protocol for a phase I-II trial, and systematic review on available evidence for radiotherapy of pNETs.

Background: Surgical resection is the standard of care for the treatment of pancreatic neuro-endocrine tumors (pNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1). However, surgery can cause significant short- and long-term morbidity. Magnetic resonance-guided radiotherapy (MRgRT) is a potential effective treatment with little side effects. With traditional radiotherapy techniques, irradiation of pancreatic tumors to high dose levels was hampered by poor visibility of the tumor during treatment. MRgRT uses onboard MRI to guide the treatment, thereby enabling delivery of ablative irradiation doses to the tumor, while sparing surrounding tissues. In this study, we describe results from a systematic review assessing efficacy of radiotherapy in pNET and present the protocol of the PRIME study. Methods: PubMed, Embase and Cochrane Library were searched for articles assessing efficacy and side effects of radiotherapy for the treatment of pNETs. Risk of bias was assessed using the ROBINS-I Risk of Bias Tool for observational studies. Descriptive statistics were used to describe results of included trials. Results: Four studies comprising of 33 patients treated by conventional radiotherapy were included. Despite the heterogeneity of studies, radiotherapy appeared to be effective for the treatment of pNETs with most patients responding (45.5%) or stabilizing (42.4%) in tumor size. Conclusion and trial design: Due to the limited literature available and concerns about damage to surrounding tissue, conventional radiotherapy is currently little used for pNETs. The PRIME study is a phase I-II trial with a single arm prospective cohort study design, investigating the efficacy of MRgRT in MEN1 patients with pNET. MEN1 patients with growing pNETs with a size between 1.0 and 3.0 cm without malignant features are eligible for inclusion. Patients are treated with 40 Gy in 5 fractions on the pNET, using online adaptive MRgRT on a 1.5T MR-linac. The primary endpoint is the change in tumor size at MRI 12 months follow-up. Secondary endpoints include radiotoxicity, quality of life, endocrine and exocrine pancreas function, resection rate, metastatic free and overall survival. When MRgRT is found effective with low radiotoxicity, it could reduce the need for surgery for pNET and preserve quality of life. Systematic Review Registration: PROSPERO https://clinicaltrials.gov/, (CRD42022325542).

Diagnostic Utility of Menin Immunohistochemistry in Patients With Multiple Endocrine Neoplasia Type 1 Syndrome.

A clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome is usually confirmed with genetic testing in the germline. It is expected that menin protein expression is lost in MEN1-related tumors. Therefore, we investigated the potential of menin immunohistochemistry in parathyroid adenomas as an additional tool in the recognition and genetic diagnosis of MEN1 syndrome. Local pathology archives were searched for parathyroid tumors from patients with MEN1 syndrome and without MEN1, including sporadic, patients with multiple endocrine neoplasia type 2A and hyperparathyroidism-jaw parathyroid tumors. Menin immunohistochemistry was performed and its use to identify MEN1-related tumors was assessed. Twenty-nine parathyroid tumors from 16 patients with MEN1 and 61 patients with parathyroid tumors from 32 non-MEN1 were evaluated. Immunohistochemical nuclear menin loss in one or more tumors was found in 100% of patients with MEN1 and 9% of patients with non-MEN1. In patients with multiple tumors, menin loss in at least one tumor was seen in 100% of 8 patients with MEN1 and 21% of patients with 14 non-MEN1. Using a cutoff of at least 2 tumors showing menin loss per patient, the positive and negative predictive values for the diagnosis MEN1 were both 100%. The practical and additional value of menin immunohistochemistry in clinical genetic MEN1 diagnosis is further illustrated by menin immunohistochemistry in 2 cases with a germline variant of unknown significance in the MEN1 gene. Menin immunohistochemistry is useful in the recognition of MEN1 syndrome as well as in the clinical genetic analysis of patients with inconclusive MEN1 germline testing.

Status of Surveillance and Nonsurgical Therapy for Small Nonfunctioning Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNETs) occur in < 1/100,000 patients and most are nonfunctioning (NF). Approximately 5% occur as part of multiple endocrine neoplasia type 1. Anatomic and molecular imaging have a pivotal role in the diagnosis, staging and active surveillance. Surgery is generally recommended for nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) >2 cm to prevent metastases. For tumors ≤2 cm, active surveillance is a viable alternative. Tumor size and grade are important factors to guide management. Assessment of death domain-associated protein 6/alpha-thalassemia/mental retardation X-linked and alternative lengthening of telomeres are promising novel prognostic markers. This review summarizes the status of surveillance and nonsurgical management for small NF-PNETs, including factors that can guide management.

Lifestyle Factors and Development and Natural Course of Gastroenteropancreatic Neuroendocrine Tumors: A Review of the Literature.

INTRODUCTION: The rarity of neuroendocrine tumors (NETs) and their heterogeneous presentation complicate the identification of risk factors for their development and natural course. Several tumor-specific prognostic factors have been identified, but less attention has been given to lifestyle factors as risk and prognostic factors. This review aimed to identify studies on smoking, alcohol use, physical activity, diet, body mass index (BMI), and diabetes and their association with the development and course of gastroenteropancreatic (GEP-) NETs. METHODS: The literature was systematically searched for articles on lifestyle factors and NETs available via PubMed and Embase. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: A total of 25 eligible studies out of 3,021 screened articles were included. Most studies reported on smoking and alcohol, reporting conflicting results. Diet seems to have an influence on NET development, but few studies were published. Articles reporting on BMI were not unanimous on the effect on GEP-NETs. Diabetes was reported as a risk factor for NETs, while a protective effect was observed with metformin use. CONCLUSION: Different tissues, i.e., the pancreas and small intestine, may respond differently to exposure to alcohol and smoking. Evidence for diet so far is too limited to draw conclusions. Diabetes seems to be an important risk factor for the development of pancreatic NETs with a protective role in disease progression, while BMI is not unequivocally associated with the development and prognosis of NETs. Hence, our findings suggest that lifestyle factors play an important role in NET development as a disease course. Future research should consider lifestyle as an influence on disease progression and treatment response.

Diagnosing pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 in daily practice.

Background: In multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (PanNETs) have a high prevalence and represent the main cause of death. This study aimed to assess the diagnostic accuracy of the currently used conventional pancreatic imaging techniques and the added value of fine needle aspirations (FNAs). Methods: Patients who had at least one imaging study were included from the population-based MEN1 database of the DutchMEN Study Group from 1990 to 2017. Magnetic resonance imaging (MRI), computed tomography (CT), endoscopic ultrasonography (EUS), FNA, and surgical resection specimens were obtained. The first MRI, CT, or EUS was considered as the index test. For a comparison of the diagnostic accuracy of MRI versus CT, patients with their index test taken between 2010 and 2017 were included. The reference standard consisted of surgical histopathology or radiological follow-up. Results: A total of 413 patients (92.8% of the database) underwent 3,477 imaging studies. The number of imaging studies per patient increased, and a preference for MRI was observed in the last decade. Overall diagnostic accuracy was good with a positive (PPV) and negative predictive value (NPV) of 88.9% (95% confidence interval, 76.0-95.6) and 92.8% (89.4-95.1), respectively, for PanNET in the pancreatic head and 92.0% (85.3-96.0) and 85.3% (80.5-89.1), respectively, in the body/tail. For MRI, PPV and NPV for pancreatic head tumors were 100% (76.1-100) and 87.1% (76.3-93.6) and for CT, 60.0% (22.9-88.4) and 70.4% (51.3-84.3), respectively. For body/tail tumors, PPV and NPV were 91.3% (72.0-98.8) and 87.0% (75.3-93.9), respectively, for MRI and 100% (74.9-100) and 77.8% (54.3-91.5), respectively, for CT. Pathology confirmed a PanNET in 106 out of 110 (96.4%) resection specimens. FNA was performed on 34 lesions in 33 patients and was considered PanNET in 24 [all confirmed PanNET by histology (10) or follow-up (14)], normal/cyst/unrepresentative in 6 (all confirmed PanNET by follow-up), and adenocarcinoma in 4 (2 confirmed and 2 PanNET). Three patients, all older than 60 years, had a final diagnosis of pancreatic adenocarcinoma. Conclusion: As the accuracy for diagnosing MEN1-related PanNET of MRI was higher than that of CT, MRI should be the preferred (non-invasive) imaging modality for PanNET screening/surveillance. The high diagnostic accuracy of pancreatic imaging and the sporadic occurrence of pancreatic adenocarcinoma question the need for routine (EUS-guided) FNA.

Four decades of experience with carcinoid heart disease: An analysis of 84 patients.

Carcinoid heart disease (CHD) is a serious cardiac condition which is caused by elevated serotonin in the systemic circulation, secreted by neuroendocrine tumours (NET). It mostly affects the right-sided heart valves, where it causes fibrotic disturbances and is associated with worse survival. In this study, we describe a large cohort of patients with CHD and provide an insight into their survival over the past decades. All consecutive patients with a serotonin producing NET and CHD referred to the Netherlands Cancer Institute that presented with CHD or developed CHD during their follow up time were included from 1984 until 2021. Patients were divided into three time periods: 1984-2000, 2000-2010 and 2010-2018. Median N-terminal pro B-type natriuretic protein (NT-proBNP) and serum serotonin levels were stratified according to tricuspid regurgitation severity. Kaplan-Meier curves and log rank test were used for visualisation of survival. Cox regression was used for identification of the characteristics associated with disease specific mortality (DSM). A total of 84 patients with CHD were included of whom 49 (58.3%) were male. Median age at NET diagnosis was 62.3 (range 23.9-81.7) years, and median time to development of CHD was 1.1 (range 0-24.2) years. NT-proBNP was significantly higher when more severe tricuspid regurgitation (TR) was present (p = .027). Median survival from CHD diagnosis for 1984-2000, 2000-2010 and 2010-2018 were 1.3 (confidence interval [CI]: 0.9-1.6), 1.9 (CI: 1.2-2.6) and 3.9 (CI: 1.7-6.2) years (p = .025). Valve replacement surgery (VSR) occurred more frequent in later time periods. VSR (hazard ratio [HR] 0.33, p = .005) and NT-proBNP (HR 1.003, 1.00-1.005, p = .036) were significantly associated with DSM. The prognosis of patients with CHD has improved over the past decades, possibly caused by more VSR. NT-proBNP is a valuable biomarker in patients with CHD. Clinical practice should be aimed at timely diagnosis and intervention of CHD.

NETest: serial liquid biopsies in gastroenteropancreatic NET surveillance.

Objective: Up to now, serial NETest measurements in individuals assessing the disease course of gastroenteropancreatic neuroendocrine tumors (GEPNETs) at long-term follow-up and treatment response were not studied. Design: The study was a longitudinal validation study of serial NETest measurements - a blood-based gene expression signature - in 132 patients with GEPNETs on therapy or watch-and-wait strategy. Methods: Serial samples were collected during 46 (range: 6-71) months of follow-up. NETest scores were compared with Response Evaluation Criteria in Solid Tumors version 1.1-defined treatment response (e.g. no evidence of disease (NED), stable disease (SD) or progressive disease (PD)). Results: Consecutive NETest scores fluctuated substantially (range: 0-100) over time in individuals with SD (n = 28) and NED (n = 30). Follow-up samples were significantly higher in SD (samples 3-5) and NED subgroups (samples 2-5) compared with baseline results, without changes in imaging. In 82% of untreated patients with PD, consecutive NETest scores consistently remained high. In patients undergoing systemic treatment, the median pre-treatment NETest score in treatment-responders was 76.5 (n = 22) vs 33 (n = 12) in non-responders (P = 0.001). Patients with low pre-treatment scores had 21 months reduced progression-free survival (10 vs 31 months; P = 0.01). The accuracy of the NETest for treatment response prediction was 0.73 (P = 0.009). Conclusion: In patients not undergoing treatment, consecutive low NETest scores are associated with indolent behavior. Patients who develop PD exhibit elevated scores. Elevated results have important predictive value for treatment responsiveness and could be used for individualizing decisions on systemic therapy. The clinical value of follow-up NETest scores for patients who choose to watch and wait requires further study.

Assessing Outcomes After Adrenalectomy for Primary Aldosteronism - Early is Accurate: Retrospective Cohort Study.

OBJECTIVE: We aimed to investigate the postoperative trend in blood pressure (BP)-related outcomes [BP and antihypertensive (AHT) drug use] during the year following adrenalectomy for primary aldosteronism (PA) to determine the optimal timing for outcome assessment and to determine the necessary follow-up length. BACKGROUND: Since the course of BP-related outcomes after adrenalectomy is unknown, the optimal timing of outcome assessment and follow-up duration are not clear. METHODS: In this retrospective single center cohort study, we used a prospectively collected database with all patients referred for difficult-to-control-hypertension-analysis. All patients diagnosed with PA who underwent adrenalectomy were included. AHT drug use [in defined daily dose (DDD)] and home blood pressure measurements (HBPMs) during the first postoperative year were collected. A mixed-effects model was developed to assess the stability of DDD and HBPM over time and adjust for potential confounders. RESULTS: In total 1784 patients were assessed for difficult-to-control-hypertension of whom 41 were included. Both the DDD and HBPM showed the strongest decrease in the first postoperative month (mean 1.6DDD; mean 140/85 mm Hg) compared with preoperative values (4.5DDD; 153/92 mm Hg). Thereafter, both outcomes showed a stable course from 4 to 6 months (1.6DDD; 136/86 mm Hg) up to 12 months postoperatively (2.0DDD; 136/83 mm Hg). CONCLUSIONS: This study showed that AHT drug use and HBPM decreased substantially within the first month after adrenalectomy for PA and afterwards generally remained stable during the year following adrenalectomy. We propose that BP-related outcomes can be assessed reliably early after adrenalectomy and question the need for routine long-term follow-up in referral centers.

Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers.

INTRODUCTION: Small intestinal neuroendocrine tumors (SI-NETs) often present with metastatic disease. An ongoing debate exists on whether to perform primary tumor resection (PTR) in patients with stage IV SI-NETs, without symptoms of the primary tumor and inoperable metastatic disease. OBJECTIVE: The aim of this study was to compare a treatment strategy of upfront surgical resection versus a surveillance strategy of watch and wait. METHODS: This was a retrospective cohort study of patients with stage IV SI-NETs at diagnosis, between 2000 and 2018, from two tertiary referral centers (Netherlands Cancer Institute [NKI] and Aintree University Hospital [AUH]) who had adopted contrasting treatment approaches: upfront surgical resection and watch and wait, respectively. Patients without symptoms related to the primary tumor were included. Multivariable intention-to-treat (ITT), per-protocol (PP), and instrumental variable (IV) analyses using 'institute' as an IV were performed to assess the influence of PTR on disease-specific mortality (DSM). RESULTS: A total of 557 patients were identified, with 145 patients remaining after exclusion of stage I-III disease or symptoms of the primary tumor (93 from the NKI and 52 from AUH). The cohorts differed in performance status (PS; p = 0.006) and tumor grade (p < 0.001). PTR was independently associated with reduced DSM irrespective of statistical methods employed: ITT hazard ratio [HR] 0.60, p = 0.005; PP HR 0.58, p < 0.001; and IV HR 0.07, p = 0.019. Other factors associated with DSM were age, PS, high chromogranin A, and somatostatin analog treatment. CONCLUSION: Taking advantage of contrasting institutional treatment strategies, this study identified PTR as an independent predictor of DSM. Future prospective studies should aim to validate these results.

Correction: Lebbink et al. Opposite Incidence Trends for Differentiated and Medullary Thyroid Cancer in Young Dutch Patients over a 30-Year Time Span. Cancers 2021, 13, 5104.

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FDG PET/CT in differentiated thyroid cancer patients with low thyroglobulin levels.

Objective: To evaluate the usefulness of [18F]fluorodeoxyglucose (FDG) positron emissive tomography (PET)/CT in patients with low detectable thyroglobulin levels suspicious for persistent or recurrent differentiated thyroid cancer (DTC). Methods: A retrospective case series study evaluating FDG PET/CT in patients with detectable thyroglobulin (Tg) levels (≥0.20 and <10.00 ng/mL) after initial treatment with total thyroidectomy and I-131 thyroid remnant ablation for pT1-3aN0-1bM0 DTC. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of FDG PET/CT were calculated. Results: Twenty-seven patients underwent FDG PET/CT. Median Tg level at FDG PET/CT was 2.00 ng/mL (range 0.30-9.00). FDG PET/CT was positive in 14 patients (51.9%): lesions suspicious for lymph node metastases were depicted in 12 patients, and lung metastases in 2. DTC was confirmed in 13/14 FDG PET/CT-positive patients. In 9/13 patients with a negative FDG PET/CT, DTC was confirmed ≤3 months after FDG PET/CT. The sensitivity, PPV, specificity and NPV were 59.1, 92.9, 80.0 and 30.8%, respectively. Conclusions: This case series shows that FDG PET/CT might be useful to detect persistent or recurrent DTC in patients with low detectable Tg. However, when FDG PET/CT is negative, this does not rule out DTC and further investigations are necessary.

Elevated Serotonin and NT-proBNP Levels Predict and Detect Carcinoid Heart Disease in a Large Validation Study.

Carcinoid heart disease (CHD) is a rare fibrotic cardiac complication of neuroendocrine tumors. Besides known biomarkers N-Terminal pro-B-type natriuretic peptide (NT-proBNP) and serotonin, activin A, connective tissue growth factor (CTGF), and soluble suppression of tumorigenicity 2 (sST2) have been suggested as potential biomarkers for CHD. Here, we validated the predictive/diagnostic value of these biomarkers in a case-control study of 114 patients between 1990 and 2021. Two time-points were analyzed: T0: liver metastasis without CHD for all patients. T1: confirmed CHD in cases (CHD+, n = 57); confirmed absence of CHD five or more years after liver metastasis in controls (CHD−, n = 57). Thirty-one (54%) and 25 (44%) females were included in CHD+ and CHD− patients, respectively. Median age was 57.9 years for CHD+ and 59.7 for CHD- patients (p = 0.290). At T0: activin A was similar across both groups (p = 0.724); NT-proBNP was higher in CHD+ patients (17 vs. 6 pmol/L, p = 0.016), area under the curve (AUC) 0.84, and the most optimal cut-off at 6.5 pmol/L. At T1: activin A was higher in CHD+ patients (0.65 vs. 0.38 ng/mL, p = 0.045), AUC 0.62, without an optimal cut-off value. NT-pro-BNP was higher in CHD+ patients (63 vs. 11 pmol/L, p < 0.001), AUC 0.89, with an optimal cut-off of 27 pmol/L. Serotonin (p = 0.345), sST2 (p = 0.867) and CTGF (p = 0.232) levels were similar across groups. This large validation study identified NT-proBNP as the superior biomarker for CHD. Patients with elevated serotonin levels and NT-proBNP levels between 6.5 and 27 pmol/L, and specifically >27 pmol/L, should be monitored closely for the development of CHD.

Risk factors for complications after surgery for pancreatic neuroendocrine tumors.

BACKGROUND: Surgical resection is the only potentially curative treatment for pancreatic neuroendocrine tumors. The choice for the type of procedure is influenced by the expected oncological benefit and the anticipated risk of procedure-specific complications. Few studies have focused on complications in these patients. This cohort study aimed to assess complications and risk factors after resections of pancreatic neuroendocrine tumors. METHODS: Patients undergoing resection of a pancreatic neuroendocrine tumor were identified within 2 centers of excellence. Complications were assessed according to the Clavien-Dindo classification and the comprehensive complication index. Logistic regression was performed to compare surgical procedures with adjustment for potential confounders (Clavien-Dindo ≥3). RESULTS: The cohort comprised 123 patients, including 12 enucleations, 50 distal pancreatectomies, 51 pancreatoduodenectomies, and 10 total/combined pancreatectomies. Mortality was 0.8%, a severe complication occurred in 41.5%, and the failure-to-rescue rate was 2.0%. The median comprehensive complication index was 22.6 (0-100); the comprehensive complication index increased after more extensive resections. After adjustment, a pancreatoduodenectomy, as compared to a distal pancreatectomy, increased the risk for a severe complication (odds ratio 3.13 [95% confidence interval 1.32-7.41]). Of the patients with multiple endocrine neoplasia type 1 or von Hippel-Lindau, 51.9% developed a severe complication vs 38.5% with sporadic disease. After major resections, morbidity was significantly higher in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau (comprehensive complication index 45.1 vs 28.9, P = .029). CONCLUSION: Surgery for pancreatic neuroendocrine tumors is associated with a high rate of complications but low failure-to-rescue in centers of excellence. Complications are procedure-specific. Major resections in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau appear to increase the risk of complications.

Update on the clinical management of multiple endocrine neoplasia type 1.

This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis: Mutation-negative patients with 2/3 main manifestations have a different clinical course compared to mutation-positive patients. As for primary hyperparathyroidism: subtotal parathyroidectomy is the initial procedure of choice. Current debate centres around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumours (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1-related tumours. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and nonfunctioning microadenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the paediatric age and initiating screening in the second decade is advisable. MEN1 has a significant impact on quality of life and US data show a significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumour behaviour and effects of more individualized interventions.

Is There a Role for Biomarkers in Surveillance of Pancreatic Neuroendocrine Neoplasms in Von Hippel-Lindau Disease?

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the development of multi-organ neoplasms. Among the manifestations of VHL are pancreatic neuroendocrine neoplasms (panNENs). In order to detect these lesions in a timely manner, patients are enrolled in a surveillance program, in accordance with the several existing VHL guidelines. However, these guidelines remain unclear about the role of biomarkers in diagnosing panNENs, despite the benefits a biomarker may offer regarding early detection of new lesions, thereby possibly limiting radiation exposure, and improving quality of life. The aim is to determine which biomarkers might be available in VHL patients and to assess their clinical relevance in diagnosing panNENs in VHL patients. We searched the databases of PubMed/Medline, Embase, and Web of Science to identify relevant articles. Seven studies assessing the diagnostic or prognostic value of biomarkers were included. The results from these studies were conflicting. Since no evident association between VHL-related panNENs and biomarkers was established in studies with larger study populations, currently biomarkers do not play a significant role in early detection or follow-up for panNENs in VHL patients. The absence of evidence underscores the need for specific research to address this unmet need.

Metastatic Patterns of Duodenopancreatic Neuroendocrine Tumors in Patients With Multiple Endocrine Neoplasia Type 1.

Patients with multiple endocrine neoplasia 1 syndrome (MEN1) often develop multifocal duodenopancreatic neuroendocrine tumors (dpNETs). Nonfunctional pancreatic neuroendocrine tumors (PanNETs) and duodenal gastrinomas are the most frequent origins of metastasis. Current guidelines recommend surgery based on tumor functionality, size ≥2 cm, grade or presence of lymph node metastases. However, in case of multiple primary tumors it is often unknown which specific tumor metastasized. This study aims to unravel the relationship between primary dpNETs and metastases in patients with MEN1 by studying endocrine differentiation. First, it was shown that expression of the endocrine differentiation markers ARX and PDX1 was concordant in 18 unifocal sporadic neuroendocrine tumors (NETs) and matched metastases. Thereafter, ARX, PDX1, Ki67 and gastrin expression, and the presence of alternative lengthening of telomeres were determined in 137 microscopic and macroscopic dpNETs and 36 matched metastases in 10 patients with MEN1. ARX and PDX1 H-score clustering was performed to infer relatedness. For patients with multiple metastases, similar intrametastases transcription factor expression suggests that most metastases (29/32) originated from a single NET of origin, while few patients may have multiple metastatic primary NETs. In 6 patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases expressed gastrin, and clustered with minute duodenal gastrinomas, not with larger PanNETs. PanNET metastases often clustered with high grade or alternative lengthening of telomeres-positive primary tumors. In conclusion, for patients with MEN1-related hypergastrinemia and PanNETs, a duodenal origin of periduodenopancreatic lymph node metastases should be considered, even when current conventional and functional imaging studies do not reveal duodenal tumors preoperatively.

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.