The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant inherited condition, causing significant morbidity, and a reduction of life expectancy. A timely and accurate diagnosis of MEN1 is paramount to improve disease outcomes. This enables early identification of tumor manifestations allowing timely treatment for reducing morbidity and improving survival. Current management of MEN1 poses two challenges regarding the MEN1 diagnosis: diagnostic delay and the issue of phenocopies. A delay in diagnosis can be caused by a delay in identifying the index case, and by a delay in identifying affected family members of an index case. At present, lag time between diagnosis of MEN1 in index cases and genetic testing of family members was estimated to be 3.5 years. A subsequent delay in diagnosing affected family members was demonstrated to cause potential harm. Non-index cases have been found to develop clinically relevant tumor manifestations during the lag times. Centralized care, monitoring of patients outcomes on a national level and thereby improving awareness of physicians treating MEN1 patients, will contribute to improved care. The second challenge relates to “phenocopies.” Phenocopies refers to the 5–25% of clinically diagnosed patients with MEN1in whom no mutation can be found. Up to now, the clinical diagnosis of MEN1 is defined as the simultaneous presence of at least two of the three characteristic tumors (pituitary, parathyroids, or pancreatic islets). These clinically diagnosed patients undergo intensive follow up. Recent insights, however, challenge the validity of this clinical criterion. The most common mutation-negative MEN1 phenotype is the combination of primary hyperparathyroidism and a pituitary adenoma. This phenotype might also be caused by mutations in the CDKN1B gene, causing the recently described MEN4 syndrome. Moreover, primary hyperparathyroidism and pituitary adenoma are relatively common in the general population. Limiting follow-up in patients with a sporadic co-occurrence of pHPT and PIT could reduce exposure to radiation from imaging, healthcare costs and anxiety.

In multiple endocrine neoplasia type 1 (MEN1), nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) are the most frequently diagnosed NETs and a leading cause of MEN1-related death. The high prevalence and malignant potential of NF-pNETs outline the need for an evidence-based screening program, as early diagnosis and timely intervention could reduce morbidity and mortality. Controversies exist regarding the value of several diagnostic tests. This systematic review aims to evaluate current literature and amplify an up-to-date evidence-based approach to NF-pNET diagnosis in MEN1. Three databases were systematically searched on the diagnostic value of biomarkers and imaging modalities. Twenty-seven studies were included and critically appraised (modified Quality Assessment of Diagnostic Accuracy Studies). Another 12 studies, providing data on age-related penetrance and tumor growth, were included to assess the optimal frequency and timing of screening. Based on current literature, biomarkers should no longer play a role in the diagnostic process for NF-pNETs, as accuracies are too low. Studies evaluating the diagnostic value of imaging modalities are heterogeneous with varying risks of bias. For the detection of NF-pNETs, endoscopic ultrasound (EUS) has the highest sensitivity. A combined strategy of EUS and MRI seems to be the most useful. Gallium 68 octreotate-DOTA positron emission tomography-CT could be added if NF-pNETs are diagnosed to identify metastasis. Reported growth rates were generally low, and two distinct phenotypes were observed. Surveillance programs should focus on and be adapted to the presence of substantial growth in NF-pNETs. The optimal age to start screening must yet be determined, as insufficient evidence for an evidence-based recommendation was available.

Background: Available neuroendocrine biomarkers are considered to have insufficient accuracy to discriminate patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) from healthy controls. Recent studies have demonstrated a potential role for circulating neuroendocrine specific transcripts analysis—the NETest—as a more accurate biomarker for NETs compared to available biomarkers. This study was initiated to independently validate the discriminative value of the NETest as well as the association between tumor characteristics and NETest score.Methods: Whole blood samples from 140 consecutive GEP-NET patients and 113 healthy volunteers were collected. Laboratory investigators were blinded to the origin of the samples. NETest results and chromogranin A (CgA) levels were compared with clinical information including radiological imaging to evaluate the association with tumor characteristics.Results: The median NETest score in NET patients was 33 vs. 13% in controls (p < 0.0001). The NETest did not correlate with age, gender, tumor location, grade, load, or stage. Using the cut-off of 14% NETest sensitivity and specificity were 93 and 56%, respectively, with an AUC of 0.87. The optimal cut-off for the NETest in our population was 20%, with sensitivity 89% and specificity 72%. The upper limit of normal for CgA was established as 100 μg/l. Sensitivity and specificity of CgA were 56 and 83% with an AUC of 0.76. CgA correlated with age (rs = 0.388, p < 0.001) and tumor load (rs = 0.458, p < 0.001).Conclusions: The low specificity of the NETest precludes its use as a screening test for GEP-NETs. The superior sensitivity of the NETest over CgA (93 vs. 56%; p < 0.001), irrespective of the stage of the disease, emphasize its potential as a marker of disease presence in follow up as well as an indicator for residual disease after surgery.

There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.

The increased breast cancer risk in MEN1 carriers was not related to other known breast cancer risk factors or familial cancer history, and therefore breast cancer surveillance from the age of 40 years for all women with MEN1 is justifiable.

The majority of patients with MEN1 have FDO for themselves and even more for their relatives. This psychological distress is associated with a lower health-related quality of life. Therefore, in the medical care for MEN1, emphasis should also be placed on FDO and quality of life.

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