Diagnosing Nonfunctional Pancreatic NETs in MEN1

The Evidence Base

Mark J. C. van Treijen; Dirk-Jan van Beek; Rachel S. van Leeuwaarde; Menno R. Vriens; Gerlof D. Valk


J Endo Soc. 2018;2(9):1067-1088. 

In This Article

Abstract and Introduction


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.


Multiple endocrine neoplasia type 1 (MEN1) is a rare familial tumor syndrome, primarily caused by germline mutations in the MEN1 gene, encoding the tumor-suppressor protein menin.[1] Glandular hyperplasia and neoplastic endocrine tumors of the pituitary, parathyroid glands, duodenum, and pancreas form the major manifestations of the syndrome. Other manifestations of MEN1 are neuroendocrine tumors (NETs) of gastric, bronchial, or thymic origin; breast cancer; adrenal adenomas; and cutaneous manifestations, such as lipomas, collagenomas, and facial angiofibromas.[2,3]

NETs are manifest in MEN1, and particularly, thymic carcinoid and duodenopancreatic NETs (dpNETs) cause a decreased life expectancy in MEN1.[4–6] dpNETs are the most prevalent NETs and can be divided in functional, e.g., hormone producing, and nonfunctional. Nowadays, nonfunctional pancreatic NETs (NF-pNETs) are the most frequently diagnosed NETs in MEN1 and a leading cause of MEN1-related death.[7,8] NF-pNETs cause symptomatic disease in only up to 13% of patients, despite their multicentric appearance.[9] The high prevalence and malignant potential outline the need for an evidence-based screening program to diagnose NF-pNETs at an early stage to enable meticulous follow-up and timely intervention to prevent metastasized disease.

Studies focusing on sporadically occurring NF-pNETs are difficult to extrapolate to MEN1-related NF-pNETs, which are characterized by their multifocal occurrence and a more indolent course of disease in contrast to their sporadic counterparts. Moreover, the onset in MEN1 is at a younger age, and NF-pNETs are diagnosed in an earlier stage because of the screening programs.[9,10] This illustrates the importance to substantiate guidelines providing recommendations for MEN1 patients, based on evidence derived from MEN1 populations.

Current guidelines advise MEN1 mutation analysis already at the age of five and subsequent presymptomatic screening for MEN1 manifestations.[3] Because of their "silent" behavior and the correlation between metastases and tumor size,[7] identification of NF-pNETs depends on sensitive biochemical biomarkers and imaging modalities.[5,7]

The use of biochemical markers for the diagnosis of NF-pNETs is currently under debate, as the most recent studies on biomarkers reported low diagnostic accuracies for pNETs in MEN1.[11,12] In addition to biochemical testing, clinical practice guidelines recommend diagnosis and surveillance of NF-pNETs by anatomical imaging modalities, such as CT scan, MRI, or endoscopic ultrasound (EUS).[3] Functional imaging, such as somatostatin receptor scintigraphy (SRS) and [gallium 68 octreotate (68Ga)]-labeled somatostatin analogs positron emission tomography (PET;68Ga-dodecanetetraacetic acid (DOTA) PET-CT), is emerging, and therefore, the best approach to NF-pNETs needs to be re-evaluated. In addition, recent studies showed insights in the very low growth rate of small NF-pNETs, fueling the discussion on timing and frequency of surveillance.[13,14] The diagnosis of small NF-pNETs with a possible indolent course of disease creates a high risk for unnecessary and expensive screening and consequently, a high burden for the patients.

Whereas consensus on the indications for surgery could not be established in 2012,[3] current cohort studies give substantial evidence that a conservative approach for tumors up to 2 cm fits within treatment goals to reduce morbidity and mortality associated with metastatic disease.[14,15] This frames the screening dilemma in MEN1: imaging modalities should reliably detect tumors below the cutoff of 2 cm, but the indolent behavior of a large proportion of NF-pNETs could lead to overdiagnosis.

The current guideline dates from 2012 and gives rise to the need of an evidence-based approach for diagnosis and follow-up in MEN1.[3] Recently, controversies in the diagnostic approach in MEN1 were outlined, but a systematic overview of up-to-date literature on NF-pNETs is lacking.[16–18] We systematically reviewed and critically appraised the present literature on the diagnostic value of biochemical biomarkers and various imaging modalities to diagnose NF-pNETs in patients with MEN1. In addition, we evaluated the optimal timing of follow-up by reviewing current literature on the age-related penetrance and tumor growth of NF-pNETs in MEN1.