What Is the Appropriate Management of Nonfunctioning Pancreatic Neuroendocrine Tumours Disclosed on Screening in Adult Patients With Multiple Endocrine Neoplasia Type 1?

Benjamin G. Challis; Ruth T. Casey; Ashley Grossman; John Newell-Price; Paul Newey; Rajesh V. Thakker

Disclosures

Clin Endocrinol. 2019;91(6):708-715. 

In This Article

What Is the Optimal Surveillance Modality for Early NF-pNETs in MEN1?

The advent of molecular genetic testing and standardised surveillance with sensitive imaging modalities have resulted in the earlier detection of pNETs in patients with MEN1. Indeed, asymptomatic pNETs have been reported in MEN1 patients less than 15 years of age,[8,15] although the largest cohort studies have reported an age-related penetrance for NF-pNETs of less than 10% by 21 years of age.[10,15,16]

The goals of surveillance for NF-pNETs in hereditary endocrine neoplasia syndromes are to enable early detection and timely intervention to reduce tumour-associated morbidity and mortality. Structured surveillance programmes also serve to reassure gene mutation carriers who have not yet developed a tumour phenotype. However, such programmes may also evoke patient anxiety whilst awaiting test results, and the investigations themselves may have adverse effects. It remains crucial, therefore, that the sensitivity and specificity of a surveillance protocol are balanced with associated risks including radiation exposure,[17] affordability and invasiveness.

Current surveillance guidance for MEN1 mutation carriers suggests annual biochemical measurements of fasting gastrointestinal hormones coupled with annual radiological examination of the pancreas and duodenum from around 10–16 years of age.[3,10,13] However, in the absence of any clinical syndrome the utility of frequently measured gut hormones is debated, as the result rarely alters clinical management. There is no consensus as to the optimal imaging modalities, and conventional methods currently used include cross-sectional imaging (CT, MRI) and/or endoscopic ultrasound (EUS), depending on local availability and expertise. Recent advances in functional imaging and radiopharmaceuticals have also expanded the armamentarium available for the localisation of occult pNETs and the characterisation of tumour burden.

Numerous studies have reported on the relative sensitivity of conventional imaging tests to localise NF-pNETs in MEN1, and collectively, these data suggest that EUS > CT/MRI > transabdominal ultrasound.[4] Owing to availability and affordability, CT is an attractive surveillance imaging test with reported sensitivities of 70%-94% for the detection of non-MEN1 and MEN-1 pNETs.[18] Specific contrast-enhanced CT protocols are necessary to optimise sensitivity, and more specifically, the timing of contrast enhancement is crucial for the detection of pNETs, as normal pancreatic tissue peak enhancement is delayed in comparison to pNETs.[19] However, in patients with MEN1, the benefits of CT must be weighed against the risk associated with lifelong cumulative exposure to ionising radiation in this young and genetically vulnerable patient population.[17] It is for this reason that the majority of centres favour MRI. The sensitivity of MRI in localising pNETs in MEN1 is approximately 88%. Furthermore, MRI is more sensitive compared with CT and somatostatin receptor scintigraphy for the detection of hepatic metastases from neuroendocrine tumours.[20] However, MRI has limited utility in the detection of tumours <1.2 cm.[5] Additional limitations of MRI include availability and dependence on patient cooperation, but diffusion-weighted imaging (DWI) sequences improve detection. Of note, emerging evidence has implicated repeated administration of gadolinium-based contrast agents, during contrast enhanced MRI examinations with gadolinium, to be associated with deposition of gadolinium in deep nuclei of the brain, which can be visualised as signal changes on MRI.[21] Whilst the clinical significance of centrally deposited gadolinium is currently unknown, it will be important to monitor this rapidly evolving research area in order to better understand the long-term implications, if any, for MEN1 patients in whom repeated MRI examinations form the cornerstone of their tumour surveillance strategy.

Endoscopic ultrasound is the most sensitive imaging modality for the localisation of pNETs. Endoscopic ultrasound is capable of detecting subcentimetre tumours as well as identifying incident tumours early in their natural history. In studies that included patients with both sporadic and MEN1 pNETs, EUS was found to have a detection rate of approximately 90%[22] and a sensitivity and specificity of 93% and 95%, respectively.[23] In one prospective head-to-head study limited to subjects with MEN1, EUS was superior for the detection of pNETs compared with either CT or MRI when used in isolation or combined with somatostatin receptor scintigraphy.[24] However, an earlier prospective study in patients with MEN1 found that EUS and MRI were comparable in the detection of pNETs ≥10 mm.[25] In addition to diagnostic performance, EUS may also facilitate fine needle aspiration of tumour cells thereby enabling tumour grade and other histopathological features to be determined. Limitations of EUS include accessibility, operator dependency, invasiveness and patient acceptability and reduced sensitivity to detect lesions in the pancreatic tail. It is notable, however, that the clinical value of detecting small (<1 cm) nonfunctional tumours in MEN1 is contentious as their identification is unlikely to alter current approaches in clinical management.

Traditional somatostatin receptor scintigraphy based on, for example, 111In-pentetreotide (OctreoScan™) or 99m-Technetium (Tecktroyd) are less sensitive modalities for the detection of pNETs <1 cm[26,27] compared with conventional modalities and are associated with reduced specificity owing to physiological uptake in the uncinate process of the pancreas. The recent development of PET/CT using 68Ga-DOTA-labelled somatostatin analogues has demonstrated improved sensitivity in the detection of pNETs, owing to both improved spatial resolution and higher affinity for the somatostatin receptor 2 (sstr2) expressed by NETs. Recent studies have demonstrated that 68Ga-DOTATATE PET/CT is comparable in sensitivity to MRI and in one study was superior for the detection of sporadic pNETs.[28,29]

In summary, we believe that either EUS or MRI should be considered as part of the first pancreaticoduodenal evaluation in patients with MEN1, in order to thoroughly assess for the presence of pancreatic lesions and provide histological confirmation of a pNET. On balance, current evidence suggests that subsequent surveillance should be principally based on MRI; however, future studies are required to determine the long-term safety of repetitive gadolinium-based MRI examinations in MEN1 patients and whether noncontrast DWI-MR or EUS is more appropriate surveillance tools.

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