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


Clin Endocrinol. 2019;91(6):708-715. 

In This Article

How Useful are Current Biomarkers at Predicting the Behaviour and Prognosis of NF-pNETs in MEN1?

Circulating biomarkers including chromogranin A (CgA), pancreatic polypeptide (PP) and glucagon have demonstrated poor diagnostic accuracy for the diagnosis of pNETs in patients with MEN1.[30] The reported sensitivities of CgA for the diagnosis of MEN1 NF-pNETs range between 27% and 70% compared with 36%-50% and 43%-83% for PP and glucagon, respectively.[13] The limited diagnostic performance of these hormonal biomarkers renders them inadequate for the diagnosis, screening and long-term surveillance of MEN1 NF-pNETs.

The WHO tumour grading system has demonstrated prognostic value for both non-MEN1 and MEN1 NF-pNETs, with tumour grade (Grade3 > Grade2 > Grade1) and higher proliferation index both associated with increased risk of metastatic or recurrent disease and overall mortality.[31,32] Notably, the majority of studies which have evaluated the prognostic utility of the WHO tumour grading system have included surgical specimens rather than biopsy specimens,[31,32] and therefore, further studies are required to determine whether cytological grading accurately predicts tumour behaviour in both MEN1 and non-MEN1 NF-pNET's.

As mentioned above, functional imaging with somatostatin scintigraphy such as [68Ga]-DOTA(0) -Tyr-(3)-octreotate PET/CT (68Ga DOTATATE PET/CT) has recognised utility as an adjunct to conventional anatomical imaging for the detection of NF-pNETs and metastatic disease in MEN1 and may identify patients most suitable for treatment with somatostatin analogues and targeted radionuclide therapy. However, it remains unclear as to whether 68Ga DOTATATE PET/CT scintigraphy is able to accurately predict the malignant potential of a NF-pNET.[33] In contrast, imaging with 18F-fluorodeoxyglucose PET/CT (18F-FDG PET/CT) has recently been posited as a biomarker with the potential to assess the aggressiveness of MEN1 NF-pNETs.[34] 18FDG-PET avidity in NF-pNETs has demonstrated a positive correlation with: (a) higher proliferation indices (Ki67 > 2%); (b) tumour grade; (c) metastatic potential; and (d) overall survival.[35,36] Importantly, recent data suggest that 18FDG-PET avidity can predict tumour aggressiveness in the setting of a low proliferation index[37] and independent of tumour size[34] (Figure 2A-C). 18FDG-PET avidity does not always predict absence of somatostatin receptor expression, highlighting the potential role for combined imaging using 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT to detect intra and intertumour heterogeneity.[38] However, the utility of molecular imaging in clinical practice must be balanced against radiation exposure and cost. Current evidence does not support the routine use of molecular imaging in the initial evaluation or surveillance management of MEN1 NF-pNETs.

Figure 2.

Case 1: Images A and B, demonstrate a 2.8-cm cystic NF-pNET in the pancreatic head visualised by CT imaging and EUS, respectively. The patient was referred for clinical surveillance at the age of 25 y following genetic confirmation of MEN1 identified through cascade family screening. C, Low-avidity in the NF-pNET on 18F-FDG PET/CT imaging; following surgical resection and histological analysis, this correlated with a nonmetastatic grade 2 well-differentiated pNET with 0/2 lymph nodes positive for metastatic disease. Case 2: D, An axial CT image demonstrating a 1.9-cm NF-pNET in the uncinate process of the pancreas detected on the first surveillance scan in a 33-year-old male with MEN1. The patient underwent a Whipple's procedure at the patient's request. E, An image from a post-operative CT pulmonary angiogram that illustrates left lower lobe collapse, consolidation in the right lung and bilateral pleural effusions (left > right) as demonstrated by the white arrows. The patient also developed severe remnant pancreatitis and necrosis, resulting in a prolonged hospital admission and significant long-term morbidity that impacted upon his livelihood and has severely compromised his quality of life. Case 3: F, Demonstrates a hyper-intense 1.5-cm pNET in the pancreatic head visualised by MRI in a patient with MEN1. This patient had previously undergone a distal pancreatectomy for an insulin-secreting pNET and was subsequently diagnosed with the new 1.5-cm NF-pNET in the remnant pancreas 4 y later. G, Demonstrates that the lesion remained stable over a 4-year period of observation, and annual surveillance continues

Given that a genotype-phenotype correlation has not been established in MEN1, identification of a specific germline MEN1 mutation currently provides no prognostic value. Whole-genome analysis of sporadic pNETs has identified driver somatic mutations in recurring genes affecting four main pathways: (a) chromatin remodelling; (b) DNA damage repair; (c) activation of mTOR signalling; and, (d) telomere maintenance.[39] Somatic mutations in MEN1 and the chromatin remodelling genes ATRX and DAXX have been most commonly reported in sporadic pNETs occurring in non-MEN1 patients,[40] and data from integrated analysis have suggested that detection of these somatic mutations may have important prognostic implications.[39] For example, loss of function mutations in DAXX and ATRX may be associated with an increased risk of tumour progression, metastatic disease and a poor prognosis in non-MEN1 patients.[39] One small clinical case series has provided proof-of-concept evidence that somatic mutational analysis is possible from DNA obtained by fine needle aspiration;[41] however, larger prospective studies are required to determine if somatic mutational analysis may be used to prognosticate for both sporadic and MEN1-associated NF-pNETs.

Recently, the NETest™, a multitranscript molecular signature for PCR-based blood analysis, has been developed as a biomarker with independent studies reporting variable diagnostic performance in its ability to detect sporadic gastro-pancreatic NETs.[42,43] The NETest™ has also been reported to be able to differentiate stable from progressive sporadic gastro-pancreatic NETs and may have the potential to predict prognosis;[44] however, additional studies are required to truly establish the clinical utility of the NETest™ in the non-MEN-1 setting. To date, in patients with MEN-1, there are no published data regarding the performance of the NETest™ in the context of MEN1-associated NF-pNETs. It may be anticipated, however, that the NETest™ will have limited utility in the MEN1 population given that the majority of MEN NF-pNETs are small and slow growing and due to the propensity of these patients to harbour co-existing neuroendocrine tumours that arise from different cellular origins.