Review
Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1

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Summary

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder, is characterised by the occurrence of pancreatic neuroendocrine tumours (P-NETs) in association with parathyroid and pituitary tumours. P-NETs, which include gastrinomas, insulinomas, and non-functioning tumours, occur in more than 80% of MEN1 patients and account for 50% of disease-specific deaths. However, there is no consensus about the optimal methods for detecting and treating P-NETs in MEN1 patients, and extrapolations from approaches used in patients with non-familial (sporadic) P-NETs require caution because of differences, such as the younger age of onset, multi-focality of P-NETs, and concomitant presence of other tumours in MEN1 patients. Thus, the early detection of P-NETs by circulating biomarkers and imaging modalities, and their appropriate treatments by surgical approaches and/or radionuclide therapy, chemotherapy, and biotherapy pose challenges and controversies. These challenges and controversies will be reviewed and possible approaches proposed.

Section snippets

Challenges

The challenges in screening for MEN1 P-NETs are to establish methods that are affordable, safe, and standardised; sufficiently sensitive to detect tumours that require intervention; and can be performed with adequate frequency to detect the majority of rapidly growing tumours. The availability of genetic testing for MEN1 coding region mutations, which can be detected in more than 90% of patients, has facilitated the identification of individuals at risk of developing MEN1-associated tumours.1,

Challenges

Establishing accurate predictors of outcomes that would guide the clinical management of MEN1 P-NETs represents a major challenge. Tumour grading and staging have been useful predictors for survival and treatment outcomes in oncology, but their use in MEN1 P-NETs remains to be established. Non-MEN1 P-NETs are graded (G) into one of three tiers as G1, G2, and G3 indicating well-differentiated, intermediate-differentiated, and poorly-differentiated tumours, respectively, using proliferation

Challenges

The selection criteria and choice of surgical procedures vary in different centres, making it difficult and challenging to provide definitive guidelines for surgical treatment of P-NETs in MEN1 patients. The ideal treatment for a non-metastatic, single, P-NET is surgical excision, as this offers the only potentially curative treatment.6 However, this situation rarely arises in patients with MEN1 who will have multiple P-NETs—eg, gastrinomas and insulinomas are multiple in more than 95% and more

Challenges

The choice of optimal anti-tumour therapies for advanced P-NETs in MEN1 patients remains a challenge as such therapies have not formally been evaluated in MEN1 patients. Thus, over ten different treatments for advanced, metastatic P-NETs in MEN1 patients are available (figure 3), and the challenge is in selecting the most appropriate one for an individual patient, as none of the treatments is wholly effective and data for efficacy are generally only available from studies in non-MEN1 patients.

Conclusion

P-NETs are the major cause of disease-specific mortality in patients with MEN1; however, very few MEN1-specific studies have been undertaken to guide the management of these tumours. Thus, in the absence of robust data, clinicians rely on expert consensus guidelines and extrapolations from studies involving non-MEN1 P-NETs to determine management in MEN1 patients. The latter is particularly concerning because MEN1 P-NETs exhibit distinct characteristics from non-MEN1 P-NETs, such as smaller

Search strategy and selection criteria

We searched PubMed on Jan 21, 2014 (reviewed Nov 14, 2014), using the search terms “MEN1” OR “Multiple Endocrine Neoplasia 1” AND “neuroendocrine tumour” OR “NET”, and limited to full-text human clinical trials or reviews/meta-analyses that were written in English in the past 5 years. Highly regarded prior publications and relevant references from the articles identified by the literature search were also reviewed.

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