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

What Is the Natural History of MEN1 NF-pNETs?

Multiple endocrine neoplasia type 1 pNETs are typically diagnosed between 30–50 years of age, although marked variability is recognised.[4,5] In contrast, the age of onset of non-MEN1 (sporadic) pNETs usually ranges between 50 and 80 years.[6] Similar to sporadic pNETs, MEN-1 pNETs may be either nonfunctioning or secretory; however, MEN-1 pNETs are typically smaller, occur on a background of diffuse microadenomatosis with a complex multihormonal expression pattern, and exhibit a more indolent disease course when compared with their sporadic counterparts.[7–9] Multiple endocrine neoplasia type 1 patients often have contemporaneous (synchronous) occurrence of multiple tumours in the pancreas, and each one of these independent pancreatic tumours can proliferate and has malignant potential. Although the frequency of the co-occurrence of clinically functioning pNETs and NF-pNETs in MEN1 patients is unknown, pancreata from MEN1 patients with NF-pNETs have been reported to also contain microadenomas immunopositive for insulin, glucagon, pancreatic polypeptide and somatostatin, consistent with the reported complex multihormonal expression pattern.[8] Therefore, when considering the most appropriate intervention for NF-pNETs in MEN1, in addition to patient choice, one must also consider the following: (a) the risk of malignancy, (b) the risk of developing a secretory tumour and (c) the risk of new tumour formation. Thus, the risk of disease progression must be measured against the benefit-to-risk ratio of surgery-related morbidity in this young patient population.

Currently, it is not possible to accurately predict the natural history of small (<2 cm) MEN1 NF-pNETs. Clinical management strategies that favour early surgical intervention for NF-pNETs in MEN1 are guided by data collated retrospectively that suggest that tumour size correlates with metastatic disease. For example, one study found metastases in 4%, 10%, 18% and 43% of MEN1 patients with NF-pNETs ≤1 cm, 1.1–2 cm, 2.1–3 cm and >3 cm, respectively.[10] However, not all studies have confirmed this association.[11] It is notable that such studies assume that the largest NF-pNET is the main source of metastases; nevertheless, given the presence of synchronous NF-pNETs in MEN1, it remains possible, indeed likely, that smaller tumours contribute to metastatic disease.

Several studies have confirmed that the majority of small MEN1 NF-pNETs grow slowly.[5,10,12] In the Dutch MEN1 study cohort, retrospective analysis of cross-sectional imaging data from 99 patients found that the overall growth rate of small (<2 cm) NF-pNETs was 0.4 mm per year (median follow-up 3 years).[12] Whilst most patients had stable disease for the duration of the study, in those individuals with progressive tumours (30% of the study population) the growth rate was 1.6 mm per year. A recent literature review of seven studies comprising data from 257 patients and 653 NF-pNETs found that tumour growth rates ranged from 0.1 to 1.32 mm per year when assessed by conventional imaging (CT/MRI and EUS).[13] In the same report, pNET incidence rates from five published studies ranged between 0.17 and 1.04 per patient per year.[13]

A recent long-term prospective study (follow-up 10.7 ± 4.2 years, mean ± SD) investigated the outcomes of 46 patients with MEN1 and small (<2 cm) NF-pNETs[14] who had not undergone surgery during an earlier three-year study.[10] The investigators found that almost two-thirds of patients (60.9%) had one or more NF-pNET <2 cm and stable disease over the follow-up period; 39% of patients exhibited progressive disease defined by either an increase in tumour size or the development of a secretory tumour. Of these, seven patients underwent surgery during the study because of an increase in tumour size (>2 cm), development of distant metastases or hormone hypersecretion. Three of these patients subsequently developed a new NF-pNET during the study. Only one patient died of metastatic NF-pNET. Of those patients with stable disease for the duration of the study (28/46, 60.8%), the median number of tumours at presentation was 2.3 ± 1.8 per patient compared with 2.9 ± 2.3 tumours per patient at study end.