2. pNETs in Multiple Endocrine Neoplasia Type 1

pNETs arise in 30–80% of patients with Multiple Endocrine Neoplasia type 1 (MEN1), a rare inherited cancer syndrome characterized by the development of multiple neuroendocrine and nonendocrine tumors in a single patient and caused by a germline heterozygote loss-of-function mutation of the MEN1 tumor suppressor gene.

A great majority of MEN1 patients develop, during their life, multiple pancreatic microadenomas (less than 0.5 cm in diameter), mostly NF-pNETs (approximately 50% of cases) ^[4], insulinomas (7–31% of cases) ^[5], and gastrinomas (about 5% of cases) ^[6]. Solitary pNETs in MEN1 manifest less frequently (less than 13% of cases), usually as large masses (macroadenomas > 2 cm), and are often nonfunctional ^[7]. MEN1 pNETs manifest at a younger mean age compared to their sporadic counterparts (10–50 years vs. 50–80 years). MEN1 gastrinomas are prevalently located within the duodenum (over 90% of gastrinomas), and less than 10% of cases affect the pancreas. Glucagonomas, somatostatinomas and vasoactive intestinal polypeptide secreting tumors (VIPomas) manifest less frequently (3–4%, <2% and <2%, respectively) ^[5]. Neuroendocrine tumors affecting the gastro-entero-pancreatic tract in MEN1 syndrome are shown in Figure 1.

Figure 1. Neuroendocrine tumors of the gastro-entero-pancreatic tract associated with MEN1 syndrome. Prevalence of these tumors in MEN1 patients is indicated between brackets. Type 2 gastric neuroendocrine tumors develop in MEN1 patients, as a consequence of Zollinster–Ellison syndrome (ZES) from duodenal and/or pancreatic gastrinomas; to date, little is known about the true prevalence of these gastric neuroendocrine lesions in MEN1 patients. Jensen et al. ^[5] indicated a prevalence of 7–35%. Recently, Manoharan et al. ^[8] demonstrated that type 2 gastric neuroendocrine tumors occur only in MEN1 patients with ZES, and less frequently than previously reported (5.3% of the total of MEN1 patients and 12.5% of MEN1 patients with ZES).

Secreting pNETs are usually associated with distinct endocrine syndromes, caused by the excessive amount of hormone released by tumor cells. As their sporadic counterpart, MEN1 pNETs result positive to immunostaining for neuroendocrine markers and, in case of functioning tumors, their specific secreted hormones.

MEN1 pNETs follow the same three-grade WHO classification and they usually present a slow growth rate, with an estimated doubling time of 5–10 years ^[9]. However, in some cases, MEN1-associate pancreatic tumors exhibit a more aggressive behavior than the sporadic forms, with metastasis described in about 23–33% of cases. Tumor size is an important predictive factor of prognosis and overall survival in MEN1 pNETs, mostly for NF-pNETs; tumors larger than 2 cm in diameter have been associated with a high risk of malignancy and metastases development. Even if characterized by a slow disease progression, when compared with the non-endocrine pancreatic cancers and their endocrine sporadic counterpart, and despite the availability of an early genetic and clinical diagnosis and the possibility of praecox surgical intervention, pNETs currently remain the main cause of death among MEN1 patients, with an estimated 10-year survival after diagnosis of NF-pNETs ranging from 23% to 62% ^[10].

Currently, no prognostic factors allow clear identification of MEN1 patients at risk of metastatic cancers, nor to tailor personalized pNET treatment. KI-67 labeling and mitotic count have both been shown to be prognostic in sporadic pNETs ^[11][12], but few data are available for MEN1 pNETs. A study by Conemans et al. ^[13] evaluated, in formalin-fixed-paraffin-embedded pNET tissues from 69 MEN1 patients, the prognostic value of Ki-67 labeling index and mitotic rate, according to the WHO grade, with respect to clinical features of the tumors (i.e., tumor size, presence/absence of liver metastases, and time of metastases diagnosis after identification of the primary tumor). They showed that the mitotic count value was associated with the development of metastases only for NF-pNETs, but not for insulinomas, with 80% of metastases occurring in the G2 cancers (mitotic rate 2–20 per 10 high-power fields) and only in 23% of G1 tumors (mitotic rate <2 per 10 high-power fields). No significant association was found between values of the Ki-67 labeling index and metastases development. Moreover, the authors confirmed that tumor size is the main risk factor associated with liver metastases, both for insulinomas and NF-pNETs (in their cohort, the cut off diameter of primary tumor causing metastases was 3 cm, with respect to the 2 cm previously indicated by the guidelines) ^[13].

Unfortunately, it is not possible to predict cancer type development, tumor behavior, or risk of metastases based on the MEN1 gene mutation. MEN1 patients have a variable clinical expressivity; clinical manifestations, including pNETs, can be different between members of the same family bearing the same MEN1 mutation, and even between homozygous twins, suggesting that other genetic, epigenetic, and environmental factors can affect MEN1 tumorigenesis and drive individual tumor development and progression.