Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors

Abstract

Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed.

Keywords: MEN1; hereditary syndromes; lung neuroendocrine tumors; pancreatic neuroendocrine tumors.

Figure 1

Molecular mechanisms and pathways that have been implicated with tumorigenesis associated with hereditary syndromes associated with PanNETs and LNETs. (P13K: Phosphatidylinositol-3-kinases, PTEN: phosphatase and tensin homolog, AKT: protein kinase B, mTORc1: mechanistic target of rapamycin complex 1, RheB: RAS homolog enriched in brain, RAS: rat sarcoma virus, NF-1: neurofibromatosis type 1, RAF: proto-oncogene, MEK: mitogen activated protein kinase, ERK: extracellular signal-regulated kinase, TSC1: tuberous sclerosis 1 (hamartin), TSC2: tuberous sclerosis complex2, P27: (Kip1), member of a family of CDK inhibitors (CDIs), HIFα: hypoxia inducible factor α-subunit, HIFβ: hypoxia inducible factor β-subunit, pVHL: von Hippel–Lindau tumor protein).

Figure 2

Steps in oncogenic process in mutation carriers of the MEN1 gene. The mutant menin gene is inherited from an affected progenitor or arises de novo (10%) and is present in all cells in all tissues. The normal allele produces sufficient amounts of the menin protein so that its tumor suppressor effect is present in all apparent “normal” cells in many tissues. However, in cells of some specific tissues related to the clinical phenotype, a somatic deletion or mutation of the normal allele causes complete loss of the function of the unaffected menin gene (no functional gene product or truncated protein), (+/− other gene mutations), leading to complete loss of menin production in these particular tissues and subsequent tumor formation.