Current understanding of pathogenetic mechanisms in neuroendocrine neoplasms

ABSTRACT

Introduction

Despite the fact that important advances in research on neuroendocrine neoplasms (NENs) have been made, consistent data about their pathogenetic mechanism are still lacking. Furthermore, different primary sites may recognize different pathogenetic mechanisms.

Areas covered

This review analyzes the possible biological and molecular mechanisms that may lead to NEN onset and progression in different organs. Through extensive research of the literature, risk factors including hypercholesterolemia, inflammatory bowel disease, chronic atrophic gastritis are evaluated as potential pathogenetic mechanisms. Consistent evidence is available regarding sporadic gastric NENs and MEN1 related duodenopancreatic NENs precursor lesions, and genetic-epigenetic mutations may play a pivotal role in tumor development and bone metastases onset. In lung neuroendocrine tumors (NETs), diffuse proliferation of neuroendocrine cells on the bronchial wall (DIPNECH) has been proposed as a premalignant lesion, while in lung neuroendocrine carcinoma nicotine and smoke could be responsible for carcinogenic processes. Also, rare primary NENs such as thymic (T-NENs) and Merkel cell carcinoma (MCC) have been analyzed, finding different possible pathogenetic mechanisms.

Expert opinion

New technologies in genomics and epigenomics are bringing new light to the pathogenetic landscape of NENs, but further studies are needed to improve both prevention and treatment in these heterogeneous neoplasms.

KEYWORDS:

• Cancer
• gastroenteropancreatic
• medullary thyroid carcinoma
• Merkel cell carcinoma
• neuroendocrine neoplasm
• neuroendocrine tumor
• pathogenetic mechanism

Article highlights

• Neuroendocrine neoplasms (NENs) may recognize different pathogenetic mechanisms according to different primaries and the onset of precursor lesions, as well as genetic alterations seem to play a pivotal role both in sporadic and familial neoplasms.

• Among gastroenteropancreatic NENs, in small intestinal neuroendocrine tumors (SI-NETs) a carcinogenic process has been hypothesized considering small intestinal enteroendocrine cells as a source of stem cells. Genomic stability with no recurrent mutation has been reported but according to epigenetic mechanisms specific miRNAs may play an important role in SI-NETs development and prognosis: downregulation of miR‐133a, miR‐145, miR‐146, miR‐222, and miR‐10b and the upregulation of miR‐183, miR‐488, and miR‐19aCb has been found in metastatic SI-NETs.

• In Type 1 gastric NETs (G-NETs) associated with chronic atrophic gastritis, a transition from atrophic gastritis to hyperplastic/dysplastic neuroendocrine nodules and ultimately to neoplasia due to hypergastrinemia stimulation has been proposed. In Type 2 G-NETs the hypertrophic oxyntic mucosa seems to be stimulated by gastrinoma in MEN1 patients and interestingly MEN1 mutation has been reported in 30-40% of cases of Type 3 G-NETs, although not associated with preneoplastic lesions. The chronic use of proton pump inhibitors (PPI) causing hypergastrinemia and cell hyperplasia has been proposed in the development of G-NENs, though genetic predisposition or environmental factors may also play a role.

• MEN1-related pancreatic neuroendocrine tumors (pNETs) seem to originate from pancreatic microadenomas and from non-islet tissue. Main driver mutations in sporadic pNETs derive from MEN1, DAXX, and ATRX alterations.

• Increased prevalence of colorectal NETs has been observed in patients with inflammatory bowel diseases, NETs did not originate from areas with chronic inflammation leading to the hypothesis that NETs development was not directly correlated to a proinflammatory microenvironment and even the presence of precursor lesions is debated.

• Nicotine and hypoxia could be crucial in the pathogenetic mechanism of lung carcinoids and carcinomas development, in particular influence directly the signaling cascades Pi3K/AKT/mTOR and MAPK both pivotal for cell proliferation, while VEGF secretion mediated by the inflow of Ca2+ could lead to an increase of angiogenesis.

• In medullary thyroid cancer (MTC) RET mutations are drivers for cancer development in familial forms, but also RAS gene mutations and epigenetic alteration seem to be pivotal, in particular in sporadic MTC.

• Data regarding pathogenetic mechanisms in NENs are currently mainly available in gastro-entero-pancreatic (GEP) NENS, maybe due to their relatively higher frequency, but better knowledge is still of utmost importance in this field, to improve cancer prevention and treatment strategies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

Conception/Design: RoMo, AC.

Collection and/or assembly of data: RoMo, AL, RoMi, GC, EB.

Data analysis and interpretation: Ro Mo, AL, RoMi, GC, EB, AC.

Manuscript writing: Ro Mo, AL, RoMi, GC, EB.

Final approval of manuscript: RoMo, AL, RoMi, GC, EB, AC.

Additional information

Funding

This paper was not funded.