Most neuroendocrine tumors (NETs) arise from random genetic mutations that accumulate over a person’s lifetime, not from a single identifiable cause. About 90% of cases are considered sporadic, meaning they develop without a known inherited condition. The remaining 10% are linked to inherited genetic syndromes. Beyond genetics, specific conditions like chronic stomach inflammation and hormonal imbalances can set the stage for NETs in certain organs.
How NETs Develop at the Cellular Level
Neuroendocrine tumors start in neuroendocrine cells, which are scattered throughout the body and act as a bridge between the nervous system and the hormone system. These cells release hormones in response to nerve signals and are found in the lungs, pancreas, stomach, intestines, and other organs. When the DNA inside these cells is damaged in specific ways, the cells can begin dividing uncontrollably and form tumors.
In the pancreas, the most commonly mutated gene in sporadic NETs is MEN1, found in about 21% of tumors. Mutations in genes called DAXX and ATRX appear in roughly 20% of cases and seem to play a key role in making tumors more aggressive. These mutations trigger a process called alternative lengthening of telomeres, which lets tumor cells keep dividing indefinitely and accumulate further genetic damage over time. Another set of mutations, affecting a growth-signaling pathway called mTOR, shows up in about 14% of pancreatic NETs. Mutations in MEN1 and the mTOR pathway tend to occur early in tumor development, acting as initial triggers. DAXX and ATRX mutations come later and push the tumor toward more dangerous behavior.
In the small intestine, NETs likely originate from a specific type of cell called an enterochromaffin cell, which produces serotonin. Research has shown that enterochromaffin cells sitting in a particular zone near the base of intestinal glands have a natural ability to revert into stem cells. When key tumor-suppressing genes (RB1 and P53) lose function in these cells, this reversion process accelerates, creating long-lived, rapidly dividing cells that are vulnerable to becoming cancerous.
Epigenetic Changes That Silence Protective Genes
Not all the damage driving NETs involves direct changes to DNA’s genetic code. Epigenetic changes, which alter how genes are read without changing the underlying sequence, play a significant role. The most studied mechanism is hypermethylation, where chemical tags are added to a gene’s “on switch,” effectively silencing it. When this happens to tumor suppressor genes, cells lose critical brakes on growth.
Two tumor suppressors, RASSF1A and CDKN2A, are silenced by hypermethylation across multiple NET types, including lung, pancreatic, and gastrointestinal tumors. In pancreatic NETs specifically, genes that normally restrain growth-promoting pathways or help repair damaged DNA are also frequently silenced this way. In gastrointestinal NETs, genes that control cell adhesion and trigger programmed cell death are shut off through the same mechanism.
At the same time, stretches of repetitive DNA sequences that are normally kept quiet become abnormally active in both pancreatic and gastrointestinal NETs. This widespread activation creates genomic instability, essentially making the cell’s DNA more fragile and prone to further errors. The combination of silenced protective genes and activated destabilizing elements creates a fertile environment for tumor progression.
Inherited Syndromes That Raise Risk
About 10% of pancreatic NETs result from inherited genetic syndromes. The most well-known is multiple endocrine neoplasia type 1 (MEN1), caused by an inherited defect in the MEN1 gene. People with this syndrome develop tumors in multiple hormone-producing glands, and pancreatic NETs are a hallmark feature.
Von Hippel-Lindau disease (VHL) is another inherited condition that predisposes people to NETs, particularly in the pancreas. It’s caused by a defective tumor suppressor gene on chromosome 3 and also raises the risk of kidney cancer, tumors in the adrenal glands, and growths in the brain and spinal cord. Neurofibromatosis type 1 (NF1), caused by a mutation in the NF1 gene on chromosome 17, occasionally leads to pancreatic NETs as well, though this is less common. Tuberous sclerosis complex (TSC), which causes benign growths in many organs, involves pancreatic NETs in only about 1% of cases. A more recently identified syndrome, MEN4, is caused by a mutation in a different gene (CDKN1B) and produces symptoms similar to MEN1.
If you have a family history of any of these conditions, genetic testing can identify whether you carry the relevant mutation, which allows for earlier screening and surveillance.
Chronic Stomach Conditions and Hormonal Triggers
Gastric NETs have a distinct and well-understood trigger in many cases: prolonged elevation of the hormone gastrin. Atrophic gastritis, a condition where the stomach lining thins and loses its acid-producing cells, is a major risk factor. This thinning can result from autoimmune mechanisms or long-term infection with the bacterium Helicobacter pylori. When the stomach can’t produce enough acid, the body responds by releasing more and more gastrin to compensate.
Gastrin has a powerful growth-promoting effect on a specific type of stomach cell called the enterochromaffin-like (ECL) cell. Over years of sustained stimulation, ECL cells go through a predictable sequence: first they multiply excessively (hyperplasia), then they develop abnormal features (dysplasia), and eventually they can form tumors. In a large U.S. cohort of patients with atrophic gastritis, the 5-year cumulative incidence of gastric NETs was 6%, rising to 18% at 10 years. High gastrin levels and alcohol use disorder were both associated with increased risk.
That said, high gastrin alone is not enough to cause tumors. It appears to be a necessary condition rather than a sufficient one, meaning additional genetic or environmental factors likely need to be present for a tumor to actually develop.
Lifestyle and Environmental Factors
Unlike many cancers, NETs have no strongly established lifestyle risk factors. Smoking, one of the most common cancer risk factors overall, has not been convincingly linked to NETs. In a clinic-based case-control study of pancreatic NETs, 53% of patients reported a history of smoking compared to 46% of controls, a difference that was not statistically significant. A couple of population-based studies have suggested a possible link between smoking and small bowel NETs, but the evidence remains limited.
Alcohol’s relationship to NETs is even less clear. One study found that alcohol use was actually less common among pancreatic NET patients than among controls, while other research has suggested alcohol may increase the risk of certain hormone-secreting tumors. No consistent pattern has emerged. There are currently no confirmed dietary, occupational, or chemical exposures that meaningfully raise NET risk across the board.
Who Gets NETs: Age, Sex, and Race
NETs have become significantly more common over the past few decades, though much of that increase reflects better detection through improved imaging and endoscopy. The age-adjusted incidence rate in the U.S. rose more than fivefold, from 1.64 per 100,000 people in 1975 to 8.52 per 100,000 in 2021. As of January 2021, an estimated 248,546 people in the U.S. were living with a NET diagnosis.
Where in the body a NET develops varies by sex and race. Women are more likely to develop NETs in the lungs, stomach, and appendix. Men are more likely to develop them in the small intestine, pancreas, colon, and rectum. Black Americans have higher rates of NETs in the stomach, small intestine, liver, pancreas, colon, and rectum compared to white Americans, but lower rates of lung and appendix NETs. The reasons for these disparities are not fully understood and likely involve a mix of genetic susceptibility, differences in exposure to risk conditions like atrophic gastritis, and variation in how and when tumors are detected.
Grading and What It Means for Tumor Behavior
The World Health Organization classifies neuroendocrine tumors based on how differentiated the cells are (how closely they resemble normal neuroendocrine cells) and how fast they’re dividing. Well-differentiated tumors, which still look somewhat like normal cells under a microscope, are graded G1, G2, or G3 based on their proliferation rate, measured by a marker called Ki67. Poorly differentiated neuroendocrine carcinomas (NECs) are a distinct category and are always high-grade. This distinction matters because well-differentiated G3 NETs and poorly differentiated NECs can look similar on paper but behave differently and respond to different treatments.
The mutations driving these two categories are also different. Well-differentiated NETs tend to carry mutations in MEN1, DAXX/ATRX, and mTOR pathway genes. Poorly differentiated NECs more often harbor mutations in P53 and RB1, the same tumor suppressors implicated in many aggressive cancers. This molecular distinction reinforces that NETs and NECs, despite both arising from neuroendocrine cells, follow fundamentally different paths of development.