Neuroendocrine tumors (NETs) are a diverse group of cancers that develop from specialized cells in the neuroendocrine system. These cells possess traits of both nerve cells and hormone-producing endocrine cells, allowing them to receive messages from the nervous system and respond by releasing hormones into the bloodstream. Because these cells are scattered throughout the body, NETs can arise in many different organs, most commonly the gastrointestinal tract, the lungs, and the pancreas. Understanding the origins of this disease requires distinguishing between cases where a cancer-causing mutation is inherited from a parent versus those where the mutation develops randomly during a person’s lifetime.
How Often Neuroendocrine Cancer is Inherited
The vast majority of neuroendocrine tumor cases develop sporadically, meaning the genetic changes that led to the cancer were acquired by chance during an individual’s life. These acquired mutations are typically confined to the tumor cells themselves and cannot be passed on to children. Researchers estimate that inherited genetic syndromes account for a small minority of all NETs, generally in the range of 5 to 10% of total diagnoses.
The proportion of hereditary cases varies significantly depending on the specific location of the tumor. For example, inherited syndromes are associated with approximately 10 to 17% of pancreatic NETs (PNETs). This rate is significantly higher for tumors of the adrenal gland and related tissues, with up to 40% of pheochromocytomas and paragangliomas linked to inherited mutations.
Specific Hereditary Syndromes
When neuroendocrine cancer is inherited, it is typically part of a specific genetic syndrome caused by a germline mutation present in all the body’s cells. These syndromes are usually inherited in an autosomal dominant pattern, meaning a person needs only one copy of the altered gene from one parent to have an increased risk. These inherited mutations predispose an individual to developing NETs, often at a younger age and frequently involving multiple tumors.
Multiple Endocrine Neoplasia type 1 (MEN1) is one of the most common inherited syndromes associated with NETs, resulting from a mutation in the MEN1 tumor suppressor gene. Patients with MEN1 have a high lifetime probability of developing NETs, with up to 80% having pancreatic NETs and others developing tumors in the duodenum, lung, or thymus. The syndrome is also characterized by tumors in the parathyroid and pituitary glands.
Von Hippel-Lindau disease (VHL) is another syndrome caused by a mutation in the VHL gene, which increases the risk of pancreatic NETs in approximately 12% of affected individuals. VHL is also characterized by tumors in the central nervous system and kidneys, along with pheochromocytomas. Neurofibromatosis type 1 (NF1), caused by an alteration in the NF1 gene, is less frequently associated with pancreatic NETs, but it does predispose individuals to pheochromocytomas.
A different group of inherited conditions involves mutations in the succinate dehydrogenase (SDH) genes, including SDHB and SDHD. These are linked to familial paraganglioma and pheochromocytoma syndromes. These tumors arise from chromaffin cells, which are primarily located in the adrenal gland (pheochromocytomas) or along major nerves (paragangliomas). Genetic changes in the SDH genes are important to identify because they can be associated with a more aggressive disease course, especially with SDHB mutations.
Risk Factors for Sporadic Cases
Since the majority of neuroendocrine tumors are not inherited, researchers focus on non-genetic factors that may increase the risk of sporadic disease. Age is consistently observed as a factor, with the risk of developing a NET increasing as people get older. Chronic conditions that cause long-term inflammation or changes in the digestive tract are also associated with certain types of NETs.
For gastrointestinal NETs, conditions such as chronic atrophic gastritis and pernicious anemia are known associations. Similarly, Zollinger-Ellison syndrome, characterized by excessive stomach acid production, is often linked to the development of duodenal NETs. These chronic changes create an environment that can foster the development of abnormal cells.
For pancreatic NETs, some studies have noted associations with a history of diabetes and heavy alcohol consumption. While the association between general lifestyle factors and well-differentiated NETs is not as strong as it is for other cancers, smoking is a known risk factor for aggressive neuroendocrine carcinomas in the lung.
Genetic Testing and Familial Screening
Genetic testing for neuroendocrine cancer is recommended for individuals whose personal or family history suggests an underlying inherited syndrome. This includes patients diagnosed at a young age, those with multiple primary tumors, or those whose tumor type, such as a pheochromocytoma, is frequently associated with a hereditary cause. The presence of other features of a syndrome, such as pituitary or parathyroid tumors, also prompts consideration for testing.
Germline genetic testing analyzes specific genes for inherited mutations. The results are important for tailoring the patient’s long-term care, as the surveillance and treatment approaches for hereditary NETs often differ from those for sporadic cases. For instance, pancreatic NETs associated with VHL may have a lower risk of metastasis, which can influence the timing of surgical intervention.
A positive test result also enables cascade screening, where at-risk relatives can be offered testing to determine if they carry the same gene mutation. Identifying a mutation in an asymptomatic family member allows physicians to implement a personalized surveillance program, often involving regular blood tests and specialized imaging. The goal of this proactive screening is to detect tumors at their earliest, most treatable stage.