Run Yu, MD, PhD, is Co-Director of the Carcinoid and Neuroendocrine Tumor Center at Cedars- Sinai Medical Center in Los Angeles, California. He is also an Associate Professor at UCLA. Dr. Yu’s clinical interest in neuroendocrine tumors of any kind. His research interests are pathogenesis of pancreatic neuroendocrine tumors, natural history of pheochromocytoma, familial neuroendocrine tumor syndromes, and rare neuroendocrine cell lesions.
A common question that patients with neuroendocrine tumors (NETs) ask is whether their NETs are caused by inheriting a defective gene. Patients also worry about whether they will pass on the defective gene to their children. In this brief article, I am going to discuss the genetic causes of pancreatic NETs and small bowel carcinoids. These two groups of tumors are the most common NETs in clinical practice.
Most patients with pancreatic NETs do not have a clear genetic cause. In a recent study of ours, only about 5% of the patients with pancreatic NETs have a clear genetic cause. The most common genetic syndrome that causes pancreatic NETs is the multiple endocrine neoplasia type 1 (MEN1). Patients with MEN1 tend to have parathyroid tumors, pancreatic NETs, and pituitary tumors, as well as lung and thymic NETs. MEN1 is not that rare and is present in 1 in 30,000 people. The second most common genetic syndrome is the von Hippel-Lindau disease (VHL). Unlike in MEN1, NETs in VHL (pheochromocytoma and pancreatic NETs), are usually not the main feature of their disease. In some patients with VHL, though, pancreatic NETs could be the main feature. Two other genetic syndromes, neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) occasionally cause pancreatic NETs. The fifth genetic syndrome, Mahvash disease, which we discovered several years ago based on our clinical practice, causes pancreatic NETs and very high glucagon levels.
The genetic syndromes that cause pancreatic NETs have unique and somewhat predictable clinical course. Most are due to inactivating mutations of tumor suppressor genes. They usually involve multiple endocrine organs but can rarely involve only the pancreas. Most are inherited in an autosomal dominant manner (with 50% chance of getting the disease from an affective parent) but rarely can be inherited in an autosomal recessive manner (with 25% chance of getting the disease from two carrier parents). Endocrine cell hyperplasia and microadenomas are always found in the pancreas before gross pancreatic NETs are seen. Because of the genetic drive, new pancreatic NETs continuously emerge. Due to these characteristics, the genetic syndromes require comprehensive management plan. Genetic counseling is important to patients and their family members. Patients with the genetic syndromes should be followed at least once a year with history and physical exam, lab tests, and if needed, imaging studies.
In contrast to pancreatic NETs, small bowel carcinoids are not associated with any known genetic syndromes. Small bowel carcinoids very rarely happen in the same family but the genetic basis of this phenomenon has not been clearly worked out.
Patients and doctors should be aware of the genetic syndromes that cause NETs. Important clues to a genetic syndrome are young age of diagnosis, one patient having multiple NETs (or other tumors) in one or more organs, family history of similar or different NETs, and endocrine cell hyperplasia and microadenomas in the surgical specimen. If not sure, patients and doctors can seek help from academic medical centers.