Pancreatic Neuroendocrine Tumor Histological Features
Since neuroendocrine tumors, including pancreatic neuroendocrine tumors, represent a heterogeneous group of tumors, the World Health Organization in 2017 updated the classification system based upon their clinical pathological criteria, regardless of origin, size, or anatomical extent of the tumor.
- Grade 1 (Low grade) well-differentiated neuroendocrine tumor
- Grade 2 (Intermediate grade) well-differentiated neuroendocrine tumor
- Grade 3 (High grade) poorly differentiated neuroendocrine carcinoma, occasionally well-differentiated neuroendocrine tumor
Differentiation is based on one measure called a Ki-67 index. The Ki-67 index calculates the number of cells that are dividing as a way to see if it is a slow-growing (well differentiated) or fast-growing tumor (poorly differentiated). Well-differentiated tumors have a Ki-67 index below 20% and poorly differentiated tumors have a Ki-67 index between 20-100%.
Presence of Clinical Syndrome
Pancreatic neuroendocrine tumors are classified as functioning or non-functioning.
A functioning pancreatic neuroendocrine tumor secretes biochemically active substances such as hormones which cause specific clinical syndromes such as Carcinoid Syndrome or Zollinger-Ellison Syndrome.
A non-functioning pancreatic neuroendocrine tumor secretes specific substances but these substances are either inactive and/or do not cause any clinical syndrome.
Pancreatic Neuroendocrine Tumor Classification
Pancreatic neuroendocrine tumors vary in clinical course, location, and hormone secretion. Pancreatic neuroendocrine tumors can occur outside of the pancreas such as the duodenum and small intestine.
Functioning Pancreatic Neuroendocrine Tumors
Characterized by excess secretion of insulin and pro-insulin which causes confusion, sweating, dizziness, weakness and unconsciousness. Prolonged hypoglycemia (low blood sugar) can have permanent impact on brain function. Insulinomas tend to be small and rarely metastasize, many report metastases in about 10% of patients. Insulinomas can be associated with MEN1.
Characterized by Zollinger-Ellison Syndrome caused by excess secretion of gastrin. Zollinger-Ellison syndrome causes diarrhea and peptic-ulcers. Patients with Zollinger-Ellison syndrome may also develop gastric carcinoid as a result of prolonged gastrin hypersecretion (over production). Patients frequently have liver and lymph node metastasis at diagnosis. Gastrinomas occur mainly in the duodenum and pancreas. When Gastrinomas occur in the duodenum they are frequently associated with MEN1. All patients with Zollinger-Ellison Syndrome should be screened for MEN1.
Characterized by hypersecretion of a glucose secretion-regulating hormone, which causes skin rash, diabetes, and weight loss. Glucagonomas occur mainly in the pancreas, are typically large, and are highly metastatic. Glucagonoma is rarely associated with MEN1.
Characterized by hypersecretion of Vasoactive Intestinal Peptide (VIP) which causes Verner-Morrison Syndrome. Symptoms of Verner-Morrison Syndrome include severe watery diarrhea, which can be life threatening.
Somatostatinomas are primarily or exclusively composed of somatostatin-producing cells. Somatostatinomas are found in the pancreas and duodenum. Somatostatinomas may not provoke clinical symptoms or they may be characterized by clinical symptoms of gallbladder stones, diabetes, weight loss, and diarrhea.
Non-Functioning Pancreatic Neuroendocrine Tumors
Non-functioning pancreatic neuroendocrine tumors are not associated with characteristic clinical symptoms from secretion of hormones. Non-functioning pancreatic neuroendocrine tumors occur in the pancreas. They do not cause hormonal symptoms but can cause pain, weight loss and jaundice. Because there is no characteristic clinical syndrome associated with non-functioning pancreatic neuroendocrine tumors they can be difficult to diagnose and are often diagnosed after presenting with large tumors and liver metastases.
Inherited Versus Sporadic
Pancreatic neuroendocrine tumors can be sporadic or familial, when the patient has genetically inherited mutations, which predispose development of tumors.
Cancer causing mutation arise randomly
Cancer causing mutations are inherited such in the case of MEN-I.
Pancreatic neuroendocrine tumors can be associated with genetic syndromes such as Multiple Endocrine Neoplasia Type 1 (MEN1), Von Hippel-Lindau Disease (VHL), Tuberous Sclerosis Complex and Neurofibromatosis Type 1 (NF1). MEN1 is the most significant genetic syndrome – over 80% of patients with MEN1 develop pancreatic neuroendocrine tumors, over 40% of patients develop gastrinomas and smaller percentages develop other types of pancreatic neuroendocrine tumors.
MEN1 is an autosomal dominant inherited syndrome characterized by multiple endocrine and non-endocrine tumors. The tumors most frequently observed in patients with MEN1 include parathyroid adenomas, pituitary adenomas, and pancreatic endocrine tumors.
VHL is an autosomal dominant inherited syndrome caused by a mutation in the VHL gene.
Pancreatic neuroendocrine tumor patients should always have a clinical examination including family history to exclude genetic syndromes like MEN1. Presence of MEN1 or another clinical syndrome may change the optimal treatment course and so it is important to rule out. If a patient has a genetic syndrome it may be advised that certain family members are tested as well.