What is a Neuroendocrine Tumor?

Neuroendocrine tumors are neoplasic lesions that arise in this system evenly distributed throughout the human body, and may originate in endocrine glands as a whole (hypophysis, parathyroid, adrenals), from other structural elements in these same endocrine glands (thyroid, pancreas), and from exocrine cells in the respiratory and gastrointestinal tract. Neuroendocrine tumors are slow growing lesions, some of them with secreting capabilities that produce specific clinical syndromes. Whilst considered rare (0.5 % of all tumors)  they occur at a rate of 40 to 50 million cases per year. Early detection has been described due to more accessible and improved laboratory and imaging techniques.

Pancreatic neuroendocrine tumors occur at a rate of 1 in 100,000; representing only 1 to 2 % of all pancreatic lesions. Incidence is evenly distributed between both sexes and ages; with a peak incidence between 30 thru 60 years of age. PNETs have been reported in 10 % of the population in studies derived from autopsy series. More than 19 % of all incidentally found pancreatic lesions are neuroendocrine in origin, a fact that suggests a larger incidence of clinically silent and benign lesions; as opposed to larger and symptomatic tumors with malignant behavior.

Neuroendocrine tumors (NET) are frequently diagnosed in advanced stages, as clinical syndromes are rare and no secreting tumors manifest only when locally invasive or present with distant metastasis. They comprise 2 % of all malignant gastrointestinal tumors, thus; they are frequently overlooked for other more common lesions or syndromes.

Our improved understanding of NET physiology allows for measurement of their hormones or byproducts, a key element in the diagnosis of these lesions. Whilst most NETs are considered nonfunctional, they may manifest clinically or biochemically at any stage of the disease. These lesions have polisecretory capabilities, and can thus change the initial clinical syndrome at any moment during the disease. A small group may produce a specific hormone however, giving its name to the corresponding tumor (e.g. insulinoma, gastrinoma).

Inheritance of neuroendocrine tumors

While the vast majority of PNETs are sporadic in origin, some may be related to hereditary syndromes; most frequently Multiple Neuroendocrine Neoplasia 1 (MEN-1), Von Hippel-Lindau Disease (VHL), Type 1 Neurofibromatosis (NF-1) and Tuberous Sclerosis Complex (TSC). Occurrence of PNETs in hereditary syndromes have been described as high as 80 to 100 % for MEN-1, and 10 to 17 % for VHL disease.

A careful familial history of diseases related to hereditary syndromes must be interrogated when interviewing a patient with a Pancreatic Neuroendocrine tumor. Careful examination of the patient in search for concomitant lesions (fibromas, cutaneous lesions) should be completed. Furthermore, associated laboratory abnormalities (hypercalcemia) during diagnostic workup should alert the clinician or surgeon of a possible hereditary association.

A patient with negative familial history of the disease should be considered as an index case, and genetic testing is highly recommended.

Pathologic features of neuroendocrine tumors

Neuroendocrine and pancreatic neuroendocrine tumors are classified as functional or non-functional. These latter occur more frequently (70 – 90 %), and thus present clinically when compressing adjacent organs or when larger than 5 cm in diameter (70 % of cases). These lesions are malignant in 60 to 90 % of cases, and 60 to 85 % of cases present with advanced disease or distant metastasis at diagnosis. Whilst biochemically silent, 70 to 100 % of patients present with Chromogranin A elevation, and 50 to 100 % with abnormal levels of pancreatic polypeptide.

Regarding functional tumors, insulinomas present more frequently, followed by gastrinomas, glucagonomas, VIPomas and somatostatinomas. Other rarely reported but well documented tumors are adrenocorticotropic secreting Pancreatic neuroendocrine tumors, Growth Hormone Factor Stimulant tumors, Parathormone related peptide, Luteinizing hormone, renin, type 2 insulin growth-like factor, type 1 glucagon-like peptide, cholecystokinin, ghrelin, calcitonin related peptide and erythropoietin secreting lesions.

While clinical syndromes may lead the clinician or surgeon to confirm the diagnosis demonstrating elevation of the corresponding hormone, additional substances and peptides may be elevated at diagnosis and may help differentiate functional from non-functional lesions.

CHROMOGRANIN A

Chromogranin A is an acid glycoprotein contained in the secretory granules of the majority of the neuroendocrine cells, and is considered the most important biochemical marker in the follow-up of neuroendocrine tumors. A sensibility of 50 to 90 % has been reported, with a specificity of 83 to 99 % for neuroendocrine and pancreatic neuroendocrine tumors. While it correlates appropriately to tumoral volume and presence of metastatic disease, its elevation is considered inversely proportional to prognosis. The only exception to this behavior are insulinomas, where an elevation has not been consistently demonstrated.

NEURONAL SPECIFIC ENOLASE

This marker is a cytoplasmic dimer from the glycolytic enolase enzyme. Its use is of limited value in pancreatic neuroendocrine tumors due to its low sensitivity and specificity. It is of relevance when facing poorly differentiated lesions, in which Chromogranin A is frequently low or negative.

PANCREATIC POLYPEPTIDE

Pancreatic polypeptide has a reported sensibility of 40 to 60 %, and a specificity of 65 % for pancreatic lesions when used alone as a diagnostic marker. As an adjunct to Chromogranin A measurement, its sensibility can reach 80 to 90 %. It is frequently used as a differential diagnosis and follow-up marker of non-functional pancreatic lesions.

Sites of neuroendocrine tumors

The gastrointestinal tract and lungs are the organs most frequently involved for neuroendocrine tumors (62 – 67 % and 22 – 27 % respectively). Tumors originating in the gastrointestinal tract are named after their embryological origin, localization and vascular supply: 1. Proximal (lung, gastric, liver, biliary tract, pancreas, first portion of the duodenum, ovaries); 2. Medial (distal duodenum, small bowel, appendix, right and proximal transverse colon); 3. Distal (distal transverse colon, left colon and rectum).

Pancreatic neuroendocrine tumors originate from pluripotential cells of the ductal epithelia of the pancreas, and thus have a specific clinical and biochemical behavior. These latter lesions are rare, representing less than 3 %of all pancreatic tumors. Whilst NEPTs too are classified as functional and nonfunctional, the former represent the large majority of lesions (60 vs 40 %) and manifest accordingly to their secreted hormone or amines. Excluding insulinomas, the vast majority of PNETs have a malignant behavior and 50 to 60 % present with distant metastases at diagnosis. Curiously, PNET patients have better survival rates and long term prognosis than their exocrine tumor counterparts.