Chapter 146: PNET: Treatment Sequencing to Include Principles of Surgery

INTRODUCTION

Pancreatic neuroendocrine tumors (PNETs) account for <3% of all pancreatic tumors and occur with an incidence of 1 to 2 per 100,000 people.^1-3 Most are sporadic; however, they may also be associated with multiple endocrine neoplasia 1 (MEN1—parathyroid, pituitary, and PNETs), Von-Hippel-Lindau syndrome (eye, CNS, renal cell carcinoma, pheochromocytoma, and PNETs), or tuberous sclerosis. PNETs are often metastatic at diagnosis, most frequently to the liver. Regional node metastases are particularly common and a regional lymph node dissection is an important part of most surgical procedures. PNETs have a wide spectrum of biologic behavior which is reflected in patients’ 5-year survival rates (97% for insulinomas, 30% for nonfunctional PNETs with metastases). Lesions with higher mitotic rates and Ki-67 index demonstrate a more aggressive biologic behavior.

Clinically, PNETs are divided into two classes based on hormone production. Functional tumors (10% to 30%) refer to those PNETs that overproduce hormones and cause clinical syndromes. The most common examples are insulinomas causing hypoglycemia, gastrinomas causing peptic ulcers, VIPomas resulting in watery diarrhea, and glucagonomas stimulating necrolytic migratory erythema. However, nonfunctional PNETs are actually more common (70% to 90%) and cause symptoms related to local mass effect (abdominal pain, jaundice, intestinal bleeding, and obstruction) and/or distant organ metastases.⁴ Although classified as nonfunctional from a clinical perspective, these tumors may actually produce multiple hormones and peptides including neurotensin, pancreatic polypeptide, chromogranin A, and neuron-specific enolase. Plasma chromogranin A levels are elevated in 60% to 100% of patients with nonfunctional PNETs and may be used to identify disease progression, recurrence following surgical resection, and response to therapy in patients with metastatic disease.⁵

MARKERS OF RISK

Ki-67

In addition to categorization based on functionality, PNETs have also been grouped by proliferation index termed Ki-67. Ki-67 is a proliferation antigen that is present in all phases of the cell cycle excluding G0. Because it is not involved in the DNA repair process, it is an excellent marker to determine the growth fraction of a cell population. Ki-67 is determined by scanning a slide for maximal staining intensity and then calculating the number of positive cells among ≥2000 cells in ≥10 representative high-powered fields. The index is also reported as MIB-1 which is a monoclonal antibody against Ki-67.⁶ The World Health Organization (WHO) utilizes the Ki-67/MIB-1 index values of <2, 2 to 20, and >20 as indicators of benign/uncertain, low, and high malignant potential, respectively.⁷ Other authors have demonstrated a significant decline in survival with a Ki-67 index >2%.⁸ Highly proliferative tumors are usually >2 cm in size, demonstrate extensive angioinvasion, a Ki-67 of >10%, and, as a result, have a high risk for harboring or developing metastatic disease. Ki-67 has been shown to be an independent prognostic factor for local-regional and distant organ disease.⁶

Chromogranin A

Chromogranin A (CgA) is believed to be ...