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Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion

Jennifer Ang Chan, MD, MPH
Matthew Kulke, MD
Thomas E Clancy, MD
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD


Neuroendocrine cells are distributed widely throughout the body, and neuroendocrine neoplasms of these dispersed cells can arise at many sites. The classification and nomenclature of neuroendocrine neoplasms arising within the digestive system has evolved over the past two decades (see "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Classification and terminology'):

Well-differentiated gastroenteropancreatic neuroendocrine tumors (NET) show a solid, trabecular, gyriform, or glandular pattern, with fairly uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm (picture 1). These tumors were traditionally referred to as carcinoid tumors when they arose in the tubular gastrointestinal tract and pancreatic neuroendocrine (islet cell) tumors when they arose in the pancreas or, in the case of gastrinomas, in the proximal portion of the duodenum. (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Morphology and immunohistochemistry' and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis", section on 'Tumor localization'.)

Although carcinoid tumors and pancreatic NET are morphologically similar on routine histologic evaluation, they differ in terms of pathogenesis, biology, and response to therapy.

Poorly differentiated neuroendocrine tumors, which are called neuroendocrine carcinomas, are generally high-grade carcinomas that can resemble small cell or large cell neuroendocrine carcinoma of the lung (picture 1) [1]. (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature' and "High-grade gastroenteropancreatic neuroendocrine carcinoma".)

However, several studies have challenged the assumption that poorly differentiated histology and high tumor grade are equivalent. There is a small subset of patients with neuroendocrine tumors that appear histologically well- or moderately-differentiated but are associated with Ki-67 proliferation indices >20 percent that fall into the high-grade range based on World Health Organization (WHO) criteria. The clinical behavior of these tumors appears to be in between poorly differentiated neuroendocrine carcinomas and intermediate-grade neuroendocrine tumors. (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Classification and terminology' and "High-grade gastroenteropancreatic neuroendocrine carcinoma", section on 'High-grade well-differentiated tumors'.)


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