Current Treatment Status in Pancreatic Neuroendocrine Neoplasms

De-Jun Liu; Rong Hua; Yong-Wei Sun


Chin Clin Oncol. 2019;8(2) 

In This Article

Abstract and Introduction


Pancreatic neuroendocrine neoplasms (P-NENs) are a group of pathologically and clinically heterogeneous tumors. In the past several decades, the incidence has been increasing. In 2010, the WHO presented a new classification dividing P-NENs into well-differentiated neuroendocrine tumors (NETs) and poorly-differentiated neuroendocrine carcinomas (NECs). Surgery is the primary and most important treatment for P-NENs, and is also the only possible curative procedure. By the 2018 NCCN guideline, observation can be considered for <1 cm, low-grade asymptomatic nonfunctional P-NETs. And for patients who are not suitable for surgery, somatostatin analogues, targeted therapy, radionuclides, ablation therapies, (chemo)embolisation and chemotherapy should be considered to improve and maintain a good quality of life. More than one hundred years has passed since termed, and in recent years, more and more molecule mechanism about P-NENs have been discovered. With the addition of several new agents, survival improved over the time. All this made P-NENs great promise.


Neuroendocrine neoplasms (NENs) once called carcinoid tumors, endocrine tumors or neuroendocrine tumors (NETs) are a group of pathologically and clinically heterogeneous tumors. These tumors mostly occurred in lung and gastroenteropancreatic (GEP) tract.[1] In the past several decades, the incidence has been increasing in both east and west nations, partly due to the wide application of modern imaging and endoscopic technologies.[2–10] According to whether these tumors can secrete hormones and amines, causing carcinoid syndrome and other clinical syndromes, they can be classified to functional NENs (F-NENs) and non-functional NENs (NF-NENs). And all the NENs have malignant potential and the malignant potential further depends on tumor site, degree of differentiation and extension of the tumors.[11] The 5-year survival rate was 30–80% for all patients, 60–100% for localized disease, 40–55% for regional disease, 19–30% for distant metastases.[8,12]

Pancreatic neuroendocrine neoplasms (P-NENs), commonly be called pancreatic endocrine tumors, insulinoma, gastrinoma or glucagonoma, comprise <2% of all pancreatic tumors.[8,13] They may produce hormones, such as insulin, gastrin, glucagon, vasoactive intestinal peptide (VIP) and so on, causing special symptoms called carcinoid syndrome. And about half of the P-NENs present clinical symptoms.[14] Of all these functional p-NENs, gastrinomas and insulinomas are the two most common, while the others are always considered together as a group called rare functional P-NENs (RFTs).[14–16]

In 1907, Oberndorfer first differentiated NENs as carcinoid from carcinomas. And because of the rareness and lacked knowledge of these tumors, people tended to lump them together in classification assessment and treatment for one hundred years.[17,18] During this period, there was no published unified nomenclatures and classifications that can be accepted by both clinicians and pathologists.[19,20]

In order to standardize the stratification and management procedures, in 2010, the WHO adopted the classification originally proposed by the European Neuroendocrine Tumor Society (ENET) from 2004 and 2007,[12,21–24] and presented a new classification. According to this new classification system, all tumors with a neuroendocrine differentiation called NENs.[25] And all GEP-NENs can be subdivided into the well-differentiated NETs and the poorly-differentiated neuroendocrine carcinomas (NECs). Furthermore, according to different definitions of proliferation by the mitotic count and/or the Ki-67 index, NENs can be graded into three types, low grade (grade 1, G1), intermediate grade (grade 2, G2) and high-grade (grade 3, G3). In general, both G1 and G2 NENs a1re considered as NETs, and G3 NENs are considered as NECs. According to this classification, tumors with Ki-67 index more than 20% or mitotic rate more than 20 per 10 high power fields are defined as G3. Meanwhile, specific TNM classification was also introduced.

However, in recent years, several studies highlighted heterogeneity that the 2010 WHO G3 category might be composed of two different entities, according to their cellular histomorphology, nuclear mitotic rate, Ki67 index, somatostatin receptor expression, plasma CGA (chromogranin) and NSE (neuron specific enolase) levels, response to platinum-based chemotherapy and prognosis.[26–31] Therefore, in 2017, the new WHO classification introduced a new category of well-differentiated pancreatic NETs (WD-pNETs) G3, different from poorly differentiated pancreatic NECs (PD-pNECs) G3.[32–34]

The 5-year survival rate of P-NENs was 80% for all stages, 60–100% for localized disease, 40% for regional disease and 29% for distant metastases.[12,35] The long-term disease-specific survival (DSS) of surgical resected P-NENs is greater than 50% at 20 years.[36]