**Abstract**

Pancreatic neuroendocrine tumors are a group of endocrine tumors that constitute 7% of all pancreatic neoplasms. They can be benign or malignant. Their presentation can vary from slow growing, non infiltrative, indolent masses to rapidly progressing, highly aggressive, metastasizing tumors. In the past, there was paucity of scientific data available about the diagnosis and treatment strategy of these neoplasms but in recent years, ongoing research has inferred much data regarding classification, prognostic stratification and therapy of pancreatic neuroendocrine tumors. In this chapter we will discuss epidemiology, clinical presentation and classification, diagnosis and management of these tumors. We will also deliberate about the latest developments in treatment of pancreatic neuroendocrine tumors with focus on recent studies done on this topic.

**Keywords:** pancreatic neuroendocrine tumors, pancreatic NET, GEP-NET, Gastroenteropancreatic tumor

#### **1. Introduction**

Neuro-endocrine tumors constitute 0.5% of all malignancies [1]. Gastroentero-pancreatic neuro-endocrine tumors (GEP-NET) originate from neuro-endocrine cells of the embryological gut and they constitute a group of heterogeneous tumors that demonstrate divergent tumor biology, different diagnostic behavior, management principles and tumor-patient outcomes [2].

#### **2. Incidence and epidemiology**

GEP-NET comprises 2% of all gastrointestinal tumors [3]. Pancreatic neuroendocrine tumors (PNETs) are one of the most common neuroendocrine tumors [4]. But they are relatively rare tumors and comprise about 7% of all cancers that occur in the pancreas [5]. According to The American Cancer Society's estimates for 2020, about 4,032 people in the United States will be diagnosed with pancreatic NET.8

With better imaging modalities coming into play, the incidence of pancreatic NETs is increasing over the years as they are often found incidentally when radiological tests such as CT or MRI scans are done for other diseases. There has also been increased sensitivity of lab tests that have escalated the ability to distinguish these tumors from other malignancies. The increased prevalence over the past few decades, is attributed to multifactorial causes mainly as a consequence of increased awareness and improved diagnostic technique [6]. It is estimated that nowadays almost 50% of PNET diagnoses are incidentalomas [7]. An aging population and

heightened awareness of the disease have also contributed to an increase in the detection of incidentalomas [8].

Majority of pNET are sporadic, i.e. non inherited while 10–30% pNET are associated with a genetic syndrome like multiple endocrine neoplasia (MEN) type 1, which is most commonly associated with it [9]. Other rare genetic conditions include MEN4, Von Hippel–Lindau disease, neurofibromatosis 1 (von Recklinghausen's syndrome), and tuberous sclerosis, which are linked to genetic type pNET [10].

There is no gender predilection for pNET although some studies have suggested a slight preponderance for men. These tumors can present at any age but the incidence of sporadic tumors rises from fifth decade and peaks around 80s [11].

### **3. Classification and staging**

In the past NETs were classified based upon the site of origin in embryological gut as foregut, midgut and hindgut tumors. It has been rather challenging to classify these tumors due to their heterogeneity, difference in their morphology, clinical presentation, molecular biology, hormone profile and treatment response.

Clinically these tumors have been classified as functioning and non functioning tumors. In 2007 WHO introduced a new classification system for neuroendocrine tumors which categorized them according to tumor's proliferation indices like mitotic index or Ki67 score as well differentiated tumors and poorly differentiated carcinomas [12]. In 2010 it also included histopathological features as a criteria for classification apart from proliferation indices, which lead to revision of the existing guidelines and NETs were further divided into three grades based upon ENETS classification (**Table 1**) [14]. Well differentiated tumors comprised of grade 1 and grade 2 NET, while poorly differentiated tumors were grade 3 NET also described as neuroendocrine carcinoma (NEC). The difference between the two has been illustrated in **Table 2** [14].

In 2017, the classification was re-revised to include NET grade1, 2 and 3 in the well differentiated category and the poorly differentiated category was NEC grade 3. See **Table 3** [15].

European neuroendocrine society has also devised a staging for GEP-NET. American cancer society has included tumor resectability as classification criteria (**Figure 1**) [17].

Mixed adenoneuroendocrine carcinoma (MANEC) of pancreas are a group of extremely rare tumors, with incidence approximately 0.2% and only a few cases are reported in literature [18]. They have both adenocarcinoma and neuroendocrine components with each component accounting for more than 30% of the tumor [19]. Due to rarity of this, tumor the clinical behavior is not studied much. It has been proposed that the treatment should depend on the aggressiveness of the cell type of the tumor [20]. In various cases studied, surgery has been considered as the first line of treatment for resectable tumors. Post operative treatment includes adjuvant chemotherapy and/or radiotherapy [21].


**Table 1.** *Who classification 2010 [13].*

#### *An Overview of Pancreatic Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.96259*


#### **Table 2.**

*The difference between NET Grade3 and NEC grade3 [15].*


#### **Table 3.**

*Who classification 2017 [13].*


#### **Figure 1.**

*Comparison of TNM classification of pancreatic NENs according to ENETS versus UICC/AJCC (TNM classification) [16].*
