Pancreatic neuroendocrine tumors (pNET), also known as endocrine tumors of the pancreas, arise from pancreatic ductal stem cells and include some distinct tumors that match the cell type of origin. 

Terminology

Pancreatic neuroendocrine tumors have commonly been referred to as "islet cell tumors", referring to the islets of Langerhans, from which they were thought to derive. It has since been shown that these tumors derive from ductal pluripotent stem cells, and "neuroendocrine tumor" is now preferred ³.

Epidemiology

Overall, pancreatic neuroendocrine tumors have an incidence of 0.001% and account for 1-2% of pancreatic neoplasms. They occur most commonly at ages 30-60 with no clear gender predilection.

Associations

Most tumors are sporadic. Approximately 10% are associated with multiple endocrine neoplasia type 1 (MEN1), von Hippel Lindau disease, tuberous sclerosis, and neurofibromatosis type 1 ⁷.

Clinical presentation

Syndromic tumors tend to present earlier, with clinical signs and symptoms related to their cell type and biological activity:

• insulinoma: Whipple triad

• gastrinoma: Zollinger-Ellison syndrome

• glucagonoma: 4D syndrome

• non-functioning tumors: tend to present late and often larger in size

Pathology

Neuroendocrine tumors are classically defined by the expression of markers of neuroendocrine differentiation (including chromogranin A and synaptophysin) and hormone production. 

These tumors can broadly be divided according to whether or not they secrete enough active compounds to be functional or not:

• non-functional tumors: account for ~67.5% (range 50–85%) of PNETs ⁷

• functional tumors

  • insulinoma

  • gastrinoma

  • glucagonoma

  • VIPoma: rare ^ref

  • somatostatinoma: rare, some of these can be non-functional

The term "syndromic" may be preferred over "functioning" since it is becoming increasingly clear that most tumors are functional (i.e. produce hormones), but either do not produce enough hormone or produce an ineffective form of the hormone, so that they may not produce a clinical syndrome ^ref.

Biological behavior also depends on the cell of origin ^ref:

• insulinoma: 10% malignant

• gastrinoma: 60% malignant

• glucagonoma: 80% malignant

• VIPoma: 75% malignant

• somatostatinoma: 75% malignant

• non-functional: 85-100% malignant

Classification

According to the 2017 World Health Organization (WHO) classification, these tumors are histologically graded as ^5,6:

• well-differentiated status

  • grade 1 (G1): tumor expressing <2 mitoses/2 mm² and ≤2% Ki-67 index

  • grade 2 (G2): tumor expressing between 2 to 20 mitoses/2 mm² and 3 to 20% Ki-67 index

  • grade 3 (G3): more than 20 mitoses/2 mm² and more than 20% Ki-67 index

• poorly-differentiated and containing components of adenocarcinoma - they are named pancreatic neuroendocrine carcinoma (pNEC) and divided into two types

  • small cell type

  • large cell type

Radiographic features

Overall these neuroendocrine tumors of the pancreas tend to be highly vascular and well-circumscribed, often displacing adjacent structures. They can demonstrate calcific or cystic change.

Ultrasound

• well-circumscribed with smooth margins

• round or oval

• hypoechoic

Liver metastases may be hyperechoic or targetoid.

CT

Smaller tumors:

• hypervascular

• tend to be homogenous and well-circumscribed

Larger tumors:

• may appear heterogeneous and contain areas of cystic or necrotic change

• can occasionally manifest as primarily cystic lesions and are distinguishable from other cystic neoplasms by their hypervascular rim

Since pNETs usually have a distinct capsule, this means that they displace rather than invade surrounding structures as they grow in size. As a result, they less frequently present with biliary obstruction, which is a classic mode of presentation for pancreatic adenocarcinomas. 

Neuroendocrine tumors of the pancreas show peak contrast enhancement in the early arterial phase (25-35 s) rather than in the late arterial phase (35-45 s) which is normally used for pancreatic imaging. This is particularly important when considering that small lesions may be missed in the late arterial phase when the tumor will appear isointense with enhancing pancreatic parenchyma. Accessory spleens or splenules can mimick small neuroendocorine tumors. However, the washout pattern of splenules mirrors that of the adjacent spleen ⁸.

MRI

Sensitivity is similar to CT

• T1: hypointense relative to pancreas

• T2: typically hyperintense relative to the pancreas, but there is a range of signal intensities

• T1 C+ (Gd): hyperintense/hypervascular relative to pancreas

• DWI/ADC: restricted diffusion is usually present and tends to correlate to the degree of tumor differentiation  

Nuclear medicine

Nuclear medicine studies play an important role in the staging of neuroendocrine tumors. 

• gallium-68 DOTATATE (or DOTATOC, or DOTANOC) PET-CT

  • superior to octreotide scan 

• F-18 FDG PET-CT

  • sensitivity limited unless poorly-differentiated

• indium-111 octreotide

  • planar or SPECT

  • sensitivity is ~80%, although limited by the somatostatin receptor characteristics of the tumor

    • reported sensitivity is highest with gastrinomas >2 cm

    • reported sensitivity is lowest with insulinomas

  • has been largely replaced by PET-CT in most centers 

Treatment and prognosis

Surgical resection for low-grade localized PNETs can be curative and should be considered for all symptomatic/functional PNETs and non-function PNETs >2 cm in size ⁷. Non-functional PNETs may be suitable for active surveillance if <1-2 cm in size ⁷.

Even patients with advanced disease can have reasonable long-term survival ^ref. Recurrence is associated with ⁷:

• tumor size >2 cm

• symptomatic tumors

• Ki67 >3%

• nodal disease

Differential diagnosis

• metastasis (e.g. renal cell carcinoma)

• intrapancreatic splenule (if in the tail of the pancreas)

• mostly-solid serous cystadenoma

Practical points

• check for concomitant metastatic disease: neuroendocrine tumors most commonly give metastases in the liver and, less frequently, in the bones