Pancreatic neuroendocrine tumours (pNET), also known as endocrine tumours of the pancreas, arise from pancreatic ductal stem cells and include some distinct tumours that match the cell type of origin.
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Terminology
Pancreatic neuroendocrine tumours have commonly been referred to as "islet cell tumours", referring to the islets of Langerhans, from which they were thought to derive. It has since been shown that these tumours derive from ductal pluripotent stem cells, and "neuroendocrine tumour" is now preferred 3.
Epidemiology
Overall, pancreatic neuroendocrine tumours 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 tumours are isolated. Approximately 1-2% are associated with multiple endocrine neoplasia type 1 (MEN1), which is characterised by the triad of parathyroid, pituitary, and pancreatic lesions.
There are also associations with von Hippel-Lindau disease and tuberous sclerosis.
Clinical presentation
Syndromic tumours tend to present earlier, with clinical signs and symptoms related to their cell type and biological activity:
non-functioning tumours: tend to present late and often larger in size
Pathology
Neuroendocrine tumours are classically defined by the expression of markers of neuroendocrine differentiation (including chromogranin A and synaptophysin) and hormone production.
These tumours can broadly be divided according to whether or not they secrete enough active compounds to be syndromic or not:
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syndromic tumours
insulinoma: most common
gastrinoma: second most common
VIPoma: rare
somatostatinoma: rare, some of these can be non-functional
non-syndromic tumours: third most common
Individual functional tumours are discussed in more detail separately.
The term "syndromic" is preferred over "functioning" since it is becoming increasingly clear that most tumours 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.
Classification
According to the 2017 World Health Organisation (WHO) classification, these tumours are histologically graded as 5,6:
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well-differentiated status
grade 1 (G1): tumour expressing <2 mitoses/2 mm2 and ≤2% Ki-67 index
grade 2 (G2): tumour 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
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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 tumours 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 tumours:
hypervascular
tend to be homogenous and well-circumscribed
Larger tumours:
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 tumours 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 tumour will appear isointense with enhancing pancreatic parenchyma.
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 tumour differentiation
Nuclear medicine
Nuclear medicine studies play an important role in the staging of neuroendocrine tumours.
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gallium-68 DOTATATE (or DOTATOC, or DOTANOC) PET-CT
superior to octreotide scan
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F-18 FDG PET-CT
sensitivity limited unless poorly-differentiated
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planar or SPECT
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sensitivity is ~80%, although limited by the somatostatin receptor characteristics of the tumour
reported sensitivity is highest with gastrinomas >2 cm
reported sensitivity is lowest with insulinomas
has been largely replaced by PET-CT in most centres
Treatment and prognosis
If diagnosed early enough (before metastases), then complete surgical resection may be curable. Even patients with advanced disease can have reasonable long-term survival. Biological behaviour also depends on the cell of origin:
insulinoma: 10% malignant
gastrinoma: 60% malignant
glucagonoma: 80% malignant
VIPoma: 75% malignant
somatostatinoma: 75% malignant
non-functional: 85-100% malignant
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 tumours most commonly give metastases in the liver and, less frequently, in the bones
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