Aetiology
The underlying cause of VIPomas is not fully known. Most cases are sporadic. Multiple endocrine neoplasia type 1 (MEN1) gene mutations have been reported in <1% of patients with VIPoma.[10]
Pathophysiology
VIPomas are functional tumours. They usually arise from the pancreatic neuroendocrine cells that normally populate the islets of Langerhans. VIPomas secrete vasoactive intestinal peptide (VIP), a hormone that is normally present within enteric neurons and shares a structural similarity with secretin.[11][12][13][14][15][16] VIP has a half-life in the circulation of <1 minute. It binds to the secretin family of G-protein-coupled receptors; stimulates pancreatic exocrine secretion, intestinal secretion, and enteric smooth muscle; and inhibits gastric acid production.
VIPoma patients have markedly raised plasma levels of VIP (due to excessive and uncontrolled secretion from the tumour), which causes overstimulation of the gastrointestinal tract and results in profuse watery diarrhoea. Resultant intestinal losses lead to dehydration, hypokalaemia, metabolic acidosis (due to loss of bicarbonate), and hypochlorhydria or achlorhydria. In some patients, VIP can directly stimulate bone resorption (resulting in hypercalcaemia), glycogenolysis (resulting in hyperglycaemia), and vasodilation (resulting in flushing). Most VIPoma patients have metastasis to regional lymph nodes or the liver at the time of diagnosis.
The exact pathophysiology for extrapancreatic VIPomas is unknown.
Classification
WHO Classification of Endocrine and Neuroendocrine Tumors (5th edition, 2022)[2]
The WHO classification of neuroendocrine tumours (NETs) describes tumour grade based on Ki67 index and mitotic index:[2][3][4]
Well-differentiated neuroendocrine neoplasm (NEN)
Grade 1
Grade 2
Grade 3
Poorly-differentiated NEN
Neuroendocrine carcinoma (NEC) (high grade)
Small cell type (SCNEC)
Large cell type (LCNEC)
Mixed endocrine non-endocrine neoplasm (MiNEN) (grade 1-3)
NET or NEC combined with a non-neuroendocrine carcinoma (e.g., adenocarcinoma or squamous carcinoma) each of which is distinct morphologically and immunohistochemically.
MiNEN is not in itself a diagnosis and individual components of the tumour must be defined using site-specific terminology.
Both neuroendocrine and non-neuroendocrine components are usually poorly differentiated, but one or both may be well differentiated and should be graded separately.
American Joint Committee on Cancer staging (8th edition, 2017): pancreatic neuroendocrine tumors[5]
The American Joint Committee on Cancer TNM staging system describes the extent of disease based on three anatomic factors: size and extent of the primary tumour (T); regional lymph node involvement (N); and presence or absence of distant metastases (M).[5]
T1 Tumour limited to the pancreas, <2 cm
T2 Tumour limited to the pancreas, 2-4 cm
T3 Tumour limited to the pancreas, >4 cm, or invading the duodenum or common bile duct
T4 Tumour invades adjacent structures
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to liver
M1b Metastasis in at least one extrahepatic site
M1c Both hepatic and extrahepatic metastases
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