Etiology

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 tumors. 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 elevated plasma levels of VIP (due to excessive and uncontrolled secretion from the tumor), which causes overstimulation of the gastrointestinal tract and results in profuse watery diarrhea. Resultant intestinal losses lead to dehydration, hypokalemia, metabolic acidosis (due to loss of bicarbonate), and hypochlorhydria or achlorhydria. In some patients, VIP can directly stimulate bone resorption (resulting in hypercalcemia), glycogenolysis (resulting in hyperglycemia), 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 tumors (NETs) describes tumor 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 nonendocrine neoplasm (MiNEN) (grade 1-3)

    • NET or NEC combined with a nonneuroendocrine 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 tumor 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 tumor (T); regional lymph node involvement (N); and presence or absence of distant metastases (M).[5]

T1 Tumor limited to the pancreas, <2 cm

T2 Tumor limited to the pancreas, 2-4 cm

T3 Tumor limited to the pancreas, >4 cm, or invading the duodenum or common bile duct

T4 Tumor 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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