Historically referred to as carcinoid tumours, neuroendocrine tumours (NETs) arise from neuroendocrine cells, which are widely distributed in the body. They are rare tumours (incidence: 5/100 000) but ‘common’ primary sites include the gastrointestinal tract (especially the appendix and terminal ileum), pancreas and lung.
The risk factors for tumour development are not well understood. A small proportion arise on the background of an inherited endocrine cancer syndrome, including MEN-1 (Chapter 33), von Hippel–Lindau syndrome (associated with pancreatic NETs), neurofibromatosis type 1 (NF1) and tuberous sclerosis.
Symptoms and signs
Because of their wide distribution, the spectrum of presentation is diverse. Many are discovered incidentally during a diagnostic work-up undertaken forother reasons. Patients with gastrointestinal NETs can present with bowel obstruction while fewer than 10% present with classic carcinoid syndrome (characterised by dry flushing and diarrhoea) (Figure 31.1). This occurs when vasogenic peptides, including serotonin, gain access to the systemic circulation, most commonly as a result of liver metastases from an intestinal primary. Patients with pancreatic NETs present with symptoms related to the tumour mass (abdominal pain, weight loss) or a hypersecretory syndrome (Figure 31.2).
Plasma chromogranin A is a useful general neuroendocrine marker that has high sensitivity for most types of NET. Falsely raised readings can be seen in patients with renal disease and in those taking proton pump inhibitor therapy.
Most intestinal NETs secrete serotonin. Its breakdown product, 5-hydroxyindoleacetic acid (5-HIAA), can be measured in a 24-hour urine collection and is typically elevated in patients with intestinal NETs and metastatic liver disease. A fasting gut hormone profile (measuring gastrin, glucagon, vasoactive intestinal peptide, somatostatin and pancreatic polypeptide) should be measured in patients with pancreatic NETs. Patients with suspected insulinoma require a supervised inpatient fast to establish the diagnosis (Chapter 34).
A variety of imaging modalities are used to help establish the site of the primary tumour and to document the extent of the disease. Cross-sectional imaging (CT or MRI) (Figure 31.3) is used commonly while endoscopy, endoscopic ultrasound and selective venous sampling are useful in selected cases, especially in patients with pancreatic disease. Somatostatin receptor scintigraphy (SSRS; Octreoscan®) is used widely, not only to define the extent of disease, but also to determine suitability for somatostatin analogue therapy and peptide receptor radionuclide therapy.
This is considered the gold standard for diagnosis. Immunohistochemistry directed against a panel of general neuroendocrine markers will confirm a neuroendocrine origin, supplemented where necessary with immunostaining for specific hormones (e.g. gastrin in suspected gastrinoma). A key part of the pathology report is to estimate the proliferative potential and grade of the tumour by measuring the Ki67 proliferation index and/or mitotic count. This helps determine prognosis but can treatment choice (e.g. chemotherapy can be used in NETs with a high Ki67 index).