Part of the TeachMe Series

Neuroendocrine tumours

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Original Author(s): Vimal Prabhu
Last updated: March 25, 2019
Revisions: 4

Original Author(s): Vimal Prabhu
Last updated: March 25, 2019
Revisions: 4

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Introduction

Neuroendocrine cells are any cells that receives input from neurotransmitters to release hormones into the bloodstream, allowing for an integration between the nervous and endocrine systems.

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) refers to neuroendrocrine tumours originating from neuroendocrine cells in the tubular gastrointestinal tract and the pancreas*, all of which have malignant potential. Pancreatic neuroendocrine tumours are discussed elsewhere on the site

The incidence of GEP-NETs in Western countries is reported at 5.25 per 100000; the majority of GEP-NETs are located in the small intestine, the remainder either in the rectum or the stomach.

*Neoplasia arising from neuroendocrine cells have historically been called carcinoid tumours when occurring in the gastrointestinal tract, however they can also occur in the pancreas and lung

Grading Classification

The WHO classification for grading GEP-NETs is divided into 3 categories:

  • Grade 1 – Well differentiated, mitotic count <2 per 10 HPF, ki index <3%
  • Grade 2 – Well differentiated, mitotic count 2-20 per 10HPF, ki index 3-20%
  • Grade 3 – Poorly differentiated, mitotic count >20 per 10HPF, ki index >20%

Risk Factors

The main risk factors for GEP-NETs are genetic. Inherited disorders such as Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1(NF-1), and the tuberous sclerosis complex (TSC) are all associated with an increased risk of developing GEP-NETs.

Clinical Features

Patients often present with non-specific symptoms, such as vague abdominal pain, nausea and vomiting, and abdominal distension. In some cases they may present with features of bowel obstruction, requiring urgent intervention

Other clinical features include unintentional weight loss or with a palpable abdominal mass. It is important to assess for features suggestive of an underlying inherited disorder (e.g. MEN-1 or VHL)

GEP-NETs can be classed as functioning or non-functioning depending on evidence of hormonal hypersecretion, however the majority of GEP-NETs are non-functioning. Well-differentiated midgut NETs can often also present with carcinoid syndrome.

Carcinoid Syndrome

Well-differentiated GEP-NETs can spread and result in carcinoid syndrome developing.

Carcinoid syndrome occurs following metastasis of a carcinoid tumour, whereby the metastasised cells begin to oversecrete bioactive mediators, such as serotonin, prostaglandins, and gastrin, into the circulation.

Oversecretion of such mediators results in patients presenting with symptoms of flushing (classically exacerbated by alcohol or coffee), abdominal pain, diarrhoea, wheezing, and palpitations.

Investigations

Laboratory Tests

Any suspected GEP-NET should have Chromogranin A and 5-HIAA levels checked, alongside routine bloods including FBC and LFTs. Chromogranin B and Pancreatic peptide can also be useful markers for GEP-NETs*.

*For pancreatic NETs, specific markers are also checked, such as serum insulin and C-peptide for insulinoma, and serum glucagon for glucagonoma

Genetic testing should be considered if the clinical history is suggestive.

Specialised Tests

If initial bloods are in keeping with a GEP-NET, further imaging is required to delineate and assess the mass, dependent on the location suspected. Gastric, duodenal, and colorectal NETs are best evaluated using endoscopy, whilst CT enteroclysis is the imaging of choice to investigate a small bowel NET.

For patients who present with metastatic disease without a known primary (and to establish the extent of disease in those with a known primary), whole body somatostatin receptor scintigraphy* (SSRS) is often warranted.

*Indium-octreotide scanning is the most widely available SSRS at present, however gallium-octreotide scanning is a newer technique which has shown to have improved accuracy in detecting a primary tumour.

Management

All patients should be discussed at a multi-disciplinary team meeting at a tertiary hospital where management can be guided. Surgery is the only curative treatment for GEP NETs. As metastatic disease is common at presentation, any surgical treatment is therefore often only palliative.

Poorly-differentiated GEP-NETs have a poor prognosis; if the disease is localised, then treatment is often surgical resection followed by chemotherapy, whilst in metastatic disease, palliative chemotherapy alone is typically advised.

Well-differentiated GEP-NETs are managed according to site, staging, and functionality. Localised disease should be resected; any liver metastases present should also be resected, along with the primary tumour, as this has been shown to improve survival rates.

Carcinoid Crisis

An important consideration requiring management prior to any surgical procedure in a patient with a NET is the possibility of carcinoid crisis intra- or post-operatively.

Carcinoid crisis is caused by an overwhelming release of hormones from the NET, resulting in a resistant severe hypotension.

Somatostatin analogues may be used for the prophylaxis of carcinoid crisis, depending on the presence of carcinoid syndrome, how well it is controlled, and the type and degree of surgery planned. In the highest risk patients, octreotide can be started 24 hours prior to the operation and continued for 48 hours post-operatively.

Surgical Management

Gastric NETs management depends on their subtype. Type 1 and type 2 have a very low metastatic potential, therefore can usually be treated with endoscopic resection and annual surveillance. Type 3 are more aggressive lesions, therefore management is often partial or total gastrectomy with lymph node clearance.

Small intestinal NETs are almost always malignant. Resection of the tumour with mesenteric lymph node clearance is performed regardless of the presence of liver metastases.

Appendiceal NETs have a more benign course than small intestinal NETs, however management depends on their size; tumours >2cm require appendicectomy with right hemicolectomy, whilst those <2cm may be treated with appendicectomy alone.

Colonic NETs have the worst prognosis of any gastrointestinal NET, with their treatment often requiring a partial colectomy and regional lymph node clearance. Rectal NETs have a more benign character, with smaller tumours treated with endoscopic resection and larger tumours requiring either AP resection or low anterior resection.

Key Points

  • Gastroenteropancreatic neuroendocrine tumours originate from neuroendocrine cells in the tubular gastrointestinal tract and the pancreas
  • They are strongly associated with inherited disorders, such as MEN1 and von Hippel Lindau
  • Any suspected case should be investigated initially via Chromogranin A and 5-HIAA serum levels
  • Surgery is the only curative treatment, however many tumours will already have metastasised at presentation