Neuroendocrine tumour (NET)

What are NETs?

  • NETs are a heterogeneous group of neoplasms originating from neuroendocrine cells. Such tumours originate from pancreatic islet cells, GIT, respiratory tract and thyroid gland. Gut derived NETs have been classified according to their embryological origin into tumours of the foregut (bronchi, stomach, pancreas, gall bladder, duodenum,), midgut (jejunum, ileum, appendix, right colon), and hindgut (left colon, rectum) tumours.
    • They have secretory characteristics and frequently present with hypersecretory syndromes.
    • NET is the preferred term rather than carcinoid.

    What are the commonest sites of NET?

    Appendix (35%), ileum (15%), rectum (10%) and lung (15%)

    Discuss the clinical features of NET?

    • Primary gut tumours can be asymptomatic but may present with obstructive symptoms (pain, nausea, and vomiting) despite normal radiology.
    • Secretory tumours can present with
      • Carcinoid syndrome
        • It is a result of metastases to the liver with the subsequent release of hormones (serotonin, tachykinins, and other vasoactive compounds) directly into the systemic circulation.
        • This syndrome is characterised by flushing, diarrhoea and palpitations. Less commonly wheezing and pellagra may occur as presenting features, with carcinoid heart disease typically not occurring unless the syndrome has been present for some years. Occasionally, similar syndromes can occur when there are no measurable hormones detected in blood or urine.
        • The carcinoid crisis is characterised by profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure. It is usually precipitated by anaesthetic induction for any operation, intraoperative handling of the tumour, or other invasive therapeutic procedures such as embolisation and radiofrequency ablation.
      • Pancreatic NETs like insulinoma, gastrinoma, glucagonoma, VIPoma and somastatinoma produce relevant secretory symptoms.

    Discuss the genetics of NET?

    NETs may occur as part of complex familial endocrine cancer syndromes such as MEN1, MEN2 etc although the majority are sporadic isolated tumours. However, it is important to search thoroughly for MEN1, MEN2, and NF1 in all patients with NETs by obtaining a detailed family history, clinical examination, and appropriate biochemical and radiological investigations.

    Discuss the diagnosis of NET?

    If a patient presents with symptoms suspicious of a gastroenteropancreatic NET: baseline tests should include chromogranin A (CgA) and 5-hydroxy indole acetic acid (5- HIAA). Specific biochemical tests should be requested depending on which syndrome is suspected. The gold standard in diagnosis is detailed histology and this should be obtained whenever possible.

    Blood and urine measurements

    • 24 h urinary 5-HIAA is usually raised (70% of patients) in midgut carcinoids.
    • Plasma CgA- CgA is a large protein which is produced by all cells deriving from the neural crest. The function of CgA is not known but it is produced in very significant quantities by NET cells regardless of their secretory status.
    • Gut hormones will be raised in pancreatic NETs.

    Currently in UK, the following hormones are normally performed when gut hormones are requested: gastrin, glucagon, somatostatin, PP, VIP and neurotensin. CgA will be performed on the same sample when requested. Blood is taken in a 10ml standard heparin bottle and spun immediately before being frozen and sent to the reference lab.

    The optimum imaging modality depends on whether it is to be used in detecting disease in a patient suspected of an NET or for assessing the extent of disease in a known case.

    • CT scan or endoscopy is useful to locate the primary in case of metastases.
    • SSRS (somatostatin receptor scan or octreoscan)-

    Neuroendocrine tumours express somatostatin receptors (SSTR) and this has led to the development of radiolabelled somatostatin analogues for diagnostic imaging.
    SSRS has a sensitivity of 90% for gut NETs and plays a central role in locating and assessing the primary in gastroenteropancreatic NETs.
    However, in patients whose octreoscan is negative and in whom no diagnosis is reached after upper and lower gastrointestinal endoscopy, a triple phase CT scan of the thorax and abdomen is regarded as the investigation of choice.
    The diagnostic test of choice to locate secondaries is SSRS. SSRS prior to surgery revised the staging and changed management in 33% in Krenning’s series

    Monitoring progression of disease

    • Spiral CT scanning, MRI, and ultrasound scans are useful for monitoring lesions.
    • Urinary 5-HIAA levels do not accurately correlate with disease progression and response to treatment.
    • CgA is a sensitive marker which correlates well with response and relapse.

    Discuss staging of NET?
    Tumours should be classified according to the recent WHO classification. This places all enteropancreatic NETs into one of four categories, based on a combination of gross and histological features

    • Well differentiated endocrine tumour of probable benign behaviour.
    • Well differentiated endocrine tumour of uncertain behaviour.
    • Well differentiated endocrine carcinoma.
    • Poorly differentiated endocrine carcinoma.

    There is currently no TNM staging system for these tumours.

    Discuss the treatment of NET?

    The aim of treatment should be curative where possible but is palliative in the majority of cases. Metastatic disease is a common presentation in patients with NETs; therefore, the aim of treatment is frequently improvement of their quality of life rather than cure. These patients often maintain a good quality of life for a long period despite having metastases.

    Discuss the role of surgery in NETs?

    This is the only curative treatment for NETs. With carcinoid, if the primary lesion is less than 2 cm in diameter, the incidence of metastasis is low.

    a. Incidental carcinoid in appendectomy specimen-

    • Right hemicolectomy is indicated if the carcinoid tumour is more than 2 cms in diameter.
    • Tumours 1–2 cm or invading the serosal surface may require further resection, particularly if atypical with goblet cell or adenocarcinoid features, or if it is located at the base of the appendix, or if histology shows mesoappendiceal and/or vascular invasion, when a right hemicolectomy with locoregional lymphadenectomy should be considered. Whether or not this is performed, the patient should be followed up for five years.
    • If the lesion is less than 1 cm in diameter- no further resection is needed, provided complete resection by appendicectomy has been undertaken. Extended follow up appear unnecessary.

    b. Stomach- 3 types of gastric carcinoid

  • Type 1 gastric carcinoids are associated with hypergastrinaemia and chronic atrophic gastritis. This can synthesise and store histamine. The frequency of metastasis is low, and surveillance only is appropriate, although limited surgery with endoscopic polypectomy and/or antrectomy may be preferable.
  • Type 2 gastric carcinoids occur in patients with hypergastrinaemia due to Zollinger-Ellison syndrome in combination with MEN type1.
  • Type 3 gastric carcinoids are sporadic and have a more malignant course. They are not associated with hypergastrinaemia. These tumours have often metastasised by the time of diagnosis. Small tumours less than 1 cm with no extension into muscle on EUS or CT could be resected endoscopically but most lesions will need resection and clearance of regional lymph nodes.
  • c. Small intestinal carcinoid

    Resection of the primary (along with mesenteric lymphadenectomy) is appropriate, even in presence of liver metastases, to delay progression that would otherwise endanger the small bowel.
    Nodal metastases cause sclerosis with vascular compromise of the associated small bowel, which can lead to pain, malabsorption, and even death.
    Patients, who only after laparotomy and histological examination are discovered to have small intestinal carcinoid, may be candidates for further surgery, notably for extensive
    mesenteric lymphadenectomy. Resection of mesenteric metastases may alleviate symptoms dramatically, and possibly prolong survival.

    d. Colorectum
    Standard resection with locoregional lymphadenectomy is appropriate. Small lesions less than 1 cm in diameter may be considered adequately treated by complete endoscopic removal but the patient will require follow up endoscopy to ensure this has been accomplished.

    e. Pancreas
    Often the diagnosis is established biochemically prior to surgery, and although preoperative localisation can be difficult, the biochemical diagnosis provides some indication of the site of the tumour. Appropriate resections are done depending on the location of the tumour.

    f. Liver
    In the presence of liver metastases, ‘‘curative’’ liver resection is possible in approximately 10% of cases if the lesions are confined to one lobe. With bilobar metastases and one very dominant lesion causing symptoms, a debulking operation may be carried out for palliation, particularly if there is resistance to medical therapy.

    Discuss the symptom control measures in NETs?

    • There are a number of treatment options available for patients displaying symptoms due to hormones/peptides secreted by a secretory tumour.
    • Somatostatin analogues- Somatostatin receptors are present in the vast majority (70–95%) of NETs. Somatostatin analogues inhibit the release of various peptide hormones in the gut, pancreas, and pituitary, antagonise growth factor effects on tumour cells, and at very high dosage may induce apoptosis.
      • Octreotide is administered subcutaneously (50–100 mg 2-3 times/day to a maximum daily dose of 1500 mg). Other long acting analogues have been synthesised recently like lanreotide (fortnightly injection), Sandostatin LAR (monthly), and Lanreotide Autogel (also monthly).
      • This lead to symptomatic control in the majority. Few side effects from somatostatin analogues have been reported and they include fat malabsorption, gall stones and gall bladder dysfunction, vitamin A and D malabsorption, headaches, diarrhoea, dizziness, and hypo- and hyperglycaemia.
    • Use of PPI in gastrinomas, diazoxide for insulinoma. Additional octreotide is usually not needed in gastrinomas and insulinomas
    • VIPomas, Glucagonoma respond to octreotide.

    What is the role of chemotherapy?

    The role of chemotherapy for NETs is uncertain but is being actively researched. One paper showed that response to chemotherapy in patients with strongly positive carcinoid tumours was of the order of only 10% whereas patients with SSRS negative tumours had a response rate in excess of 70%. The highest response rates with chemotherapy are seen in the poorly differentiated and anaplastic NETs: response rates of 70% or more have been seen with cisplatin and etoposide based combinations.

    Discuss any other treatment options?

    Targeted radionuclide therapy
    This is a useful palliative option for symptomatic patients with inoperable or metastatic tumour. The principle of treatment is only to give radionuclide therapy when there is abnormally increased uptake of the corresponding imaging agent.
    The gamma emitting imaging radionuclide is replaced by a beta imaging therapy radionuclide: 131 I-MIBG for 123 I-MIBG, 90Y-octreotide for 111In-octreotate, and 90Y-lanreotide for 111In-lanreotide. Contraindications include pregnancy and breast feeding, myelosuppression, and renal failure (glomerular filtration rate, <40 ml/min). Symptom control is up to 80% and a five year survival rate of 60% has been recorded. Treatment is well tolerated and toxicity limited to temporary myelosuppression 4–6 weeks post therapy

    Embolisation of hepatic artery
    This procedure is indicated for patients with non-resectable multiple and hormone secreting tumours with the intention of reducing tumour size and hormone output. There are two types of embolisation: particle and chemoembolisation. Particles used include polyvinyl alcohol and gel foam powder. For chemoembolisation, agents such as doxorubicin and cisplatin are used primarily. Contraindications for chemoembolisation include complete portal vein obstruction, liver insufficiency, and biliary reconstruction.

    Radiofrequency ablation
    This has been used with some effect in stabilising or reducing tumour size but randomised trials are lacking. It may be indicated in patients with inoperable bilobar metastases in whom hepatic artery embolisation has failed. Destroying the largest lesion may not necessarily switch off hormone production. To achieve a reduction in hormone secretion it is necessary to ablate at least 90% of the visible tumour

    External beam radiotherapy

    Carcinoid tumours are radioresistant. However, it may provide excellent relief of the pain from bone secondaries.

    What is the prognosis?

    • 5 year survival is 83% following complete surgical resection of the primary tumour and liver metastases if present.
    • 5 year survival is 30-70% if curative surgical resection is not feasible.

    How do you prevent carcinoid crisis?
    When a functioning carcinoid tumour is found before surgery, a potential carcinoid crisis could be prevented by prophylactic administration of octreotide, given by constant intravenous infusion at a dose of 50 mg/h for 12 hours prior to and at least 48 hours after surgery. It is also important to avoid drugs that release histamine or activate the sympathetic nervous system.


    1. British Society of Gastroenterology Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumour

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