Revised 27 November 2018

General aspects - introduction

The most common gastrointestinal neuroendocrine tumours (NETs) include gut carcinoids and tumours of the endocrine pancreas. They are uncommon tumours that arise from the diffuse endocrine system (DES), which comprises at least 15 specialized epithelial cells of endodermal origin. DES cells and the neoplasms that arise from them express several antigens that they share with neural elements; hence, the designation neuroendocrine tumours. As treatment continues to improve, a significant proportion of these patients can expect a good intermediate term prognosis. It is important, therefore, that a multidisciplinary management plan be in place. Referral to a BC Cancer centre for guidance is recommended. The first part of this section deals with general aspects of diagnosis and management of NETs, while the second section provides more details of specific tumour types.

Clinical aspects

From a clinical standpoint, NETs can be divided into two groups: functioning and nonfunctioning. Functioning NETs hypersecrete hormones that cause specific syndromes (e.g. carcinoid syndrome) and they are named according to the hypersecreted hormone (insulinoma, gastrinoma, etc). The symptoms caused by the hypersecretion of these hormones often lead to their discovery. Nonfunctioning tumours, which account for about one-third to one-half of NETs, are not associated with a hypersecretion-related clinical syndrome. They come to attention because of their “mass effect” due to tumour bulk. Metastatic disease is often present at diagnosis. Because they are usually slow growing, NETs are frequently diagnosed late in their course. Those arising in the gut can cause intermittent abdominal discomfort for months or years, often interpreted to be a functional disorder. Later, bowel obstruction occurs secondary to desmoplastic reaction of the mesentery or, less commonly, from the tumour.

Pathology

A correct histological diagnosis is critical and this requires an adequate biopsy. A distinction should be made between a well-differentiated and a poorly differentiated neoplasm as well as between well differentiated benign endocrine neoplasms, neoplasms of uncertain behaviour and malignant neoplasms. This distinction can be aided by several features of the tumour: size, invasion of adjacent tissue or wall, invasion beyond the submucosa, angioinvasion, perineural invasion, a solid organoid structure, presence of necrosis, mitoses per high power field, Ki67 index, loss of chromogranin A immunoreactivity or hormone expression.

Tumour markers

1. Chromogranin A is present in the wall of secretory granules and is co-released with the hormones. Serum chromogranin A is a useful marker for both functioning and nonfunctioning NETs
   
2. 5-hydroxyindoleacetic acid (5HIAA) is a metabolic product of serotonin and is excreted in the urine. Measurement of this in a 24-hour urine collection is useful for the diagnosis and follow-up of NETS, especially mid-gut NETs (carcinoid tumours)
3. Other markers are useful for specific subtypes of NETs (e.g. gastrin for gastrinoma or insulin for insulinoma)

Imaging studies

Radiologic studies and nuclear imaging play an important role in the diagnosis and management of patients with NETs.

1. Conventional imaging
   • Conventional imaging, such as ultrasound and CT scan can be helpful in diagnosis and staging of NETs.
   • MRI is not routinely used to evaluate NETs, but it is useful when CT scan or ultrasound gives conflicting or inclusive results.
   • Conventional PET with FDG is not useful for well-differentiated NETs, but it may detect less well-differentiated tumours.
2. 111In-pentreotide scintigraphy (Octreoscan)
   • Pentetreotide is a somatostatin analog which shares the receptor-binding profile of octreotide and it concentrates in tumours containing the somatostatin receptors subtypes 2 and 5. It is highly sensitive for NETs, and both functioning and nonfunctioning tumours can be imaged. Small tumours can be detected by Octreoscan, and it is, therefore, useful as a staging test before surgery. Avidity on Octreoscan can also predict a positive response to octreotide therapy.
   • MIBG scintigraphy
     • MIBG (meta-iodobenzylguanidine) is concentrated in NETs and the occasional tumour will take up MIBG and not octreotide. Octreoscan is, however, considered, the superior diagnostic test.
   • Gallium 68 DOTATE PET imaging – Ga68 imaging has demonstrated increased sensitivity for neuroendocrine disease as compared to CT and FDG-PET (Sadowski JCO). Access to Ga68 imaging is currently available in BC through a clinical trial. Requests for Ga68 imaging at BC Cancer will be triaged by priority based upon the following indications*:
     1. For diagnosis of NET in patients with symptoms and/or biochemical evidence of disease (elevated urine 5HIAA or serum chromogranin) but negative CT and Octreoscan imaging.
     2. Staging to confirm extent of disease prior to definitive-intent surgical management (particularly for patients being considered for hepatic resection or liver transplantation)
     3. Eligibility for PRRT in patients with a negative Octreoscan.
     4. Ga68 imaging may also be considered for other indications if approved through a multidisciplinary tumour conference.

   NB: As requests will be triaged based upon urgency and priority, repeat requests with updated clinical information should be submitted by the ordering physician if the Ga68 scan is not booked within 6 months of the initial request.

   Principles of management

   Definitive management includes tumour resection for cure. When this is not achievable, the goals of treatment include symptom control, biochemical control (i.e. controlling excess bioactive peptides), objective tumour control and improving patient quality of life. In recent years, the management has become complex with the introduction of a number of new strategies; hence, a multidisciplinary approach is recommended.

   Surgery

   Surgery is the mainstay of management for localized disease and offers the best chance of cure. Small pancreatic NETs or localized NETs of the gut are amenable to surgical resection even in the presence of regional nodal metastases. Small tumours (<2 cm) can be excised, but more radical surgery is required for larger tumours. Complete surgical resection may be hindered by the large bulk of the tumour or the presence of unresectable regional or distant metastases. Because of the slow growth of NETs in general, cytoreductive therapy should be considered. This includes tumour resection, radiofrequency ablation, and tumour embolization. These measures often improve hormone-related symptoms. A meta-analysis of cytoreductive partial hepatectomy in patients with carcinoid tumour showed a 5-year survival rate of 71% and complete resolution of the carcinoid syndrome in 86% of patients, which lasted 4 to 120 months.

   Hepatic artery embolization alone or in combination with intra-arterial chemotherapy (doxorubicin, 5FU or mitomycin C) can reduce clinical symptoms. In 70-90% of patients, there is a biochemical response, and in 30-50% there is significant tumour reduction. Patients with NET of the mid-gut should be considered for palliative resection even in the presence of metastatic disease, since the mesenteric fibrosis that develops can make later resection difficult.  Patients with progressing liver-limited disease may be considered for trans-arterial radioembolization through a liver tumour board review. (UGIYTT)

   Liver transplantation may be an option for young patients with no extra-hepatic sites of metastases. Recurrence of disease within months or years has, however, been observed in patients who have undergone liver transplantation.

   Systemic medical treatment

   Patients should be referred to Medical Oncology for systemic therapy evaluation.

   Adjuvant - there is no established adjuvant therapy for patients with completely resected NETs.

   The following systemic regimens are approved for BC Cancer funding in advanced non-pancreatic (GI/Lung) NET disease – refer to the specified protocols in the Chemotherapy Protocols section for details on eligibility and indications.

   Non-Pancreatic (GI/Lung) NET

   Somatostatin analogues (SSAs) if functional UGIOCTLAR or UGILAN

   Everolimus UGINETEV

   cytotoxic chemotherapy with capecitabine/temozolomide or streptozocin/5FU is generally not effective in well-differentiated (low to intermediate grade) non-pancreatic NET cisplatin and etoposide if high-grade (GIPE

   PRRT if octreotide avid disease (per Octreoscan or Ga68) and progressing on SSA

   
   

   *PRRT – Peptide radionuclide receptor therapy. Patients being considered for radionuclide therapy should be reviewed at a BC Cancer GI multidisciplinary conference.

   Additional information for Specific Non-Pancreatic NET Sites

   Foregut Neuroendocrine Tumours

   The foregut NETs include tumours arising in the stomach, duodenum, pancreas as well as in the lung and thymus.

   Stomach Neuroendocrine Tumours

   The incidence of stomach NETs is 0.2 per 100,000 population.

   Pathology

   The majority are well-differentiated and composed of enterochromaffin-like cells (ECL). Rarely, gastrin-producing (G), somatostatin-producing (D) or serotonin-producing (EC) cell tumours may occur. Four types are identified:

   • Type 1 is the most common, representing 70-85% of stomach NETs. They are more common in women. Multiple, small benign polyps are present (WHO group 1). They are secondary to hypergastrinemia associated with chronic atrophic gastritis, and ECL-cell hyperplasia is always evident. The prognosis is excellent.
     
   • Type 2 is rare and is associated with primary hypergastrinemia. This type is part of the Zollinger-Ellison syndrome (ZES) associated with MEN-1. They are multiple benign polyps and only rarely are they malignant. The prognosis is very good with median survival of 84 months.
     
   • Type 3 accounts for 13-20% of gastric NETs. There is no definite predisposing factor. The tumour appears as a single lesion and belongs to WHO group 2: Ki-67 >2%, >2cm in diameter, infiltrative growth and metastases to regional nodes and liver. A small minority (5%) may produce histamine, causing the “atypical carcinoid syndrome”. The median survival is 28 months.
     
   • Poorly differentiated tumours with positive staining for synaptophysin occur rarely (<5%). They are highly malignant (WHO group 3). The prognosis is poor with median survival of 7 months.
     
   
   

   Clinical presentation

   Stomach NETs are usually asymptomatic. They may be found incidentally or in patients with pernicious anemia. Larger tumours can bleed. An atypical carcinoid syndrome can occur with generalized flushing, lacrimation, wheezing and diarrhea.

   Special Diagnostic Procedures

   1. Tumour imaging
      • Gastroscopy and endoscopic ultrasound (EUS), abdominal ultrasound or abdominal CT scan, and octreotide scintigraphy
   2. Biochemistry
      • Chromogranin A and gastrin
      • Parietal cell antibodies
      • MEN-1 is excluded by measurement of ionized calcium, PTH and possibly pituitary hormones

   Surgical Management

   This is a potentially curative modality.

   • Type 1 and 2 tumours
     • Polyps < 1 cm in diameter: Surveillance yearly
     • Polyps > 1 cm in diameter: If 1-6 polyps - endoscopic resection and surveillance
     • If > 6 polyps, extension to muscularis, repeated recurrences – surgical resection or antrectomy (to reduce gastrin stimulation from antral cells)
     • Any evidence of malignant transformation: partial or total gastrectomy
   • Type 3 tumours and poorly differentiated tumours
     • Partial or total gastrectomy with lymph node dissection (similar to gastric adenocarcinoma)
   
   

   Duodenal Neuroendocrine Tumours

   Duodenal NETs are rare (<1 per 100,000 population). Patients present with dyspepsia with duodenal ulcer. Anemia may be present. Most are found incidentally. Overall five-year survival is 51%; for localized disease the five-year survival is 66%, for regional disease 28%, and for distant metastases 17%.

   Pathology

   The majority is well-differentiated and composed of gastrin-producing (G) cells, somatostatin-producing (D) or serotonin-producing (EC) cells.

   Special Diagnostic Procedures

   1. Tumour Imaging
      • Endoscopy, EUS, CT scan and octreotide scintigraphy
   2. Biochemistry
      • Chromogranin A
      • Further tests depending on clinical presentation: gastrin, calcitonin, somatostatin, urinary 5HIAA
   
   

   Surgical Management

   Surgery is curative for localized disease. Small duodenal tumours may be resected by endoscopy or surgery. Large tumours require pancreaticoduodenal resection or Whipple’s resection. Unresectable tumours may be stented or a surgical by-pass procedure performed.

   Symptom Management

   For gastrin-producing tumours, proton pump inhibitors should be used to control acid-related symptoms.

   Neuroendocrine Midgut Tumours

   Epidemiology

   The incidence of endocrine midgut tumours is 0.28-0.8 per 100,000 population. The terminal ileum, close to the ileocecal valve, is the most common site. Both men and women are affected equally and the disease has a peak incidence in the 6th and 7th decade. The cancers are often multicentric, and in 15% of patients there may be a metachronous cancers, such as GI adenocarcinoma or breast cancer. Appendiceal NETs account for 19% of all GI NETs. They are more common in women and occur commonly in the 4th and 5th decade of life.

   Clinical Presentation

   Nonfunctioning tumours are usually discovered incidentally or during a search for liver metastases of neuroendocrine origin. The main symptom is intermittent abdominal discomfort for months or years, caused by angulation of the small bowel from the desmoplastic reaction of the mesentery. Appendiceal NETs are mostly found during appendectomy. They can cause appendicitis by blocking the lumen.

   Functioning NETs can give rise to carcinoid syndrome (flushing, diarrhea, intermittent bronchospasm and carcinoid heart disease), which is the present in 4-10% of patients at diagnosis. Abdominal discomfort may also occur. Rarely, a pellagra-like rash is present.

   Special Diagnostic Procedures

   In addition to the usual diagnostic tests, colonoscopy may identify a primary in the distal ileum or the ileocecal valve region. Small bowel enteroclysis can be useful. Capsule endoscopy is a promising new method to find a primary in the small intestine.

   Management

   1. Surgery
      • Midgut NETs: Surgery can be curative for NETs confined to the bowel or with regional nodal metastases. In the presence of liver metastases, cytoreductive surgery can be considered if >90% of the tumour can be safely removed. Removal of the primary tumour should be considered even in the presence of metastases to prevent intestinal obstruction or ischemic complications due to fibrotic reaction in the mesentery.
      • Selective chemoembolization is a useful option when surgery is not feasible as a cytoreductive procedure. For chemoembolization, doxorubicin is the agent most often used. Local ablative therapy by radiofrequency ablation is indicated in suitable patients with metastatic liver disease.
      Appendiceal NETs: These can be cured by appendectomy if the tumour is located at the tip of the appendix and the tumour diameter is <1cm. A right hemicolectomy is indicated if any of the following feature is present: tumour diameter >1cm; vascular or perineural invasion, location of the tumour at the base of the appendix; histology consistent with goblet cell carcinoid or mixed endocrine-exocrine tumour, tumour between 1 and 2 cm in size with mesoappendiceal involvement and/or positive margins.
      
      

   Medical management

   1. Octreotide is effective in improving symptoms in 40-80% of patients and is indicated for functioning midgut NETs.
      
   2. Systemic chemotherapy is not effective in patients with well differentiated non-pancreatic NETs. For fast-growing tumours, cisplatin plus etoposide may be effective.
      
   3. PRRT - Patients whose tumours are receptor-positive, as proven by an Octreoscan or Ga68, are candidates for radionuclide therapy.
   
   

   BC Cancer Referral Process for Peptide Receptor Radionuclide Therapy (PRRT) using Lutetium

   ¹⁷⁷Lu-Dotatate (Lutathera) for Treatment in Patients with Somatostatin Receptor Positive Midgut Neuroendocrine Tumours

   Updated: March 8, 2022

   At this time, PRRT is only available at BC Cancer – Vancouver Centre. Please see the UGIPRRT protocol for details of patient eligibility. If you have a patient that meets these criteria and is interested in able/willing to travel to Vancouver for treatment, we have outlined below the steps for referral.

   Prior to referral, please have the following investigations completed:

   1. Functional imaging demonstrating somatostatin receptor positive disease within 6 months of planned therapy start date.
   2. Cross sectional imaging showing progression of disease within the prior 6 months.
   3. CBC, electrolytes, urea, creatinine, calcium, magnesium, albumin, total bilirubin, ALT, alkaline phosphatase, GGT, LDH, random glucose, INR and PTT.
   4. A transthoracic echocardiogram within the past year evaluating for valvular heart disease.
   5. An in-person history and physical with their referring provider within 3 months (exclusion possible for remote patients or those from Yukon).
   
   

   After these investigations are in place, please refer the case to the provincial Tuesday morning GI multidisciplinary tumour board for review and approval. After approval by the tumour board, a conference note should be dictated and placed on the chart and approval for funding of the UGIPRRT protocol should be performed through the BC Cancer Compassionate Access Program (CAP) by the referring provider. After these have been approved, the Vancouver PRRT team will arrange an in person consultation and further therapy.

   During PRRT, patients will be reviewed by the treating team in Vancouver, however treating oncologists at other sites are requested to continuing managing long acting somatostatin analogue prescriptions and supportive medications and to facilitate a transfer of care after completion of PRRT. For any questions, please contact Dr. Jonathan Loree (Medical Oncology) or Dr. Don Wilson (Nuclear Medicine).

   Carcinoid heart disease
   

   About 50% of patients with carcinoid syndrome are at risk of developing carcinoid heart disease, which characteristically affects the right side of the heart and can lead to right-sided heart failure and death. Screening for carcinoid heart disease should be performed on a regular basis in these patients, especially if the urinary 5HIAA is >50mg/24 hours. A baseline echocardiogram should be done at diagnosis of carcinoid syndrome, and then yearly. Those patients with any cardiac changes should be followed by a cardiologist. Patients with valvular heart damage should be referred to a cardiac surgeon for consideration of valve replacement. Because the morbidity and mortality of cardiac surgery in carcinoid patients is high when symptoms of right heart failure are advanced, early intervention is favoured. The role of octreotide in suppressing 5HIAA levels to protect against heart damage is controversial, but it seems reasonable to suppress 5HIAA levels as low as possible with adequate doses of octreotide.

   Neuroendocrine Tumours of the Hindgut

   Hindgut NETs are located distal to the watershed in the transverse colon (middle colic artery).

   Epidemiology

   Most are in the rectum and the incidence appears to be increasing. They account for 27% of all GI NETs. Colonic NETs are uncommon and make up about 8% of NETs.

   Clinical presentation

   Rectal NETs: They may cause bleeding per rectum or lower bowel symptoms (tenesmus, rectal discomfort or a change in bowel pattern) or can be found incidentally at endoscopy. Symptoms of carcinoid syndrome are rare.

   Colon NETs: They tend to present late with metastatic disease. Patients have symptoms of fatigue, weight loss and abdominal discomfort or pain. The presumptive diagnosis is often colon adenocarcinoma until confirmed by histology.

   Special Diagnostic Procedures

   1. Biochemistry
      • Chromogranin A is likely to be elevated, but 5HIAA is usually normal. Serum acid phosphatase and HCG levels may be elevated.
   2. Endoscopy
      • A full colonoscopic assessment is required to rule out a concomitant bowel lesion, such as carcinoma. An endorectal ultrasound is recommended to assess the tumour size depth of invasion and pararectal nodal involvement for rectal carcinoids.
   
   

   Management

   1. Surgery
      • Rectal NETs can be cured by surgery if localized. For more advanced disease, the benefits of surgery are unclear. Features which favour poor outcome include tumour size >2cm, high grade, poorly differentiated histology, invasion beyond the muscularis propria, lymphatic or vascular invasion, perineural invasion, and high mitotic index (high Ki67 index).
      • Lesions < 1cm should be completely resected endoscopically or by another transanal technique. Lesions >2cm have a high risk of metastases (about 60-80%). It is unclear if radical surgery will improve patient outcome. Lesions between 1 and 2 cm have a metastatic potential between 10% and 15% and it is not certain whether radical surgery is more beneficial than local surgery. However, tumours with cellular atypia or invasion beyond the muscularis propria should be treated aggressively.
      • Colonic NETs of the hindgut are treated similarly as adenocarcinoma by localized colectomy and resection of the lymph nodes.
   
   

   Medical therapy

   1. Biotherapy
      • Carcinoid syndrome is uncommon in hindgut NETs. In the uncommon case of a functioning hindgut NET, octreotide is indicated.
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   2. Systemic chemotherapy
      • This has limited value for slow-growing NETs, but may be indicated for poorly differentiated, fast-growing tumours (cisplatin-etoposide).

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