Updated 1 November 2005

General Aspects - Introduction

The neuroendocrine tumours (NETs) include gut carcinoids and tumours of the endocrine pancreas. They are uncommon tumours that arise from the diffuse endocrine system (DES) of the gut, which comprises at least 15 specialized epithelial cells of endodermal origin. Gut DES cells and the neoplasms that arise from them express several antigens that they share with neural elements; hence, the designation neuroendocrine tumours. These are uncommon tumours and make up 0.25% of oncologists’ patient load. As treatment continues to improve, a significant proportion of these patients can expect a good intermediate term prognosis. It is important, therefore, that a management plan be in place. Referral to a BC Cancer Agency 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 hypersecreted-related clinical syndrome. They come to attention because of their “mass effect” due to tumour bulk. Metastatic disease is usually 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 behavior 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, >2 mitoses per high power field, Ki67 index >2%, 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 the less well-differentiated tumours.
2. 111In-penetreotide scintigraphy (OctreoScan)
   Penetreotide 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.
3. MIBG scintigraphy
   MIBG (meta-iodobenzylguanidine) is concentrated in NETs and the occasional tumour will take up MIBG and not octroetide. OctreoScan is, however, considered, the superior diagnostic test.

Principles of management

The principal goal of management is 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.

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.

Medical treatment

Systemic treatment for NETs includes therapy with somatostatin analogs, interferon-alfa and cytotoxic agents. In addition, other agents can be useful, including loperamide for diarrhea or H1 or H2 blockers for histamine-secreting tumours.

1. Octreotide is a synthetic analog of the hormone somatostatin which exerts its effects through binding to somatostatin receptors subtype 2 and, to a lesser extent, 3 and 5. Octreotide can control hypersecretion in NETs that express somatostatin receptors. In these tumours, long-term administration of octreotide can control clinical symptoms due to hypersecretion of hormones. In addition, it may have some anti-proliferative effects. Patients who benefit from octreotide include those with functioning NETs of the gut or pancreas. The use of octreotide in nonfunctioning NETs is controversial.
   
   Octreotide is generally well tolerated. Side effects include nausea, abdominal cramps, loose stools and mild steatorrhea. Most of these are dose-dependent and usually subside within the first few weeks of treatment. Impaired glucose tolerance or diabetes mellitus may occur infrequently. Long-term usage results in formation of gallstones in 50% patients and monitoring by 6-monthly ultrasound is recommended. A very rare side effect of octreotide is gastric atony.
   
   Patients should be started on s.c. injections of the IR formulation for 3-7 days to test tolerability. The initial dose may range from 100 to 500 mcg s.c. two to four times daily. The usual starting dose is 150 mcg s.c. three times daily. Patients can be switched to the more convenient LAR formulation. The usual dose is 20 mg every 28 days. However, this can be increased by increments of 10 mg up to 60 mg every four weeks, as necessary, to control symptoms.
2. Interferon-alfa may be considered in selected cases to control clinical symptoms of hormone hyper-secretion. Symptomatic and biochemical responses are reported in 50% of patients with tumour reduction in 10-15%. Side effects include flu-like symptoms and autoimmune phenomena (e.g. thyroiditis).
3. Chemotherapy has a limited role in the management of NETs. Pancreatic NETs appear to be more chemoresponsive than carcinoids. The usual drugs are streptozotocin with 5FU or doxorubicin. Patients with indolent NETs may be offered a trial of BCNU-5FU infusional therapy. Patients with poorly differentiated NETs should be treated with cisplatin-etoposide.
4. Somatostatin receptor radionuclide therapy
   
   Many NETs express somatostatin receptors, especially subtype 2, and patients with metastatic disease whose tumours are receptor-positive, as proven by an OctreoScan, are candidates for radionuclide therapy. Stabilization of disease and symptom improvement can be achieved by this therapy. Referral to the BC Cancer Agency is advised for assessment and approval of this procedure which is done at the Cross Cancer Institute in Edmonton, Alberta.

Specific 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 Tumors

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), somatostain-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

Management

1. Surgery
   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)
2. Systemic therapy
   Biotherapy
   1. Octreotide may induce regression of Type 1 and 2 tumours associated with atrophic gastritis or ZES/MEN-1, but is not recommended.
   2. Experience with interferon is limited.
   3. Chemotherapy
      This is indicated for metastatic tumours, mainly Type 3 or poorly differentiated tumours. The standard protocol is the combination of streptozotocin plus 5FU or doxorubicin. For poorly differentiated tumours, cisplatin-etoposide may be useful.
      For gastrin-producing tumours, proton pump inhibitors should be used to control acid-related symptoms.

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

Management

1. Surgery
   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.
2. Systemic
   1. Biotherapy
      Octreotide can be used for patients with symptoms due to hormone hypersecretion
   2. Interferon can be used for metastatic disease, but experience is limited
   3. Chemotherapy should be used only for metastatic disease. Streptozotocin with 5FU or doxorubicin is indicated for tumours with low or moderate proliferation, while cisplatin-etoposide is indicated for poorly differentiated tumours.

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

Pancreatic Neuroendocrine Tumours

Pancreatic NETs are uncommon with an annual incidence of 0.4-1.2 per 100,000 population. The tumours can occur at any age and both sexes are affected equally. About 15-30% of patients have MEN-1.

Clinically, they can be divided into functioning tumours, associated with hormonal symptoms, or nonfunctioning. The distribution of the subtypes is as follows:

1. Nonfunctioning tumours 50%
2. Functioning tumours 50%
   1. Insulinomas (25%)
   2. Gastrinomas (15%)
3. VIPomas
4. Somatostatinomas
5. Glucagonomas

Patients may present with mixed syndromes or the tumours may change clinically over time.

Diagnostic Procedures

1. Tumour Imaging
   Ultrasound, EUS, CT and octreotide scintigraphy. For surgical candidates, MR-angiography is useful.
2. Biochemistry
   Chromogranin A is the most useful tumour marker and is increased in most pancreatic NETs. Specific markers can be assayed for individual tumour types: gastrin, insulin, VIP, glucagons, calcitonin and somatostatin.

Management

1. Surgery
   Surgery is the only curative modality. The indications for surgery depend on the size and location of the primary. Surgical procedures include a pancreaticoduodenectomy (Whipple’s resection), distal pancreatectomy, tumour enucleation and enucleation in combination with resection. For malignant NETs, a regional lymph node dissection is required.
   
   There is a general consensus that surgery should be considered in patients with “limited” metastatic disease. Patients with liver metastases from either functioning or nonfunctioning tumours may benefit from surgery if >90% of the tumour mass can be removed. This can delay the progression of the disease.
   
   Because hormonal release can occur during manipulation of the tumour during surgery, a crisis is possible. An anesthesiological consultation is recommended preoperatively, and perioperative octreotide infusion is indicated. If possible, a cholecystectomy should also be done at the same time to prevent gallstone formation due to any subsequent therapy with octreotide.
2. Cytoreductive therapy
   Cytoreductive therapy by selective embolization of peripheral arteries can reduce hormonal symptoms due to liver metastases. At chemoembolization, cytotoxic drugs (doxorubicicn, 5FU or mitomycin C) are injected intra-arterially with embolization material, but it is not clear if this is better than bland embolization.
   
   Radiofrequency ablation (RFA) can be used to reduce hepatic tumour masses and, thus, reduce hormonal symptoms.
3. Medical Therapy
   Biotherapy
   
   1. Octreotide
      Octreotide is the primary treatment for patients with functioning pancreatic NET. About 80-90% of patients experience prompt improvement of their symptoms. Caution should be taken with the use of octreotide in patients with insulinomas, since concomitant suppression of GH and glucagon can lead to a worsening of hyperglycemia. A significant tumour regression may be observed in <10% of patients, but stabilization of tumour growth may occur in 30-50% of patients. After a period of control, some patients may experience recurrence of their symptoms. The dose of octreotide should be increased or the interval between treatments reduced. The treatment schedule is described in Part 1.
   2. Interferon
      Interferon can reduce circulating hormones in 30-60% of patients and result in an improvement of symptoms. Partial tumour regression may be observed in 10-15% of patients, and in 40-60% there may be stabilization of the disease. Side effects include fatigue, clinical depression, and auto-immune conditions (thyroiditis, SLE, myositis, vasculitis). Myelosuppression and elevation of liver enzymes can occur and must be monitored.
   3. Systemic chemotherapy
      Systemic chemotherapy with streptozotocin in combination with 5FU or doxorubicin can produce biochemical responses in >50% of patients and partial tumour regression is observed in 20-35%. For elderly patients with slowly progressive disease, an alternative regimen is BCNU with infusional 5FU. Responses are seen in all types of endocrine pancreatic tumours. Poorly differentiated neuroendocrine tumours with a high proliferative index (Ki67 >15-20%) are treated with cisplatin-etoposide. The response rate is 55-80% with median survival of 8-11 months.
   4. Somatostatin receptor radionuclide therapy
      Patients with metastatic NETs whose tumours are receptor-positive, as proven by an OctreoScan, are candidates for radionuclide therapy.

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 appenditis by blocking the lumen.

Functioning NETs can give rise ot carcinoid syndrome (flushing, diarrhea, intermittent brochospasm 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 meso-appendiceal 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 NETs. For fast-growing tumours, cisplatin plus etoposide may be effective.
3. Somatatostatin receptor radionuclide therapy

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 favored. 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 favor 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.
2. Systemic chemotherapy
   This has limited value for slow-growing NETs, but may be indicated for poorly differentiated, fast-growing tumours (cisplatin-etopside).

References

1. Crocetti E, Paci E. Malignant carcinoids in the USA, SEER 1992-1999. Anepidemiological study with 6830 cases. Eur J Cancer Prev 2003;12(3):191-4.
2. Fjallskog ML, Granberg DP, Welin SL, Eriksson C, Öberg KE, Janson ET, Eriksson BK. Treatment with cisplatin and etoposide in patients with neuroendocrine tumours. Cancer 2001;92(5):1101-7.
3. Florman S, Toure B, Kim L, Gondolesi G, Roayaie S, Krieger N, Fishbein T, Emre S, Miller C, Schwartz M. Liver transplantation for neuroendocrine tumours. J Gastrointest Surg 2004;8(2):208-12.
4. Kaltsas G, Rockall A, Papadogias D, Reznek R, Grossman AB. Recent advances in radiological and radionuclide imaging and therapy of neuroendocrine tumours. Eur J Endocrinol 2004;151(1):15-27.
5. Kaltsas G, Korbonits M, Heintz E, Mukherjee JJ, Jenkins PJ, Chew SL, Reznek R, Monson JP, Besser GM, Foley R, Britton KE, Grossman AB. Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumours. J Clin Endocrinol Metab 2001;86(2):895-902
6. Modlin IM, Lye KD, Kidd M. A 5-Decade Analysis of 13,715 Carcinoid Tumours. Cancer 2003;97:934-59.
7. Modlin IM, Lye KD, Kidd M. A 50-year analysis of 562 gastric carcinoids: small tumour or larger problem? Am J Gastroenterol 2004;99(1):23-32.
8. Moertel CG, Kvols LK, O'Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68(2):227-32.
9. Moller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors associated with progression of carcinoid heart disease. N Engl J Med 2003;348(11):1005
10. Di Luzio S, Rigolin VH. Carcinoid Heart Disease. Curr Treat Options Cardiovasc Med 2000;2(5):399-406.
11. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Neuroendocrine Tumours – v.1.2005. (accessed at http://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf
12. Nehar D, Lombard-Bohas C, Olivieri S, Claustrat B, Chayvialle JA, Penes MC, Sassolas G, Borson-Chazot F. Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours. Clin Endocrinol 2004;60(5):644-52.
13. Öberg K, Astrup L, Eriksson B, Falkmer SE, Falkmer UG, Gustafsen J, Haglund C, Knigge U, Vatn MH, Valimaki M; Nordic NE Tumour Group. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I – general overview. Acta Oncol 2004;43(7):617-25.
14. Öberg K. Interferon in the management of neuroendocrine GEP-tumours: a review. Digestion 2000;62 Suppl 1:92-7.
15. Öberg K, Astrup L, Eriksson B, Falkmer SE, Falkmer UG, Gustafsen J, Haglund C, Knigge U, Vatn MH, Valimaki M; Nordic NE Tumour Group. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including 15 bronchopulmonary and thymic neoplasms). Part II – specific NE tumour types. Acta Oncol 2004;43(7):626-36
16. Öberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering AE, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumours of the gastroenteropancreatic system. Ann Oncol 2004;15:966-973.
17. Öberg K, Eriksson B. Nuclear medicine in the detection, staging and treatment of gastrointestinal carcinoid tumours. Best Pract Res Clin Endocrinol Metab 2005;19(2):265-76.
18. Plöckinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, de Herder WW, Goede A, Caplin M, Wiedenmann B, Öberg K, Reubi JC, Nilsson O, Delle Fave G, Ruszniewski P, Ahlman H. Guidelines for the Diagnosis and Treatment of Neuroendocrine Gastrointestinal Tumours. Neuroendocrinology 2004;80:394-424.
19. Plöckinger U, Wiedenmann B. Diagnosis of Non-Functioning Neuro-Endocrine Gastro-Enteropancreatic Tumours. Neuroendocrinology 2004;80 (Suppl. 1):35-38.
20. Que FG, Sarmiento JM, Nagorney DM, et al. Hepatic surgery for metastatic gastrointestinal neuroendocrine tumours. Cancer Control 2002;9(1):67-79. Sutcliffe R, Maguire D, Ramage J, Rela M, Heaton N. Management of neuroendocrine liver metastases. Am J Surg 2004;187(1):39-46.
21. Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, Hawkins R, McNicol AM, Reed N, Sutton R, Thakker R, Aylwin S, Breen D, Britton K, Buchanan K, Corrie P, Gillams A, Lewington V, McCance D, Meeran K, Watkinson A on behalf of UKNETwork for Neuroendocrine Tumours. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005;54 Suppl 4:iv1-16.
22. Roche A, Girish BV, de Baere T, Baudin E, Boige V, Elias D, Lasser P, Schlumberger M, Ducreux M. Trans-catheter arterial chemoembolization as first-line treatment for hepatic metastases from endocrine tumours. Eur Radiol 2003;13(1):136-40.
23. Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003;197(1):29-37.
24. Sokmensuer C, Gedikoglu G, Uzunalimoglu B. Importance of proliferation markers in gastrointestinal carcinoid tumours: a clinicopathologic study. Hepatogastroenterology 2001;48(39):720-3.
25. van der Horst-Schrivers AN, Wymenga AN, Links TP, Willemse PH, Kema IP, de Vries EG. Complications of midgut carcinoid tumours and carcinoid syndrome. Neuroendocrinology 2004;80 Suppl 1:28-32.