Provincial Health Services Authority (PHSA) improves the health of British Columbians by seeking province-wide solutions to specialized health care needs in collaboration with BC health authorities and other partners.
Revised 27 November 2018
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.
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.
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.
Radiologic studies and nuclear imaging play an important role in the diagnosis and management of patients with NETs.
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.
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 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.
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 functionalUGIOCTLAR or UGILAN
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.
The foregut NETs include tumours arising in the stomach, duodenum, pancreas as well as in the lung and thymus.
The incidence of stomach NETs is 0.2 per 100,000 population.
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:
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.
This is a potentially curative modality.
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%.
The majority is well-differentiated and composed of gastrin-producing (G) cells, somatostatin-producing (D) or serotonin-producing (EC) cells.
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.
For gastrin-producing tumours, proton pump inhibitors should be used to control acid-related symptoms.
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.
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.
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.
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:
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).
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.
Hindgut NETs are located distal to the watershed in the transverse colon (middle colic artery).
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.
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.
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
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.
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