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Revised 15 July 2013
Staging Diagram & TNM Classification
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.
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.
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.
Radiologic studies and nuclear imaging play an important role in the diagnosis and management of patients with NETs.
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 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.
This site is under construction. If you are concerned about care for a specific patient, please contact the oncologist at your local centre.
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), somatostain-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.
Special Diagnostic Procedures
This site is under construction. If you are concerned about care for a specific patient, please contact the oncologist at your local centre.
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.
For gastrin-producing tumours, proton pump inhibitors should be used to control acid-related symptoms.
See next section for Pancreatic Neuroendocrine Tumours.
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 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.
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.
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.
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.
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Added 15 July 2013
Pancreatic NETs are uncommon with an annual incidence of 0.4-1.2 per 100,000 population. The endocrine cells give rise to pNETs which account for less than 4% of pancreatic neoplasms. The tumours can occur at any age and both sexes are affected equally.
pNETs can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1; von Recklinghausen disease) and tuberous sclerosis complex (TSC) with the most common association , up to 80%, in MEN1 patients.
Current terminology divides pNETs into:
Diagnostic and Staging Work-Up
CT scan of the chest and abdomen/pelvis is recommended to assess the extent of local involvement and to exclude distant metastases. A pancreas-protocol CT scan or MRI is indicated if the patient is thought to be an operative candidate. If a mass is not clearly identified or if there is uncertainty regarding vascular involvement, an EUS should be performed.
If there appears to be an isolated pancreatic lesion, refer to a hepatobilliary surgeon who will determine if the disease is resectable or unresectable. A biopsy is not always required but may be performed if clinically indicated.
If there are obvious metastases, then the pancreatic mass or metastases can be biopsied percutaneously with ultrasound CT guidance or by endoscopic with fine needle aspiration. In patients who have carcinoid syndrome, a potential carcinoid crisis should be prevented by prophylactic administration of octreotide, given by constant intravenous infusion at a dose of 50 mcg/h for 12 hours prior to and at least 48 hours after the procedure.
PNETs should be staged using 111In-pentetreotide scintigraphy (octreotide scan). Those with negative octreotide scans can be imaged with MIBG scintigraphy.
All patients with PNETs should have 24-hour urinary 5-HIAA and chromogranin A (CgA) measured at diagnosis.
Patients presenting with jaundice and cholangitis should receive antibiotics and undergo biliary decompression, usually by ERCP.
Patients with jaundice only who are potentially operative candidates do not require stenting unless operative intervention will be delayed by > 1-2 weeks.
Patients without jaundice do not require stenting.
Primary Surgical Therapy
Surgical treatment of pancreatic cancer should be undertaken by surgeons having expertise and experience with these tumours.
For resectable pNETs: definitive resection of the primary tumour should always be performed whenever technically feasible. In patients who have carcinoid syndrome, a potential carcinoid crisis should be prevented by prophylactic administration of octreotide, given by constant intravenous infusion at a dose of 50 mcg/h for 12 hours prior to and at least 48 hours after the procedure.
Prophylactic cholecystectomy should be considered during any surgery for neuroendocrine tumours.
For localized, locoregional, or resectable metastatic pNETs, curative surgery should be considered if technically and clinically feasible.
For unresectable metastatic pNETs, cytoreductive surgery to achieve maximal debulking and palliation of symptoms should be considered if technically feasible and clinically appropriate.
Pathology (per College of American Pathologists 2012)
In addition for pNETs:
Treatment options are based on current evidence
Surgery is the only curative treatment. Indications for surgery depend upon the size and location of the pNET. Surgical procedures include:
Patients with “limited” metastatic disease should be considered for surgery.
Patients with liver metastases from either functioning or non-functioning tumours where greater than 90% of the tumour mass can be removed may have a delay in disease progression.
Carcinoid crisis: hormonal release can occur with manipulation of the tumour(s) during surgery. A pre-operative anesthesia consultation is recommended and a peri-operative octreotide infusion is indicated.
Cholecystectomy should be done at the same time as any surgery to prevent complications from gallstone formation from any subsequent therapy with octreotide.
May be considered in symptomatic patients - selective embolization of hepatic arteries can reduce hormonal symptoms due to liver metastases.
Transarterial chemoembolization (TACE) involves injection of cytotoxic drugs (doxorubicin, 5FU or mitomycin C) intra-arterially with embolization material. This requires an assessment by a multidisciplinary team comprised of gastroenterologists, surgeons, radiologists and oncologists.
Transarterial radioembolization (TARE) is available at Vancouver General Hospital (VGH) and requires an assessment by the multidisciplinary team at VGH Liver Rounds. It involves injection of Yttrium-90 glass microspheres (see protocol UGIYTT).
Radiofrequency ablation (RFA) can be used to treat hepatic tumour masses of approximately 3 cm or less and, thus, reduce hormonal symptoms.
Octreotide is the primary treatment for patients with symptomatic functioning pancreatic NET. About 80-90% of patients experience prompt improvement of their symptoms (see protocol UGIOCTLAR).
Chemotherapy with streptozocin and doxorubicin can reduce hormonal symptoms and slow progression of PNETs (see protocol GIENDO2).
Poorly-differentiated neuroendocrine tumours with a high proliferation index (Ki67 index greater than 20%) are treated with cisplatin and etoposide (see protocol GIPE).
Targeted agents have recently shown activity in the treatment of PNETs. Patients may be treated with one of the following:
The choice and sequence of systemic therapy is determined by disease-related factors, patient factors and patient preferences as assessed by the medical oncologist.
Consider treatment on a clinical trial, if available
Symptom management (including celiac or intrapleural block for tumour-related pain), best supportive care, and involvement of palliative care services as indicated by patient’s clinical status.
Somatostatin Receptor Radionuclide Therapy
Patients with progressive and/or symptomatic metastatic NETs whose tumours are receptor-positive as proven by an OctreoScan or MIBG scan, and have a ki67 less than or equal to 20% may be candidates for referral to a specialized centre for consideration of radionuclide therapy.
Low-risk Resected Disease
High-risk Resected Disease
Any of the following: primary greater than 2 cm, nodal involvement, high Ki67 (≥5%)
5-HIAA (if functional)
every 3 – 6 months
every 6 months
Octreotide or MIBG scan
if any of the above are abnormal
Post-debulking with no visible residual disease
Years 2 - 3
5-HIAA (if functional)
every 3 – 6 months
if any of the above are abnormal
Unresected disease (metastatic or residual-positive post-debulking)
every 4 – 6 months
every 3 months
every 4 - 6 months
annually if 5-HIAA is over 70 mg/24 hours
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