Refer Quickly to Specialist Neuroendocrine Centres if Suspected NET 

Becky McCall


September 28, 2020

Refer a patient with a neuroendocrine tumour (NET) to a multidisciplinary team of specialists - don't sit on it and try your best, says UK expert in NETs.

Speaking at the Royal Society of Medicine, Endocrinology and Diabetes section webinar series, entitled, EDN50: What's new in endocrinology and diabetes 2020? Dr John Ayuk, consultant endocrinologist, University Hospitals Birmingham NHS Foundation Trust, discussed what's new in NETs and stressed the need to draw on expertise in specialist centres.

"When you get a patient with this type of tumour, don't just sit on it and try to do your best," said Dr Ayuk. "You need to refer the patient to one of the specialist neuroendocrine tumour centres with multi-disciplinary teams comprised of these different specialties." 

NETs, sometimes referred to as carcinoid tumours, are rare and develop from hormone-secreting cells, and can cause characteristic syndromes. Only 2% of malignant gastrointestinal (GI) tumours are NETs (incidence is 5-6 per 100,000/yr). They are generally slowly progressive but show variable biological behaviour and are frequently metastatic at the time of diagnosis. However, often patients still have prolonged survival. NETS typically invade the lymph nodes and cause distant metastases.

Most NETs are gastroenteropancreatic (GEP) (70%) and Dr Ayuk focussed on these in his talk.  Around 35% are functioning tumours, and 65% non-functioning. Of the functioning tumours, 55% produce carcinoid-type symptoms, and the remaining 45% are pancreatic/duodenal tumours (VIPomas, insulinomas, glucagonomas and gastrinomas).

"Because of the nature of these tumours, they involve many different systems," he said, explaining that, "Although they are found in the gastrointestinal system, these tumours secrete hormones systemically and therefore require the involvement of an endocrinologist. The NET can lead to carcinoid heart disease so a cardiologist is needed, perhaps a liver surgeon or hepatologist due to liver metastases, and so on."

Increasingly, more and more patients are being managed in specialist centres after a big push by UKI NETS (UK and Ireland Neuroendocrine Tumour Society), so things have changed in recent years, he pointed out. There are around 10 ENETS (European Neuroendocrine Tumour Society) Centres of Excellence in the UK with a further 10 or so centres with multi-disciplinary teams (MDTs) that can manage NETs.

Carcinoid Syndrome: Masquerades as Heart Failure

A patient with a NET usually has their levels of 5-HIAA (5-hydroxyindoleacetic acid, a breakdown product of serotonin that is secreted by some NETs) tested. This gives an indication of elevated serotonin levels, which can lead to carcinoid syndrome and potential damage to the heart valves. As the level of 5-HIAA increases then the prognosis worsens, said Dr Ayuk. Development of carcinoid syndrome is associated with reduced survival, with a 5-year survival 30-67%. 

Carcinoid syndrome is usually caused by NET tumours in the small bowel and usually manifests in the presence of liver metastases, but this is not always the case. 

Patients with carcinoid heart disease usually present with symptoms typical of heart failure, such as breathlessness, or oedema in the limbs, explained Dr Ayuk. "When someone with an unknown NET presents in this way then it is often too late. Without prior knowledge of a NET, an emergency doctor would easily start appropriate treatment for heart failure under any circumstances. However, because this does not address the underlying factor, the symptoms will continue being a problem, and a window of opportunity might be missed." 

Dr Ayuk's centre in Birmingham has an effective way of managing such patients, but he relates that in some cases patients deteriorate very quickly, even while they were being treated and monitored.  

"In the scheme of things, when a patient presents with heart failure, carcinoid heart disease will be low down on the list. But patients who have carcinoid heart disease usually have quite advanced NET with extensive metastases. We usually know they have the NET before the carcinoid heart disease develops."

Most NETS Diagnosed When Metastasised

Generally, GEP-NETS are slowly progressive, but importantly show variable biological behaviour. They are frequently metastatic at time of diagnosis but often still have prolonged survival.  "By the time we detect the disease, patients usually have metastases, but it is not the end of the story because many have prolonged survival. Patients are very relieved to hear this."

Early on in the development of the disease, many patients will present with vague abdominal symptoms but no red flag symptoms like weight loss or blood in the stool. If blood tests are fine, then a GP might conclude it is irritable bowel syndrome, said Dr Ayuk. "Because NETs are so indolent, the patient might present with non-specific abdominal symptoms for 10 years. If they repeatedly present then do think beyond irritable bowel and get a urine sample to test for 5-HIAA. This can be done either at the local surgery or the local gastroenterology centre. By the time that it manifests with additional symptoms then the patient might generally have metastatic disease." 

Like most endocrine tumours, histology alone is insufficient in judging the malignant potential of GEP-NET tumours, he said. "We look at invasion into the lymph nodes and distant metastases."

With respect to survival, if a patient's NET is identified with primary disease it can be treated with surgery and survival rate is good overall. "Once a patient presents with metastatic disease this survival drops significantly," he said. For example, Dr Ayuk presented data showing that around 64% of patients reach 5-year survival with a stomach NET, with regional involvement this drops to just under 40%, and with distant metastases to around 10%.

Once the patient develops carcinoid heart disease then survival drops significantly (3-year survival rate 31% - in conjunction with NYHA class III or IV symptoms median survival 11 months). The heart shows evidence of fibrotic plaque formation, and predictors of carcinoid heart disease include peak 5HIAA concentration and cytotoxic chemotherapy. Biomarkers are NT-proBNP, 5HIAA, Chromogranin (Cg), and management involves pharmacotherapy, nutrition, and valve replacement surgery.

Somatostatin analogues are the mainstay of treatment because somatostatin receptors are expressed on 75-90% of NETs and these agents can be highly effective in relieving symptoms due to hormone excess (70%) and slowing tumour growth.

Dr Ayuk drew attention to results of a phase 3 Trial of 177Lu-Dotatate for midgut NETs in the NETTER study. 177Lu-Dotatate, which has radioactive molecules attached to the octreotide agent, showed improved outcomes compared to octreotide LAR 60 mg with an objective response rate of 18% versus 3% respectively, and complete and partial response in 18 versus 3 patients. "It's an injection that's attracted to wherever the tumour cells are and it irradiates them." 177Lu-Dotatate is recognised by the National Institute for Health and Care Excellence.

COI: Dr Ayuk has declared no conflicts of interest.

Presented at the Royal Society of Medicine, Endocrinology and Diabetes section webinar series, entitled, EDN50: What's new in endocrinology and diabetes 2020? September 21, 2020


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