Clinical use: Diagnosis and subsequent monitoring of a diverse group of neoplasms that arise from the endocrine and nervous systems. The large number of potential serum tumour markers associated with tumours of this type necessitates a panel of markers being assembled resulting in the screens listed below. Patient symptoms may aid the clinician in selecting the appropriate screen.
Background:

Neuroendocrine Tumours – NETs are a group of tumors that can be a challenge to diagnose. Common features are similar morphology, presence of secretory granules and the production of biogenic amines and polypeptide hormones. Prevalence is 35/ 100,000 of which two-thirds are carcinoid tumours. Certain NETs can produce vague, nonspecific symptoms (such as diarrhea, abdominal pain, flushing, and hypoglycemia) that are easily mistaken for other conditions, such as irritable bowel syndrome and inflammatory bowel disease.

NET 2 can form in multiple locations throughout the body, including difficult-to-pinpoint areas within the midgut. It is not unusual for patients to suffer for years before a NET is correctly diagnosed. The majority of NETs originate in the gastrointestinal tract or pancreas, and are collectively referred to as gastroenteropancreatic NETs (GEP-NETs). There are several different types of GEP tumours (gastroenteropancreatic tumours). They tend to develop in the organs of the digestive system such as the stomach, intestines and the pancreas. NETs that are not gastrointestinal or pancreatic in origin can arise in the respiratory tract, ovaries, and testes, as well as in other endocrine tissue (e.g thymus, adrenal gland).

Also included in the NET classification are some inherited conditions including Multiple Endocrine Neoplasia type 1 (MEN1), MEN2, neurofibromatosis and Von-Hippel-Lindau (VHL) disease.

Multiple Endocrine Neoplasia is a rare genetic condition that is caused by a faulty gene and is usually hereditary, although not always. There are two types – MEN1 and MEN2, they are completely separate conditions with different genetic causes. MEN1 tumours can be non-cancerous (benign) or cancerous (malignant). Almost all people with MEN1 will develop hyperparathyroidism at some stage in their life. There may be tumours in the parathyroid glands, which are usually benign. Tumours can also develop in the digestive system (gastrointestinal tract or GI tract), usually in the stomach, intestines, pituitary and/or adrenal glands and/or pancreas. Rarely, people may develop a particular type of tumour (known as a carcinoid tumour) in the chest, thymus gland (behind the breast bone), or the gastrointestinal tract.

Many people with MEN2 develop medullary cell carcinoma of the thyroid. This is a malignant tumour. Some people who have MEN2 will develop Pheochromocytoma.

Patients with MEN 2A commonly develop hyperplasia of the parathyroid glands. People with MEN 2B develop benign neuromas that appear as swellings on their tongue, lips, eyelids, or lining of their mouths. In familial MTC, people tend to get medullary thyroid cancer only.

Neuroendocrine Tumour Screen (NET2) – This is an appropriate screen for mid gut carcinoids and when the location of the primary tumour is unknown. It is also suitable for primary pancreatic tumours.
Tests will be done in two groups:
Group 1 – Chromogranin A, Neurokinin A, Gastrin and Pancreatic Polypeptide.
Group 2 – Pancreastatin, Somatostatin, Glucagon, Vasoactive Intestinal Peptide and Insulin.
MEN1 Screen (MEN1) – Optimal screen for multiple endocrine neoplasia type 1
Tests will be done in two groups:
Group 1 – Chromogranin A, Gastrin and Pancreatic polypeptide.
Group 2 – Somatostatin, Glucagon, Vasoactive Intestinal peptide and Insulin.
Carcinoid Screen (CARC) – This is an appropriate test for mid-gut and lung carcinoids. Most carcinoid tumours start in the appendix or the small bowel. They may also start in other parts of the digestive system such as the large bowel, or less often, in the stomach, pancreas, bile ducts or gall bladder. NB. Not advised to use this test as an initial carcinoid screen as urinary 5-HIAA still considered the most appropriate first line screening test.
Tests will be done in two groups:
Group 1 – Chromogranin A, Neurokinin A and Pancreatic polypeptide
Group 2 – If the CGA is elevated a Pancreastatin report will follow within 4 weeks.
Endocrine Diarrhoea Screen (EDS) – Measures those peptides that may be the cause of endocrine diarrhoea and includes Vasoactive Intestinal Peptide which increases secretions from the intestines, Neurokinin A which contracts smooth muscle and Pancreatic Polypeptide which affects gastro-intestinal secretions and increases gut motility.
Tests will be done in two groups:
Group 1 – Chromogranin A, Neurokinin A, Gastrin and Pancreatic polypeptide.
Group 2 – Pancreastatin and Vasoactive Intestinal Peptide.

Reference ranges:
PANC (Pancreastatin) 0 – 50 ng/L
CGA (Total Chromogranin A) 0 – 3 nmol/L
NKA (Neurokinin A) 0 – 20 ng/L
INSU (Insulin) 0 – 15 mU/L
VIP (Vasoactive intestinal peptide) 0 – 120 ng/L
GAS (Gastrin) 1 – 100 ng/L
PP (Pancreatic polypeptide) 0 – 200 ng/L
NGLUC (N-Terminal glucagon) 0 – 250 ng/L
CGLUC (C-Terminal glucagon) 0 – 150 ng/L
SOMA (Somatostatin) 0 – 50 ng/L
CALCI (Calcitonin) Male: 0 – 8.4 ng/L
Female: 0 – 5.0 ng/L
Associated diseases:
Patient preparation: For suspected gastrinomas, patient off proton pump inhibitors for 2 weeks, then request Gastrin, Chromogranin A and Pancreatic Polypeptide. H2 receptor antagonists do not affect values.
Specimen requirements:

Plasma – EDTA tube

Fasting sample is required if pancreatic tumour e.g Zollinger – Ellison for suspected gastrinoma.

Samples should be placed on ice or a cool pack and transported immediately to the laboratory for separation.

Number of EDTA tubes required for each screen is as follows:-

  • Neuroendocrine Tumour (NET2): 3 x EDTA tubes (full)
  • Multiple Endocrine Neoplasia (MEN): 2 x EDTA tubes (full)
  • Carcinoid Screen: 2 x EDTA tubes (full)
  • Endocrine Diarrhoea Screen (ED): 2 x EDTA tubes (full)
Turnaround time: Chromogranin A, Neurokinin A, Gastrin and Pancreatic Polypeptide will be reported in 2 weeks from receipt.Pancreastatin, Somatostatin, Glucagon, Vasoactive Intestinal Peptide and Insulin will be reported in 4 weeks from receipt.
Time limit for retrospective requesting: N/A
Additional information: Gastrin Releasing Peptide (GRP), Calcitonin Gene related peptide (CGRP) and Calcitonin (CALCI) no longer included as part of a neuroendocrine screen. These can be done as single tests if specifically requested.
Referred test: Referred Test
Location: SAS Laboratory