Neuroendocrine tumours or NETs are epithelial neoplasms with predominant neuroendocrine differentiation and can arise in most organs of the body. In the literature several different nomenclature systems are used and this can be confusing. The term “carcinoid tumour” is currently included in the WHO classification of NETs of the lung and thymus but is also commonly used as a synonym for NETs at other sites. For clarity the term carcinoid is avoided in this document.
Morbidity and mortality in MEN type 1r
In patients with MEN type 1 life expectancy is shortened by 10–20 years. Historically gastric bleeding from hypergastrinaemic peptic ulcer disease (Zollinger Ellison syndrome) was the biggest cause of mortality. Medical treatment (including proton pump inhibitors and somatostatin analogues) for hypergastrinaemia means mortality is now most commonly due to malignant GDP-NET or malignant thymic NET.
Age for predictive genetic testing and commencement of tumour screeningrrr
MEN type 1 predominantly presents clinically after the age of 21 years and the penetrance of disease is nearly 100% by age 50 years. It is uncommon for children under the age of 10 years to present with clinically significant MEN type 1-related problems.
Predictive genetic testing of children is recommended at age 10 years. Genetic testing of younger children may be appropriate in individual families, or if a child has symptoms or features of a MEN type 1-related disorder.
There is no international consensus on the age to begin tumour screening in MEN type 1. Published penetrance figures are an overestimate of risk as most published data have not excluded probands from the penetrance calculations. The recommendations in this protocol for second yearly radiological screening are a compromise between the risk of missing a clinically important tumour (more likely with less frequent screening) and the economic and psychological burden of annual screening. A recent international consensus statement proposed delaying genetic testing and/or screening until age 16 years and to consider extending surveillance follow up if no clinically relevant organ manifestations are detected at initial screening as rapid progression of organ manifestations is rarely observed.r
Primary hyperparathyroidism (PHPT)rr
PHPT due to parathyroid hyperplasia and/or adenoma is the most common endocrine manifestation of MEN type 1. It occurs predominantly in the third decade of life, reaching 100% penetrance by age 50 years. Multifocal disease is common with recurrent PHPT occurring in up to 50% at age 12 years.
Gastroduodenopancreatic NET (GDP-NET)rrrr
GDP-NETs are common (30–70% of patients with MEN type 1), are frequently multifocal and are the most common cause of mortality in MEN type 1. They predominantly occur after age 30 years. Small, non-functional pancreatic NETs commonly behave in an indolent fashion and monitoring prior to consideration of resection can be considered for lesions under 2 cm.
MEN type 1-associated GDP-NET typically arise in the pancreas or duodenum, but are also seen in the stomach. Jejunal, ileal and appendiceal NET are not associated with MEN type 1.
The accurate diagnosis and management of GDP-NET presents significant challenges. In adults, the most common GDP-NETs are non-secretory (hence biochemical markers are insensitive for surveillance and monitoring) followed by gastrinoma and insulinoma.
Insulinoma is the most frequent GDP-NET identified in children.
The diagnostic accuracy of general neuroendocrine markers (CgA, pancreatic polypeptide, and glucagon) for the detection of GDP-NET is low, especially for non-functioning GDP-NET, and thus the annual use of these hormones for the diagnosis of MEN type 1 is not recommended.
A recent systematic review of the diagnostic accuracy of radiological approaches for surveillance of non-functioning pancreatic NETS concluded that MRI is preferred. CT has reduced sensitivity plus greater radiation exposure, and EUS is comparatively more invasive, operator dependent with variable sensitivity throughout the pancreas. There is no consensus regarding the frequency, ranging from annually to 5-yearly depending on the clinical situation.
In MEN type 1 the mean age at diagnosis of pituitary adenomas is 38 years (±15.3 years). MEN type 1-associated pituitary tumours are more likely to be macroadenomas, be locally invasive/recurrent and be less responsive to medical or surgical treatment.
The aggressive behaviour of MEN type 1-associated pituitary tumours was the reason for some experts recommending screening at age 5 years. However, pituitary adenomas requiring intervention under age 10 years are rare and MRI in a 5 year old may require general anaesthesia. This expert group believes that screening at age 10 years represents an acceptable balance between these two factors.
Although rare, MEN type 1-associated thymic NETs comprise the second most common MEN type 1-related cause of death and have a high mortality rate. There is a strong degree of heritability (risk is higher in kindreds with a history of thymic NET) with heavy smoking and male sex being potential risk factors.
Thymic NETs in MEN type 1 are primarily non-functional thus life-long radiological screening is required. MRI is preferred to CT to minimise radiation exposure. Radiological screening every 2 years has been recommended by some experts, but it is not clear whether this is sufficient to confer survival benefit. Risk-reducing transcervical thymectomy is typically performed at the time of parathyroidectomy for PHPT. This does not eliminate the risk of development of a recurrent thymic NET due to residual thymic tissue.
The incidence of asymptomatic adrenocortical tumours is approximately 40%. Most tumours are benign and non-functioning (90%), and will not be detected by biochemical screening. The 10% of tumours that display hormonal hypersecretion most commonly cause primary hyperaldosteronism or ACTH-independent Cushing’s syndrome. The overall incidence of adrenocortical carcinoma is low (1%).
There is no consensus for optimal radiological screening with one expert group recommending annual imaging (to coincide with pancreatic imaging), and another 1-5 yearly imaging depending on the clinical situation.
MEN type 1-associated bronchopulmonary NETs are seen in up to 23%. Some studies report they are more common in females (reported ratios range from 1:1 to 4:1 for female:male). Although most behave indolently, they have the potential for local mass effect, metastasis, and recurrence after resection.
There is no consensus for optimal radiological screening with one expert group recommending 1–2 yearly imaging, and another consideration of annual imaging.
When they occur, the majority of meningiomas are asymptomatic and most do not require surgical management. There is no evidence for benefit of radiological surveillance for meningioma, however, a number are likely to be documented incidentally at the time of pituitary imaging.