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.
Mortality in MEN type 1
Life expectancy of patients with MEN1 is shortened by 10–20 years.
Historically gastric bleeding from hypergastrinemic 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 GEP-NET or malignant thymic NET.
Patients should be aware that lifestyle measures, including smoking cessation, alone will NOT be sufficient to abrogate the increased risks from MEN type 1 (see evidence about thymic NET below).
Age for predictive genetic testing and commencement of tumour screeningrrr
It is uncommon for children under the age of 10 years to present with clinically significant MEN1 related problems. Mild-to-moderate primary hyperparathyroidism often emerges during adolescence and pituitary disease can occur in this age group. Both functioning and nonfunctioning GEP-NET can be observed in the teenage years and early 20s.r
Predictive genetic testing of children is recommended at 10–12 years of age. 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. Published penetrance figures are an over-estimate 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.
Gastroenteropancreatic NET (GEP-NET)
GEP-NETs are common (30–80% of patients with MEN type 1), are frequently multifocal and are the most common cause of mortality in MEN type 1. MEN type 1 associated GEP-NET typically arise in the pancreas or duodenum, but are also seen in the small intestine and stomach. In MEN type 1, GEP-NET have a greater risk of invasiveness and poor response to therapy compared to sporadic tumours. However, the likelihood of malignant transformation in any one lesion is difficult to predict.
Although the majority of GEP-NET occur over the age of 30, at least 10% of mutation carriers develop one or more GEP-NET in their later teens.r In a small cohort of younger patients GEP-NET penetrance was 40–50% by the age of 20 years, but this data has ascertainment bias.r
The accurate diagnosis and management of GEP-NET presents significant challenges. The most common GEP-NETs are non-secretory (hence biochemical markers are insensitive for surveillance and monitoring).
There is no consensus for optimal biochemical screening. Most expert groups recommend annual biochemical evaluation of a fasting gastrointestinal tract hormone profile, but there are differences in the recommendations about which hormones to measure and the age to begin.rr
There is no consensus for optimal radiological screening. One group of international experts, which included representation from a range of different specialties, suggests a minimum imaging protocol that includes annual imaging of the pancreas and duodenum by MRI, CT or endoscopic ultrasound.r Another expert group recommends 1–5 yearly imaging depending on the clinical situation.r
MRI, CT or endoscopic ultrasound can be used for screening; as life-long screening is required MRI is preferred to CT to minimise radiation exposure.
Thymic tumours are rare (2–8%) but mortality is high. The median survival after the diagnosis is approximately 9.5 years, with 70% of patients dying as a direct result of the thymic tumour.r
In European populations MEN type 1 associated thymic NET occur predominantly in men (20:1 male to female ratio), in the 5th decade, and almost all in smokers/ex-smokers. A recent Japanese study reported a less marked 2:1 male to female ratio.
Thymic NET are not hormonally secreting therefore imaging is critical for screening. As life-long screening is required MRI is preferred to CT to minimise radiation exposure. Radiological screening every 2 years is recommendedrr but it is not clear whether this is sufficient to confer survival benefit if a tumour is detected, while the low prevalence means a high number to screen per detected tumour.
The role of prophylactic thymectomy is controversial. It does not completely eliminate the risk of thymic NET, presumably because of residual intrathoracic thymic tissue, so post-surgical surveillance is required. In the Dutch MEN1 study (which included >90% of the Dutch MEN type 1 population) approximately 30% (n=97) had prophylactic thymectomy at the time of parathyroidectomy. None of these patients developed a thymic carcinoma after a median follow up of 8 years, compared to 3.4% of the total MEN type 1 population (male and female), and 10.1% of males without thymectomy.r Based on this experience it seems reasonable to consider cervical thymectomy at the time of therapeutic parathyroidectomy, particularly in male smokers. Some experts recommend thymectomy where there is a family history of aggressive thymic NET but efficacy in this setting is unproven.
In MEN type 1 the mean age at diagnosis of pituitary adenomas is 38.0 years (±15.3 years). MEN type 1-associated tumours are more aggressive and less responsive to medical or surgical treatment than sporadic tumours.
Some experts recommend MRI screening every 3 years from the age of five years.rr However, pituitary adenomas requiring intervention under the age of 10 years are rare and the youngest individual in the largest published cohort of MEN1-associated pituitary adenomas was 12 years at the time of diagnosis. MRI in a 5 year old may require general anaesthesia. This expert group believes beginning screening at 10 years represents an acceptable balance between the potential benefit of identifying a pituitary adenoma under 10 years of age, and an adverse event related to general anaesthesia in a child under 10 years of age (both of which are unlikely events).
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.r The overall incidence of adrenocortical carcinoma is low (1%) but increases to approximately 13% in MEN1 patients with adrenal tumours larger than 1 cm.r
There is no consensus for optimal radiological screening with one expert group recommending annual imaging (to coincide with pancreatic imaging)r, and another 1-5 yearly imaging depending on the clinical situation.r
MEN type 1 associated bronchopulmonary NETs are seen in up to 13%.r 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 imagingr, and another consideration of annual imaging.r
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.