Overview

We all know that Neuroendocrine Tumours (NETs) and their syndromes are complex but there is even more complexity to be found in a group of related disorders known as Multiple Endocrine Neoplasia (MEN).  I recommend all NET patients should try to understand the basics of MEN and vice versa, particularly as both conditions seem to come with a plethora of endocrine-related effects.

MEN patients will normally have a tumour in at least two endocrine glands – thus the terms ‘Multiple’ and ‘Endocrine’ (tumours can also develop in other organs and tissues).  Neoplasia is just another name for tumours.

MEN syndromes can comprise varying combinations of tumours and many will be aware of the tumour risks from family knowledge.  So putting the heredity aspects to one side, it’s potentially an extremely challenging surveillance and subsequent diagnostic scenario if (and when) these risks are realised.  To add to the complexity, some of the associated tumours can be sporadic (non-hereditary) classic Neuroendocrine Tumours in various locations. 

What is particularly distinctive with MEN is that they are inherited disorders, often called Familial  Cancer Syndromes.   That means that they can be passed down in families, with each child of an affected parent having a 1 in 2 or 50% risk of inheritance in the case of Autosomal dominant inheritance.  Consequently, genetic screening/testing is normally undertaken in established MEN families and those at risk of MEN. 

It is important to understand the following terms.

• Germline mutations occur in a parent’s reproductive cells (egg or sperm). These mutations change the genetic material that the child receives from their parent (hereditary). You can inherit germline mutations from either parent.  Somatic mutations are a change to a person’s DNA that occurs after conception to any cell that isn’t a germ cell (egg or sperm cell).
• Somatic mutations don’t pass from parents to their children (not hereditary) and happen sporadically or randomly, without the mutation existing in a person’s family history. They also can’t pass to future generations.

MEN Types

MEN is actually an umbrella term for a number of types (syndromes) of the disease – MEN1, MEN2a and 2b (2b was formerly MEN3). There’s are new kids on the block called MEN4 and MEN5 which are extremely rare.

In the most basic of terms regarding the relationship with tumours:

MEN1 seems to be centred on tumours of the parathyroid glands, the pituitary gland, and the pancreas (the 3 P’s). There can be other issues present including various skin issues and manifestations of foregut NETs, typically bronchial or thymic, and sometimes gastric. 

MEN2a mainly focuses on medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia or adenomas (causing hyperparathyroidism), and occasionally cutaneous lichen amyloidosis or Hirschsprung disease (HSCR).

MEN2b is related to medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, and often a marfanoid habitus and other skeletal abnormalities.

MEN4 – Multiple endocrine neoplasia type 4 (MEN4) is a relatively new type with clinical features that overlap with the other MEN syndromes. The most common phenotype of MEN4 that have been described to date is primary hyperparathyroidism (PHPT), followed by pituitary adenomas (PitNETs). MEN4 is caused by germline pathogenic variants in the tumor suppressor gene CDKN1B (CDKN1B cyclin dependent kinase inhibitor 1B).  Overall, due to the inconstant presentation of MEN4, the recognition and the diagnosis of MEN4 can confirmed by genetic testing. Such genetic testing is recommended in patients with MEN1 phenotype, but are negative for MEN1 mutations

MEN5 – Germline variants in the MAX tumor suppressor gene cause the autosomal dominant MEN5. Patients develop pheochromocytomas of the adrenal medulla, which are often bilateral and can have multiple lesions within one adrenal gland. Malignant and/or metachronous disease is common. Less frequently, extra-adrenal sympathetic paragangliomas, ganglioneuromas, ganglioneuroblastoma, composite pheochromocytoma/ganglioneuroma and neuroblastomas are described. Parathyroid adenomas and functional pituitary NET (prolactinomas or somatotropinomas) often occur after pheochromocytomas. In contrast to MEN2, medullary thyroid carcinomas and C-cell hyperplasia are not described. MAX-associated tumors are often multiple, bilateral and/or multicentric, but are indistinguishable from their sporadic counterparts. Adrenal medullary hyperplasia may occur in this syndrome, although it is less common than in patients with MEN2 syndrome and SDH-defcient PPGL. At present, MAX immunohistochemistry in routine clinical practice is limited and it is not recommended as a screening test of MAX mutation.