Multiple Endocrine Neoplasia type 2B is a complex neoplastic neurocristopathy. MEN 2B is the rarest and most aggressive form of MEN. Prognosis in patients with MEN 2B syndrome depends on early diagnosis and surgical treatment. According to literature data, MTC occurs in 100% of MEN 2B and is very aggressive [2
]. When it becomes clinically manifest, it can be too late for curative surgery. Metastases are present at surgery for clinical or biochemical evidence of MTC in 45% of MEN 2B patients [26
In agreement with literature data, in our series of patients the first clinical signs of MEN 2B affected the gastroenteric system [32
]. These symptoms are associated with typical marphanoid facies and multiple ganglioneuromas. The marphanoid features are not easy to identify in the first years of life, and ganglioneuromas at that time may be evident, but can be found if searched carefully. Gastrointestinal symptoms of MEN 2B generally include constipation or stipsis alternating with diarrhoea. These signs generally appear very early and sometimes are present already at birth, but they rarely suggest the diagnosis of MEN 2B. In children with constipation or stipsis alternating with diarrhoea, the presence of ganglioneuromas on the tongue and oral mucosa should be investigated, as well as the typical facies of MEN 2B and the family history of MTC or PC. In suspected cases, rectal biopsy has to be performed [29
]. In both cases, the pathognomonic picture of MEN 2B was observed, namely: submucous plexus hyperplasia with giant ganglia (GN and GNf), submucous fibromatosis, and ectopic ganglia (Figure and ) [74
]. In our opinion, rectal biopsy should be performed at first, as it allows diagnosis at an early disease stage. RET analysis is fundamental to confirm the diagnosis, and has to be extended to relatives. All carriers of MEN 2B mutations should undergo total thyroidectomy. On the basis of our experience and of literature data, prophylactic thyroidectomy is justified within the first year of life in patients with genetic diagnosis of MEN 2B [76
The presentation of MEN 2B with thyroid mass can occur in cases with delayed diagnosis. In these patients the neuromas, the typical facies and the gastrointestinal symptoms are usually present. In these patients the diagnosis must be confirmed as soon as possible, with rectal biopsy and molecular analysis, in order to perform a total thyroidectomy associated with limphadenectomy. Fine needle aspiration of the mass is not advisable, in our opinion, because the result does not change the treatment, which anyway is based on surgery.
In the pre-operative work up we include cervical sonography and measurement of biochemical MTC markers: CT and CEA, useful for the follow up [27
]. In case of thyroid mass, it is advisable to perform CT-scan, abdominal sonography and skeletal scintigraphy, in order to search for lymph node, hepatic or bone metastases.
Today, PGT has been replaced with molecular genetic analysis, which is much safer. Actually in pediatric patients PGT can be ill-tolerated and give false negative results. When positive, it can indicate the presence of carcinoma or C cell hyperplasia [79
]. For these reasons, in our opinion this test is no longer indicated in the diagnosis of MEN 2B, whereas evaluation of basal plasma calcitonin CT in MEN 2B patients can play a role in their follow up.
In MEN 2B molecular genetic diagnosis, exon 16 is primarily screened since more than 95% of cases present the M918T mutation [4
]. Finally, all HSCR patients were screened for mutations in exon 10, since some families presenting the association of HSCR and FMTC/MEN2A segregate one of the mutations affecting the cysteine residues in exon 10 [32
]. A second point mutation at codon 883 has been found in 2%-3% of individual with MEN 2B [35
]. Tandem RET mutations of codons 805, 806 and 904 in cis
configuration with the p.V804M mutation have also been reported in individuals with MEN 2B [37
After the genetic diagnosis of a patient affected with MEN 2B, every member of his/her family have to be screened for the M918T mutation. Even in the presence of family history of MEN 2B, genetic analysis should always be associated with enzymo-histochemical study on rectal biopsy, as it allows rapid diagnosis (1 day).
An interesting aspect is the association of MEN 2 with HSCR. It is well known that RET mutations can be causative for both HSCR and MEN 2 [80
]. In particular, in MEN 2A patients the most frequent RET mutation (85%) affects codon 634 of exon 11, while in MEN 2B patients codon 918 of exon 16 is almost always involved. In HSCR, RET mutation can affect any portion of the gene. Interestingly, the most frequent mutations found in patients with the association of HSCR and MEN 2A/FMTC involve codons 609, 618 and 620 of exon 10 [82
In HSCR patients, molecular analysis of standard MEN 2A/FMTC mutations is therefore recommended to identify a subpopulation of patients carrying mutations with potential oncologic risk.
The Ret protein is a tyrosine kinase receptor, that plays an important role in the activation of signalling pathways, through the phosphorylation of key tyrosine residues, in response to different ligands. In MEN 2A and MEN 2B, gain of function RET mutations result in the constitutive activation of the tyrosine kinase receptor, with subsequent phosphorylation and overtrasmission of the signal by different downstream pathways. The latter can be specifically activated by the different mutations, which therefore result in a large spectrum of possible phenotypes (MEN 2A, MEN 2B, FMTC, with different degrees of penetrance and expressivity). On the contrary, RET inactivating mutations are associated with HSCR. Loss of function mutations result in a reduction of the amount of functional Ret protein on the cell surface. Mutations found in patients with HSCR and MEN 2 association are able to activate the signalling pathways, like in isolated MEN 2, but the mutated isoform is unable to translocate to the cell surface. The result of activation in the thyroid and adrenal glands is tumorigenesis, while the decrease of functional protein on the cell surface causes HSCR phenotype [34
In agreement with literature data, we believe that central compartment cervical lymphadenectomy should be performed during thyroidectomy for MEN 2B [26
]. Homolateral lymph node exploration (2 compartments) has to be performed in cases with macroscopic evidence of carcinoma at surgery, and bilateral lymphadenectomy (3 compartments) is necessary in the presence of evident lymph node metastases. If mediastinal lymph nodes are metastatic according to CT-scan, limphadenectomy has to be extended to the mediastinum (4 compartments) [81
Despite autotransplantation of parathyroid glands in the forearm is usually performed, in pediatric patients we prefer to preserve them in their primary site, in order to avoid traumas and mechanical insults, that are frequent in childhood upper limbs [76
MEN 2B patients have to be followed year by year with measurement of CEA and CT, markers of possible MTC relapse (more strictly in the first year after surgery). While urinary metanephrines and fractionated catecholamines (epinephrine, norepinephrine, dopamine) are useful to identify possible development of PC.
In conclusion, early diagnosis and treatment of patients with MEN 2B are essential to their survival. The rarity of this syndrome can cause delayed diagnosis. MEN 2B is characterized by early clinical signs as nonspecific alvus disorders and, later, development of the typical facies and presence of ganglioneuromas. These signs, that precede tumor development, should suggest the diagnosis, which is based on rectal biopsy and genetic analysis. The protocol and diagnostic algorithm of MEN 2B that we propose (see Additional file 1
) seems to offer the best life expectancy to patients affected by MEN 2B syndrome [84
]. Moreover, recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities.