Sporadic Medullary Thyroid carcinoma
The most common clinical presentation of sporadic MTC is a single nodule or thyroid mass found incidentally during routine examination. The presentation does not differ from that observed in papillary or follicular thyroid carcinoma. A thyroid nodule identified by physical examination is generally evaluated by ultrasonography and radioisotopic scanning (Figure 1). MTC shows hypoechogenic regions, sometimes with calcifications, and a thyroid scan almost always shows no trapping of radioactive iodine or technetium. Cytological examination of the cold hypoechogenic nodule will lead to a strong suspicion, or a correct diagnosis in most cases, of sporadic MTC.
Fig1. Clinical evaluation of patients at risk for medullary thyroid carcinoma.
A plasma Ctn measurement can clarify the diagnosis, since pre operative Ctn levels correlate significantly with tumour size and, in the presence of a palpable MTC, the plasma Ctn concentration will usually be greater than 100 pg/ ml. The CEA level will be elevated in most cases with clinically evident tumours. Therefore, measurement of plasma Ctn in patients with thyroid nodules has been advocated as a routine procedure by some European consensus groups.
Genetic testing for RET mutations in patients with elevated Ctn levels may also be helpful in apparently sporadic cases of MTC, since, if a mutation is found, it will imply that the disease is hereditary and that the family should be screened. The frequency of germline mutations, either inherited or de novo, in a larger series of apparently sporadic MTC patients varied between 1% and 7%.
Metastases to cervical and mediastinal lymph nodes are found in two- thirds of patients at the time of initial presentation. Distant metastases to lung, liver, and bone occur late in the course of the disease. Diarrhoea is the most prominent of the hormone- mediated clinical features of MTC and is often seen in patients with advanced disease. In addition, occasional tumours secrete ACTH causing Cushing’s syndrome. Given the possibility that any patient with MTC may have MEN 2, preoperative testing must also include a 24- hour urinary excretion of catecholamines (to rule out phaeochromocytoma) and measurement of calcium (to rule out hyperparathyroidism).
Hereditary Medullary Thyroid carcinoma
The clinical presentation and manifestation of familial MTC in index cases does not appear to differ from that in patients with sporadic MTC. MTC is often the initial manifestation of MEN 2 syndrome, as the other manifestations, phaeochromocytoma and hyperparathyroidism, develop later in the course of the disease. Less common presentations of MTC include recognition during search initiated after an associated disease such as bilateral pheochromocytoma or multiglandular hyperparathyroidism becomes apparent. The diagnosis of familial MTC in index cases is often made postoperatively when pathohistological examination may show multifocal bilateral MTC accompanied by diffuse C- cell hyperplasia. Rare variants of MEN 2A exist, including MEN 2A with cutaneous lichen amyloidosis and FMTC (or MEN 2A) with Hirschsprung’s disease. The diagnosis of FMTC can only be considered when four or more family members across a wide range of ages have isolated MTC. In general, the clinical course of MTC in familial MTC is more benign and typically has a late onset or is not a clinically manifest disease.
MEN 2B has a typical phenotype with visible physical stigmata such as raised bumps on the lips and tongue (due to cutaneous neuromas), ganglioneuromas throughout the gastrointestinal tract, and a marfanoid habitus (long thin extremities, an altered upper– lower body ratio, slipped femoral epiphysis, pectus excavatum) with skeletal deformations and joint laxity. These patients have disease onset in the first year of life with the most aggressive form of MTC.
DNA testing becomes the optimal test for early detection of MEN 2 especially in ‘at risk’ families. At present, genetic testing is per formed before the age of 5 years in all first- degree relatives of an index case (in MEN 2B patients directly after birth). Mutations in the RET proto- oncogene can be used to confirm the clinical diagnosis and identify asymptomatic family members with the syn drome (Figure 2). Those who have a negative test can be reassured and require no further biochemical screening.
Fig2. Work- up of family members at risk for medullary thyroid carcinoma/ multiple endocrine neoplasia type 2.
Fig3. Recommended postoperative management of patients with medullary thyroid carcinoma. LN, lymph node.
The age of onset of MTC and tumour aggressiveness in MEN 2 depends on the codon mutated. This genotype– phenotype correlation is the basis for stratifying mutations into three risk levels concerning the risk for MTC development and growth. Decision making in the clinical management of MEN 2 patients depends on the risk level classification and calcitonin level, especially the timing of prophylactic thyroidectomy and the extent of surgical resection in presymptomatic RET mutation carriers.
Phaeochromocytoma
Phaeochromocytomas occur in approximately 20– 50% of MEN 2A patients depending on the mutation. Phaeochromocytomas are as sociated with codon 634 and 918 mutations in approximately 50% of patients, and are associated with mutations in exon 10 (codons 609, 611, 618, and 620) in about 30% of patients and rarely in exon 15 (codons 791 and 804). As with MTC, the phaeochromocytomas of MEN 2 are also multicentric with diffuse adrenomedullary hyperplasia developing bilateral phaeochromocytomas in one- half of the cases, but often after an interval of several years. Almost all phaeochromocytomas are located in an adrenal gland, and malignant phaeochromocytomas are rare. In index cases, the clinical manifestation of phaeochromocytoma associated with MEN 2 is similar to that in sporadic cases with signs and symptoms such as headache, palpitations, nervousness, tachycardia, and hypertension. However, phaeochromocytomas are usually identified early as a result of regular biochemical screening in gene carriers, and clinical manifestations are thus subtle or absent. It is unusual for phaeochromocytoma to precede the development of MTC and be the initial manifestation of MEN 2. Annual biochemical screening by measuring plasma and/ or 24- h urinary excretion of catecholamines and metanephrines should be performed. Once the biochemical diagnosis is made, imaging studies such as MRI or metaiodobenzylguanidine (MIBG) scanning are appropriate. The presence of phaeochromocytoma must be ruled out before any surgical procedure. Patients with MTC should be evaluated for possible phaeochromocytoma. A coexisting phaeochromocytoma should be removed before thyroidectomy.
Primary Hyperparathyroidism
Primary hyperparathyroidism, with hypercalcaemia and an elevated serum parathyroid hormone level occurs in 10– 25% of MEN 2 gene carriers (especially codon 634). Hyperparathyroidism develops slowly, is usually mild, and clinical features do not differ from those seen in mild sporadic hyperparathyroidism. The diagnosis is established by finding high parathyroid hormone concentrations in the presence of hypercalcaemia. Pathological findings show chief cell hyperplasia involving multiple glands. Annual measurement of serum calcium concentration in gene carriers is probably adequate for screening purposes.
